7.

Stereoisomers
CHEMISTRY OF CARBOHYDRATES
FUNCTIONS
● Carbohydrates are the main sources of energy
in the body.
● Brain cells and RBCs are almost wholly
dependent on carbohydrates as the energy
source.
● Energy production from carbohydrates will be 4
kcal/g.
● Storage form of energy (starch and glycogen).
● Excess carbohydrate is converted to fat.
● Glycoproteins and glycolipids are components
of cell membranes and receptors.
● Structural basis of many organisms: Cellulose
of plants; exoskeleton of insects, cell wall of
microorganisms, mucopolysaccharides as
8. Glycosides
ground substance in higher organisms.
GENERAL STRUCTURAL FORMULA
● The general molecular formula of carbohydrates is Cn
(H2O)n.
● For example, glucose has the molecular formula
C6H12O6.
● Carbohydrates are polyhydroxy aldehydes or ketones or
compounds which yield these on hydrolysis.
● Compounds having the same structural formula,
but differing in spatial configuration are known
as stereoisomer
● While writing the molecular formula of
monosaccharides, the spatial arrangements of
H and OH groups are important, since they
contain asymmetric carbon atoms.
● Asymmetric carbon means that four different
groups are attached to the same carbon.
● The reference molecule is glyceraldehyde
(glycerose) which has a single asymmetric
carbon atom.
● The number of possible stereoisomers
depends on the number of asymmetric carbon
atoms by the formula 2n where n is the
number of asymmetric carbon atoms.
● When the hemiacetal group (hydroxyl group of
the anomeric carbon) of a monosaccharide is
condensed with an alcohol or phenol group, it
is called a glycoside
● The non-carbohydrate group is called aglycone.
● Do not reduce Benedict's reagent, because the
sugar group is masked.
● Alpha-glycosides are hydrolyzed by maltase
from yeast, while beta-glycosides are
hydrolyzed by Emulsin from almonds.

NOMENCLATURE AND CLASSIFICATION OF SUGARS

TERMS:
1. Monosaccharides
● Molecules having only one actual or potential
sugar group are called monosaccharideS.
● Greek, mono = one; saccharide = sugar.
● They cannot be further hydrolyzed into smaller
units.
2. Disaccharide
● When two monosaccharides are combined
together with elimination of a water molecule, it
is called a disaccharide (e.g. C12H22O11). MONOSACCHARIDES
3. Oligosaccharides Commonly occurring monosaccharides:
● Trisaccharides contain three sugar groups.
● Further addition of sugar groups will
correspondingly produce tetrasaccharides,
pentasaccharides and so on, commonly known
as oligosaccharides.
● Greek, oligo = a few
4. Polysaccharides.
● When more than 10 sugar units are combined,
they are generally named as polysaccharides.
● Greek, poly = many
● Having only one type of monosaccharide units
are called homopolysaccharides
● those having different monosaccharide units are
heteropolysaccharides.
5. Aldoses ● PENTOSE
● Sugars having aldehyde group are called ○ Sugars containing 5 carbon atoms.
aldoses ○ Ribose is a constituent of RNA. Ribose is also
6. Ketoses seen in coenzymes such as ATP and NAD.
● Sugars with the keto group are ketoses. Deoxyribose is seen in DNA
● ○ Ribulose is an intermediate of the HMP shunt
 pathway. Arabinose is present in cherries and after hydrolysis
seen in glycoproteins of the body. ● INVERT SUGAR: Equimolar mixture of glucose
○ The name arabinose is derived as it was and fructose. Sweeter than sucrose.
originally isolated from gum arabic. SUCRASE OR INVERTASE
○ Xylose is seen in proteoglycans. Xylulose is an ● Enzyme-producing hydrolysis of sucrose
intermediate of the uronic acid pathway. 2. Maltose and Isomaltose
● Also a reducing sugar
● Contains 2 glucose units, combined in alpha-1,6
linkage.
● Partial hydrolysis of glycogen and starch
produces isomaltose.
● Enzyme oligo-1,6 glucosidase present in
intestinal juice can hydrolyze isomaltose into
glucose units.
3. Lactose
● Present in milk
● Reducing disaccharide
● Beta glycosidic linkage is present
● Osazone: Pincushion with pins;
● HEXOSE
Hedgehog; flower of touch-me-not
○ The molecular formula: (C6H12O6) represents
16 different monosaccharides, due to spatial POLYSACCHARIDES
arrangement of constituent groups.
○ Glucose is the most predominant sugar in the HOMOG HETEROGLYCANS
human body. It is the major source of energy. It L
is present in blood YCAN
○ D-glucose is dextrorotatory. In clinical practice,
it is often called dextrose Starch A MUCOPOLYSAC GLYCOPROTE
○ Galactose is a constituent of lactose (milk Glycogen g CHARIDES INS AND
sugar) and glycoproteins. Cellulose a MUCOPROTEI
○ Galactose is epimerized to glucose in the liver Inulin r NS
and then utilized as a fuel. Dextrans
○ The term galactose is derived from the Greek
word “gala”, meaning milk. Chitin Hyaluronic acid Proteoglycan
○ Mannose is a constituent of many Heparin Glycoprotein
glycoproteins. Mannose was isolated from Chondroitin Glyco
plant mannans. Sulfate phorin
Keratan Sulfate Mucoprotein
Dermatan Sulfate

● STARCH
○ Reserve carbohydrates in plant
kingdom
○ Sourcess: Potatoes, Tapioca, cereals,
food grains
○ Composition: Amylose and
Amylopectin

● AMYLOSE AND AMYLOPECTIN

○ When starch is treated with boiling water:

DISACCHARIDES
● When two monosaccharides are combined together by
glycosidic linkage.
● Important disaccharides are:
1. Sucrose
● Cane sugar; present in sugarcane
● Not a reducing sugar; not form osazone
● Originally non-reducing, but becomes reducing
 ○ Lubricant in joint cavities
● AMYLASES ○ Found: in connective tissues, tendon, synovial
○ Alpha amylases fluid and vitreous humor
○ Beta amylases ○ Composition: N-acetyl-glucosamine à beta-1,
4-Glucoronic acid à
beta-1-3-N-Acetylglucosamine
Alpha amylases Beta amylases
● CHONDROITIN SULFATE
○ Found: in ground substance of connective
Kinds Salivary amylase Plant origin
tissue, cartilage, bone, tendons, cornea and
Pancreatic amylase Almond,
germinating seeds skin
○ Composition: glucuronic acids à
beta-1,3-N-acetyl galactosamine sulfate à
beta-1,4
Splits Splits to smaller units Form beta-maltose
(dextrins) to SUGAR SUBSTITUTES
Alpha-maltose ● Sugar substitutes can be used in the initial phase of
dieting plan for an obese child. Unless diabetic, you
should avoid them.
Action Random alpha 1,4, Act on amylose to
glycosidic bonds split maltose units ● ASPARTAME
○ Made from aspartic acid (AA) and phenylalanine
(AA)
● When beta amylase acts on amylopectin à ○ 200 times sweeter than sugar
maltose units liberated from ends of ○ Not suitable for people with
amylopectin à enzyme is blocked at alpha 1,6 PHENYLKETONURIA
glycosidic linkage à action stops at branching ○ Underhigh and low pH conditions generate
points à leaving large molecule à LIMIT OR Methanol by hydrolysis metabolized to
RESIDUAL DEXTRIN Phenylalanine, aspartic acid and methanol
○ Calorie content: 4kcal per gram
● GLYCOGEN
○ Reserve carbohydrates in animals ● SACCHARIN
○ More branched and more compact than ○ AKA: Benzoic Sulfimide
amylopectin ○ Made from anthranilic acid
○ Storage: liver and muscle ○ Artificial sweetener
○ 5% WT. of the liver made of by glycogen ○ 300 times sweeter than sugar
○ Excess carbs are deposited as glycogen ○ Used in: drinks, candies, medicines and
○ Molecular weight: 5 million toothpaste
○ Composition: Alpha 1,4 link in straight chains & ○ Note: no food energy but triggers the release of
Alpha 1,6 at branching points insulin
○ GLYCOGENIN: primer protein in the innermost ○ Calorie content: nil
core of glycogen
● SUCRALOSE
● CELLULOSE ○ Made from sucrose or table sugar
○ Supporting tissues of plants ○ 600 TIMEs sweeter than sugar; twice as
○ Most abundant organic material in nature saccharin and 3.3 times sweet as aspartame
○ Constitutes: 99% Cotton, 50% ○ CALORIE CONTENT: nil
Wood
○ Composition: beta 1,4 linkages ● XYLITOL
straight line ○ Found in fibers of many fruits and vegetables
○ Molecular weight.: 2 to 5 million ○ As sweet as sucrose 2/3 FOOD ENERGY
○ Hydrolyzed by: Cellobiase (not present in ○ Safe for people with diabetes; do not impact
animal GIT; except herbivorous) insulin levels
○ Is found in the fibers of many fruits and
● DEXTRANS vegetables, including various berries, corn
○ Highly branched homopolymers husks, oats, and mushrooms
○ Composition: 1-6,1-4, 1-4 linkages
○ Synthesized by: Bacteria or microorganisms
○ Molecular weight.: 1 to 4 million
○ Used for: infusion as plasma volume expander
for treatment of hypovolemic shock.

● HYALURONIC ACID
 ● Fatty acids are included in the group of derived lipids .
● It is the most common component of lipids in the body.
● Generally found in ester linkage in different
classes of lipids.
● Fatty acids are aliphatic carboxylic acids and have
the general formula, R-CO-OH, where COOH
(carboxylic group) represents the functional group.
Depending on the R group (the hydrocarbon chain),
the physical properties of fatty acids may vary.

COMMON FATTY ACIDS

CHEMISTRY OF LIPIDS
● Constitute a heterogeneous groups of compounds of
biochemical importance
● Compounds which are relatively insoluble in water but
freely soluble in non-polar organic solvents such as
benzene, chloroform, ether, hot alcohol, acetone, etc.

FUNCTIONS
1. Storage form energy ( triacylglycerol)
2. Structural components of biomembranes
(phospholipids and cholesterol)
3. Metabolic regulators (steroid hormones
and prostaglandins)
4. Act as surfactants , detergents and emulsifying
agents (amphipathic lipids)
5. Act as electric insulators in neurons
6. Provide insulation against changes in
external temperature ( subcutaneous fat)
7. Give shape and contour to the body
8. Protect internal organs by providing a cushioning
effect (pads of fat )
9. Help in absorption of fat soluble vitamins ( A,D,E and K
)
10. Improve taste and palatability of food.

CLASSIFICATIONS ACCORDING TO CHEMICAL

STRUCTURE

● SIMPLE LIPIDS
○ They are esters of fatty acids with glycerol or
other higher alcohols.

● COMPOUND LIPIDS
○ They are fatty acids esterified with alcohol;
but in addition they contain other
groups.depending on these extra groups,
they are subclassified into two:
PHOSPHOLIPIDS containing
PHOSPHORIC ACID and NON- CLASSIFY FATTY ACIDS
PHOSPHORYLATED LIPIDS
● CHAIN LENGTH
● DERIVED LIPIDS ○ Short (2-6)
○ They are compounds , which are derived from ○ Medium (8-14)
lipids, eg. fatty acids , steroids. ○ Long (14-24)
○ Very long (>24)
FATTY ACIDS ● TOTAL CARBON ATOMS
 ○ Odd chain expression or eicosanoid
○ Even chain production
● NATURE OF CHAIN
○ Saturated
○ Unsaturated
○ Branched
○ Hydroxy
● SYNTHESIS IN BODY
○ Essential
○ Non-essential

COMMON SATURATED FATTY ACIDS

● Acetic, Butyric, Caproic, Capric, Lauric, Myristic,
Palmitic, Stearic, Arachidic
● They have general formula : CH3–(CH2)n–COOH
● Named by adding “anoic” after the hydrocarbon
● The 2 carbon Acetic acid and 4 carbon Butyric acid
are important metabolic intermediates
● The C16 (Palmitic acid) and C18 (Stearic acid) are
most abundant in body fat
● Each animal species will have characteristic pattern of
FA composition
○ Human body fat contains
■ 50% Oleic acid
■ 25% Palmitic acid
■ 10% Linoleic acid
■ 5% Stearic acid
○ Carbon atoms of FA are numbered differently
○ When starting from COOH group - C1,
C2, etc.
○ When starting from Methyl end - omega
-1,2,3 etc
COMMON UNSATURATED FATTY ACIDS
● Palmitoleic, Oleic, Erucic, Nervonic, Linoleic,
Linolenic, Arachidonic, Timnodonic, Clupanodonic,
Cervonic
● Named by adding “enoic
● Similar to Saturated FA in the reaction of carboxylic
group but also show properties due to presence of
double bond
● Exhibit geometrical isomerism at double bonds
○ All naturally occurring FA have cis
configuration but during metabolism in the
body, trans FA are formed
PHOSPHATIDATE
CLINICAL SIGNIFICANCE OF POLYUNSATURATED FATTY
ACIDS
● Exist in cis configuration in naturally occurring lipids
● Omega-3-FA have positive roles in child
development, cancer, cardiovascular diseases and
various mental illness (e.g. depression, ADHD and
dementia)
○ These FA have pleiotropic effects
including effects against inflammation,
platelet aggregation, hypertension and
hyperlipidemia
■ These effects may be mediated by
several distinct mechanism
including
● Alterations in cell
membrane composition
and function, gene
TRANS FATTY ACIDS
● Are present in dairy products and hydrogenated edible
oils
● Considered as injurious to health but used in food
industry as they increase the shelf life of fried food
● Oils containing PUFA also have high content of TFA
● Fast food preparations have high TFA
● TFA affects multiple risk factors for chronic
diseases, including composition of blood lipids and
lipoproteins, systemic inflammation, endothelial
dysfunction, insulin resistance, diabetes and
adiposity
● High in processed foods and bakery products, where
partially hydrogenated vegetable oils are used for
cooking.
NEUTRAL FAT
● Aka Triacylglycerols (TAG) or Triglycerides (TG)
● Esters of Trihydric alcohol, glycerol with fatty
acids
PHOSPHOLIPIDS
● Contain glycerol, fatty acids and nitrogenous base
● Derivatives of Phosphatidic acid (simplest form of
phospholipid)
○ Phosphatidic acid is made up of 1 glycerol
to which FA residues are esterified to
carbon atoms 1 and 2. The 3rd hydroxyl
group is esterified to a phosphoric acid
○ Its molecule has an asymmetric carbon
atom and exhibit optical isomerism.
○ L-isomer is found in nature
Amphipathic Nature
● Phospholipids are amphipathic esp. Lecithin
● Have both hydrophobic and hydrophilic portion in
their molecule
○ Polar head - glycerol + phosphoric acid and
choline
○ Nonpolar tail - hydrocarbon chains of FA
Micellar formation
 ● When phospholipids are distributed in water, their (other than alpha carboxyl) can combine with
hydrophobic parts keep away from water, forming ammonia to form the corresponding amide.
molecular aggregates called Micelles
○ For example:
○ Micelles are involved in solubilization in
lipids in aqueous media and help in ■ Aspartic acid + NH3 → Asparagine
digestion and absorption of lipids ■ Glutamic acid + NH3 → Glutamine

CHEMISTRY OF PROTEINS ●These amides are also components of

CLASSIFICATION BASED ON METABOLISM
protein structure. The amide group of
● Proteins are made up of amino acids linked by peptide
bonds. Despite having ~300 amino acids occurring in glutamine serves as the source of nitrogen
nature, only 20 of them are seen in the human body. for nucleic acid synthesis.
Most amino acids are Alpha amino acids except AMINO GROUP:
Proline
● Transamination
● Alpha amino acids have their Amino group
attached to the same carbon atom to which ○ The alpha amino group of amino acid can be
Carboxyl group is attached transferred to alpha keto acid to form the
corresponding new amino acid and alpha
CLASSIFICATION BASED ON NUTRITIONAL keto acid.
REQUIREMENTS ○ This is an important reaction in the body for
the interconversion of amino acids and for
Purely Ketogenic and Purely synthesis of non-essential amino acids.
ketogenic Glucogenic glucogenic
● Oxidative Deamination
Amino acid is During They enter only ○ The alpha amino group is removed from the
converted to metabolism, part in the glucogenic amino acid to form the corresponding keto
ketone bodies of the carbon pathway acid and ammonia.
skeleton of ○ In the body, Glutamic acid is the most
amino acids will common amino acid to undergo oxidative
enter ketogenic deamination.
pathway and the
other part to ● Formation of Carbamino Compound
glucogenic ○ Carbon dioxide adds to the alpha amino group
pathway of amino acids to form carbamino compounds.
○ The reaction occurs at alkaline pH and serves
Leucine Lysine, All remaining 14
as a mechanism for the transport of carbon
Isoleucine, amino acids
dioxide from tissues to the lungs by
Phenylalanine,
hemoglobin.
Tyrosine,
Tryptophan SIDE CHAIN:
● Transmethylation
GENERAL REACTION OF AMINO ACIDS ○ The methyl group of Methionine, after
CARBOXYL GROUP: activation, may be transferred to an acceptor,
● Decarboxylation which becomes methylated.
○ The amino acids will undergo alpha ○ Methionine + Acceptor → Methylated Acceptor
decarboxylation to form the corresponding + Homocysteine
amine (Fig. 3.17). Thus, some important amines
are produced from amino acids. ● Ester Formation by the OH Group
○ The hydroxy amino acids can form esters with
phosphoric acid. In this manner, the Serine
and Threonine residues of proteins are
involved in the formation of phosphoproteins.
○ Similarly, these hydroxyl groups can form
O-glycosidic bonds with carbohydrate
residues to form glycoproteins.

● Reaction of the Amide Group:

○ The amide groups of Glutamine and
● Amide formation
Asparagine can form N-glycosidic bonds with
○ The-COOH group of dicarboxylic amino acids
carbohydrate residues to form glycoproteins.

● Reactions of SH Group
○ Cysteine has a sulfhydryl (SH) group and it
can form a disulfide (S-S) bond with another
cysteine residue. The two cysteine residues
can connect two polypeptide chains by the
formation of interchain disulfide bonds or
links.
○ The dimer formed by two cysteine residues is
sometimes called Cystine or Dicysteine.
PEPTIDE BOND
● Alpha carboxyl group of one amino acid reacts with
the alpha amino group of another amino acid to form a
peptide bond or CO-NH bridge (Fig. 3.21).
● Proteins are made by polymerization of amino acids
through peptide bonds.
Peptide Linkages and Peptide Chain
• Aggregated into long chains
• Amino radical of one amino acid bonds with the carbon of the
carboxyl radical of the other amino acid.
• (H+) released forming a molecule of water (H2O) radicals
(-COOH & -NH2) are capable of combining with additional
amino acids to form a peptide chain.
CLASSIFICATION OF PROTEINS
● Classification based on functions:
1. Catalytic proteins, e.g. enzymes
2. Structural proteins, e.g. collagen,
elastin
3. Contractile proteins, e.g. myosin,
actin.
4. Transport proteins, e.g. hemoglobin,
myoglobin, albumin, transferrin
5. Regulatory proteins or hormones,
e.g. ACTH, insulin, growth hormone
6. Genetic proteins, e.g. histones
7. Protective proteins, e.g.
immunoglobulins, interferons,
clotting factors.
● Classification based on composition and solubility
A. Simple Proteins: According to definition, they
contain only amino acids.
● Albumins: They are soluble in water and
coagulated by heat. Human serum albumin
has a molecular weight of 69,000, e.g
lactalbumin of milk and egg albumin.
● Globulins: These are insoluble in pure water,
but soluble in dilute salt solutions. They are
also coagulated by heat, e.g. egg
globulin,serum globulins, legumin of peas.
● Protamines: These are soluble in water,
dilute acids. They are notcoagulated by
heating. They contain a large number of
arginine and lysine residues, and so are
strongly basic. Hence they can combine with
other acidic proteins. Protamine zinc
insulinate is a common commercial
preparation of insulin.
● Prolamins: They are soluble in 70–80%
alcohol, but insoluble in pure water. They are
rich in proline but lack in lysine, e.g. zein from
corn, gliadin of wheat, hordein of barley.
● Lectins: Lectins are precipitated by 30–60%
ammonium sulfate. They are proteins having
high affinity to sugar groups. Lectin from
Dolichos biflorus will agglutinate human blood
group A1 RBCs. Phytohemagglutinin (PHA), a
lectin from Phaseolus vulgaris (red kidney
bean) agglutinates all RBCs and WBCs.
Concanavalin-A (ConA) from legumes will
specifically attach to mannose and glucose.
The attachment of lectins on normal and
cancer cells will be different, this property is
sometimes utilized to differentiate cancer
cells.
● Scleroproteins: They are insoluble in water,
salt solutions and organic solvents and
soluble only in hot strong acids. They form
supporting tissues, e.g. collagen of bone,
cartilage and tendon; keratin of hair, horn, nail
and hoof.
B. Derived Proteins: They are degradation products of
native proteins. Progressive hydrolysis of protein
results in smaller and smaller chains: Protein →
peptones → peptides → amino acids.

● Classification based on shape:
A. Globular Proteins
● They are spherical or oval in shape. They are
easily soluble, e.g. albumins, globulins and
protamines.
B. Fibrous Proteins
● The molecules are elongated or needle
shaped. Their solubility is minimal. They resist
digestion.
BIOENERGETICS
THERMODYNAMICS
● Concerned with the flow of heat and it deals with the
relationship between heat and work.
BIOENERGETICS
● Or biochemical thermodynamics, is the study of the
energy changes accompanying biochemical
reactions.
● Biological systems use chemical energy to power
living processes.
● Essentially isothermic and use chemical energy to
power living processes. The way in which an animal
obtains suitable fuel from its food to provide this
energy is basic to the understanding of normal
nutrition and metabolism.
○ Death from starvation occurs when available
energy reserves are depleted, and certain
forms of malnutrition are associated with
energy imbalance (marasmus).
○ Thyroid hor- mones control the metabolic
rate (rate of energy release), and disease
results if they malfunction.
○ Excess storage of surplus energy causes
obesity, an increasingly common disease of
Western society which predisposes to many
diseases, includ- ing cardiovascular disease
and diabetes mellitus type 2, and lowers life
expectancy.
FREE ENERGY
● Gibbs change in FREE ENERGY (ΔG) is that portion of
the total energy change in a system that is available for
doing work—that is, the useful energy, also known as
the chemical potential.
ENTROPY AND ENTHALPY
● ENTROPY is the extent of disorder or randomness of
the system and becomes maximum as equilibrium is
approached. Under conditions of constant
temperature and pressure, the relationship between
the free-energy change (ΔG) of a reacting system and
the change in entropy (ΔS) is expressed by the
following equation, which combines the two laws of
thermodynamics:
∆G=∆H−T∆S
● where ΔH is the change in ENTHALPY (heat) and T is
the absolute temperature.
● In biochemical reactions, since ΔH is approximately
equal to the total change in internal energy of the
reaction or ΔE, the above relationship may be
expressed in the following way: ∆G=∆E−T∆S
○ If ΔG is negative, the reaction proceeds
spontaneously with loss of free energy, that is,
it is exergonic.
○ If, in addition, ΔG is of great magnitude, the
reaction goes virtually to completion and is
essentially irreversible.
○ On the other hand, if ΔG is positive, the
reaction proceeds only if free energy can be
gained, that is, it is endergonic.
○ If, in addition, the magnitude of ΔG is great,
the system is stable, with little or no tendency
for a reaction to occur.
○ If ΔG is zero, the system is at equilibrium and
no net change takes place.
○ When the reactants are present in
concentrations of 1.0 mol/L, ΔG0 is the
standard free-energy change. For bio-
chemical reactions, a standard state is
defined as having a pH of 7.0. The standard
free-energy change at this standard state is
denoted by ΔG0′.
● The standard free-energy change can be
calculated from the equilibrium constant
Keq∆G0′ =−RTlnK′ eq
● where R is the gas constant and T is the
absolute temperature (see Chapter 8).
○ It is important to note that the actual
ΔG may be larger or smaller than
ΔG0′ depending on the
concentrations of the various
 reactants, including the solvent,
various ions, and proteins.
○ In a biochemical system, an enzyme
only speeds up the attainment of
equilibrium; it never alters the
final concentrations of the
reactants at equilibrium.
LAW OF THERMODYNAMICS
FIRST LAW OF THERMODYNAMICS
● States that the total energy of a system, including
its surroundings, remains constant.
○ It implies that within the total system, energy
is neither lost nor gained during any change
○ Energy may be transferred from one part of
the system to another, or may be
transformed into another form of energy.
○ May be transformed into heat or into
electrical, radiant, or mechanical energy.
SECOND LAW OF THERMODYNAMICS
● States that the total entropy of a system must
increase if a process is to occur spontaneously.
● Entropy is the extent of disorder or randomness of
the system and becomes maximum as equilibrium is
approached.
○ combines the two laws of thermodynamics
Biological Importance:
● Isothermic
● Starvation
● Metabolic rate
EXERGONIC AND ENDERGONIC REACTIONS
Endergonic Processes Proceeding By Coupling To
Exergonic Processes
Vital processes e.g
● Biosynthetic reactions
● Muscular contraction
● Nerve impulse conduction
● Active transport
➔ obtain energy by chemical linkage, or coupling,
to oxidative reactions.
● Exergonic and Endergonic - used to indicate that a
process is accompanied by loss or gain, of free
energy in any form, not necessarily as heat.
CATABOLISM
● breakdown or oxidation of fuel molecules
ANABOLISM
● synthetic reactions that build up substances
● The combined catabolic and anabolic processes
constitute metabolism.
● These relationships supply a basis for the concept of
respiratory control
○ the process that prevents an organism
from burning out of control
● Extension of the coupling concept is provided by
dehydrogenation reactions, which are coupled to
hydrogenations by an intermediate carrier
● In the living cell, the principal high-energy
intermediate or carrier compound is ATP
Note: An alternative method of coupling an exergonic to an
endergonic process is to synthesize a compound of
high-energy potential in the exergonic reaction and to
incorporate this new compound into the endergonic reaction,
thus effecting a transference of free energy from the
exergonic to the endergonic pathway.
HIGH-ENERGY PHOSPHATES IN ENERGY CAPTURE AND
TRANSFER
➔ To maintain living processes, all organisms must
obtain supplies of free energy from their
environment.
● Autotrophic
○ organisms utilize simple exergonic
processes;
○ e.g the energy of sunlight (green plants), the
reaction Fe2+ → Fe3+ (some bacteria)
● Heterotrophic
○ organisms obtain free energy by coupling
their metabolism to the breakdown of
complex organic molecules in their
environment.
★ ATP plays a central role in the transference of free
energy from the exergonic to the endergonic
processes.
• ATP is a nucleotide consisting of
the nucleoside adenosine (adenine
linked to ribose) and three
phosphate groups
★ ATP plays a central role in the transference of free
energy from the exergonic to the endergonic
processes.
• ATP is a nucleotide consisting of the
nucleoside adenosine (adenine
linked to ribose) and three
phosphate groups it functions as
the Mg2+ complex
The importance of phosphates in intermediary
metabolism became evident with the discovery of
● the role of ATP
● adenosine diphosphate (ADP)
● inorganic phosphate (Pi) in glycolysis
STANDARD FREE ENERGY OF SOME
ORGANOPHOSPHATES
 lower in energy, than ATP

ATP ACTS AS THE “ENERGY CURRENCY” OF THE CELL

● Standard free energy of hydrolysis of a number of ● ATP/ADP cycle
biochemically important phosphates ○ connects those processes that generate ~
● Group transfer potential to those processes that utilize ~
○ estimate of the comparative tendency of each ○ continuously consuming and
of the phosphate groups to transfer to a regenerating ATP
suitable acceptor may be obtained from the
ΔG0′ of hydrolysis at 37°C There are three major sources, taking part in energy
● Value for the hydrolysis of the terminal phosphate of conservation or energy capture:
ATP (when ATP is converted to ADP + Pi) two 1. Oxidative phosphorylation
groups. 2. Glycolysis
1. LOW ENERGY PHOSPHATES - having a low 3. Citric acid cycle
group transfer potential, exemplified by the
ester phosphates found in the intermediates
of glycolysis, have G0′ values smaller than
that of ATP.
2. HIGH ENERGY PHOSPHATES - with a more
negative G0′, the value is higher than that of
ATP.
Components including ATP
a. anhydrides (eg, the
1-phosphate of
1,3-bisphosphoglycerate)
b. enol phosphates
(eg,
phosphoenolpyru
PHOSPHAGEN
vate),
● act as storage forms of group transfer potential and
c. phosphoguanidines (eg, include creatine phosphate
creatine phosphate, arginine ● which occurs in vertebrate skeletal muscle, heart,
phosphate). spermatozoa, and brain, and
● Thus, ATP has a high group transfer potential, whereas ARGININE PHOSPHATE
the phosphate in adenosine monophosphate (AMP) is of ● which occurs in invertebrate muscle
the low-energy type since it is a normal ester link.
● Intermediate position of ATP allows it to play an
important role in energy transfer
◆ high free-energy change on hydrolysis of
ATP is not in itself caused by the breaking of
the P-O bond linking the terminal phosphate
to the molecule
◆ It is the consequences of this bond breakage
that cause net energy to be released

Note: When ATP is rapidly being utilized as a source of energy

➔ Strong electrostatic repulsion between the negatively
charged oxygen atoms in the adjacent phosphate for muscular contraction, phosphagens permit its concentrations
groups of ATP to be maintained, but when the ATP/ADP ratio is high, their
➔ Orthophosphate produced is greatly stabilized by the concentration can increase to act as an energy store.
formation of resonance hybrids in which the three
negative charges are shared between the four
oxygen atoms
◆ products of hydrolysis, ADP and
orthophosphate, are more stable, and so
 Step 3 of Glycolysis
BIOCHEMICAL REACTIONS THAT ARE MAJOR SOURCES ● Fructose-6-phosphate is further phosphorylated
OF HIGH-ENERGY PHOSPHATES: to fructose1,6-bisphosphate
GLYCOLYSIS ● The enzyme is phosphofructokinase.
● Phosphofructokinase (PFK) is the rate
● EMBDEN-MEYERHOF PARNAS limiting enzyme of glycolysis.
● Glycolytic pathway glucose is converted to pyruvate ○ The enzyme catalyzes the second
(aerobic condition) or lactate (anaerobic condition), phosphorylation step of glycolysis using
along with production of a small quantity of energy. a second molecule of ATP.
○ the only pathway that is taking place in all ○ important key enzyme
the cells of the body.
○ only source of energy in erythrocytes.
○ when muscle tissue lacks enough oxygen,
anaerobic glycolysis forms the major source
of energy for muscles
○ considered as the preliminary step before
complete oxidation
○ provides carbon skeletons for synthesis of
non-essential amino acids as well as glycerol
part of fat
○ glycolytic pathways are reversible, which are
also used for gluconeogenesis.

Step 4 of Glycolysis
● The 6 carbon fructose-1,6-bisphosphate is cleaved
into two 3 carbon units; one
glyceraldehyde-3-phosphate and another molecule of
dihydroxy acetone phosphate (DHAP)
● Since the backward reaction is an aldol
condensation, the enzyme is called aldolase

Step 4-A of Glycolysis

● Dihydroxyacetone phosphate is isomerized to
Step 1 of Glycolysis glyceraldehyde-3-phosphate by the enzyme
phosphotriose isomerase.
● phosphorylated to glucose-6-phosphate
● enzyme is Hexokinase (HK), which splits the
ATP into ADP, and the Pi is added on to the
glucose.
● Hexokinase is a key glycolytic enzyme. The
kinase reaction is irreversible.
○ is circumvented by another
enzyme glucose-6-phosphatas
● Hexokinase and glucokinase may be considered Step 5 of Glycolysis
as iso-enzymes
● Glyceraldehyde-3-phosphate is dehydrogenated and
Step 2 of Glycolysis simultaneously phosphorylated to
1,3-bisphosphoglycerate (1,3-BPG) with the help of
● Glucose-6-phosphate is isomerized to NAD+
fructose-6-phosphate by phosphohexose isomerase. ● The enzyme is glyceraldehyde-3-phosphate
This is readily reversible. dehydrogenase.
● This isomerisation of aldose to ketose involves ● The product contains a high energy bond. This is a
the opening of the glucopyranose ring of reversible reaction.
glucose-6-phosphate to a linear structure which then
changes to the furanose ring structure of
fructose-6-phosphate
 Step 6 of Glycolysis
● The energy of 1,3-BPG is trapped to synthesize one
ATP molecule with the help of bisphosphoglycerate
kinase
○ This is an example of substrate level
phosphorylation, where energy is trapped
directly from the substrate, without the
help of the complicated electron transport
chain reactions.
○ When energy is trapped by oxidation of
reducing equivalents such as NADH, it
is called oxidative phosphorylation

Step 7 of Glycolysis
● 3-phosphoglycerate is isomerized to
2-phosphoglycerate by shifting the phosphate group
from 3rd to 2nd carbon atom. The enzyme is
phosphoglyceromutase.
Step 8 of Glycolysis
● 2-phosphoglycerate is converted to
phosphoenol pyruvate by the enzyme enolase.
One water molecule is removed
○ A high energy phosphate bond is produced.
○ Enolase requires Mg++, and by
removing magnesium ions, fluoride will
irreversibly inhibit this enzyme. Thus,
fluoride will stop the whole glycolysis
Step 9 of Glycolysis
● Phosphoenol pyruvate (PEP) is dephosphorylated
to pyruvate, by pyruvate kinase
● One mole of ATP is generated during this
reaction. This is again an example of substrate
leveL phosphorylation
● Pyruvate kinase is a key glycolytic enzyme
 Step 10 of Glycolysis ● Acetyl-CoA is a metabolite derived from
● Anaerobic condition, pyruvate is reduced to lactate glucose, fatty acid, and amino acid catabolism.
by lactate dehydrogenase (LDH)
● During glycolysis, glucose is broken down into
● Aerobic conditions, the pyruvate enters the citric acid
two three-carbon molecules of pyruvate.
cycle for complete oxidation.
● Acetyl CoA enters the cycle, and is
○ The end product of anaerobic glycolysis is
completely oxidized.
lactate which enters the Cori's cycle. ○ During this process, energy is trapped.
○ The acetyl CoA derived from beta
oxidation is formed in the mitochondria
■ All the enzymes of citric acid cycle
are located inside the
mitochondria.
13.6

PRODUCTS
Glycolysis has three major end products that include:

● two molecules of pyruvate,

● two molecules of ATP, and.
● two molecules of NADH.

CITRIC ACID CYCLE

FUNCTIONS of the Citric Acid Cycle
1. The final common oxidative pathway that oxidizes acetyl CoA
to CO2.
2. The source of reduced co-enzymes that provide the substrate
for the respiratory chain.
3. The link between catabolic and anabolic pathways (amphibolic
role).
4. Provides precursors for synthesis of amino acids and
nucleotides.
5. Components of the cycle have a direct or indirect controlling
effects on key enzymes of other pathways.

SOURCES OF PYRUVATE
● The major source of pyruvate is the last step of
glycolysis, where pyruvate kinase converts
phosphoenolpyruvate to pyruvate. Other
significant sources include lactate via lactate
dehydrogenase (LDH) and alanine via alanine
aminotransferase (ALT).

FATE OF PYRUVATE
● Under aerobic conditions, pyruvate can diffuse
into mitochondria, where it enters the citric acid
cycle and generates reducing equivalents in the
form of NADH and FADH2. These reducing
equivalents then enter the electron transport chain,
leading to the production of 32 ATP per molecule of
glucose

SOURCES OF ACETYL COA


STEPS AND ENZYMES:
● First Step: Formation of Citric Acid
○ enzyme is citrate synthase
● Second Step: Formation of Isocitrate
○ Citrate is isomerized to isocitrate by
aconitase
● Third Step: Formation of Alpha Keto Glutarate
○ two-step process, both catalyzed by the
same enzyme, isocitrate dehydrogenase
● Fourth Step: Formation of Succinyl CoA
○ alpha ketoglutarate is oxidatively
decarboxylated to form succinyl CoA by the
enzyme alpha ketoglutarate dehydrogenase
● Fifth Step: Generation of Succinate
○ the next reaction involves a substrate
level phosphorylation whereby a high
energy phosphate is generated from the
energy trapped in the thioester bond of
succinyl CoA.
■ enzyme is succinate thiokinase
● Sixth Step: Formation of Fumarate
○ Succinate is dehydrogenated to fumarate, an
unsaturated dicarboxylic acid, by succinate
dehydrogenase
■ The enzyme is a flavoprotein
● Seventh Step: Formation of Malate
○ formation of malate from fumarate is
catalyzed by fumarase
● Eighth Step: Regeneration of Oxaloacetate
○ Finally malate is oxidized to oxaloacetate by
malate dehydrogenase
VITAMINS THAT PLAY IMPORTANT ROLES
● Carbohydrates are metabolized through a glycolytic
pathway to pyruvate, then converted to acetyl CoA,
which enters the citric acid cycle.
● Fatty acids, through beta oxidation, are broken down
to acetyl CoA and then enter this cycle.
● Glucogenic amino acids after transamination enter at
some or other points in this cycle. Ketogenic amino
acids are converted into acetyl CoA.
● The integration of metabolism is achieved at junction
points by key metabolites. Several pathways can
converge at this point with the result that carbon atoms
from one source can be used for synthesis of another.
Important intermediates are pyruvate, acetyl CoA and
oxaloacetate
● Vitamins such as riboflavin, niacin, and thiamine work as
coenzymes in this cycle, while pantothenic acid forms
the CoA part of acetyl-CoA.
OXIDATIVE PHOSPHORYLATION
● Transfer of electrons from the reduced co-enzymes
through the respiratory chain to oxygen is known
as biological oxidation.
● Energy released during this process is trapped
as ATP.
● This coupling of oxidation with phosphorylation
called oxidative phosphorylation.
● In the body, this oxidation is carried out
by successive steps of dehydrogenations
➔ Oxidative phosphorylation is a cellular process
that harnesses the reduction of oxygen to
generate high-energy phosphate bonds in the
form of adenosine triphosphate (ATP)
STEPS:
Major steps of oxidative phosphorylation in
mitochondria include:
● Delivery of Electrons by NADH and FADH2
● Electron Transport and Proton Pumping
● Splitting of Oxygen to form Water
● ATP Synthesis
● Chemiosmosis
● Electron Transport Chain
The three steps of cellular respiration are
1. Glycolysis
2. Krebs cycle
3. Oxidative phosphorylation.
● Glycolysis is the conversion of glucose into a
molecule called pyruvate. The Krebs cycle
converts pyruvate into high-energy intermediates,
and oxidative phosphorylation uses the electrons
from those intermediates to make ATP.
PRODUCTS
What is produced from oxidative phosphorylation?
Adenosine triphosphate is the major product of oxidative
phosphorylation, as it is the premier energy molecule of the
cell. Oxidative phosphorylation also produces NAD+, FAD,
and water.
AEROBIC AND ANAEROBIC CELLULAR RESPIRATION
● Aerobic respiration takes place in presence of oxygen;
whereas anaerobic respiration takes place in absence
of oxygen.
 ● The similarities between aerobic and anaerobic
respiration, is that they both use glucose as the
starting molecule. This is called the substrate.
● In addition, both aerobic and anaerobic respiration
produce ATP, however, aerobic respiration produces
a lot more ATP compared to anaerobic respiration.
DIGESTION AND ABSORPTION OF NUTRIENTS IN GIT AND
TRANSPORT IN THE BLOODSTREAM
CARBOHYDRATES
● In the mouth, salivary α-amylase cleaves starch by
breaking α-1,4 linkages between glucose residues
within the chains.
● Dextrins (linear and branched oligosaccharides) are the
major products that enter the stomach.
● In the intestine, the stomach contents pass into the
intestine where the bicarbonate secreted by the
pancreas neutralizes the stomach acid, raising the pH
into the optimal range for the action of the intestinal
enzymes.
Digestion by pancreatic enzymes:
a. The pancreas secretes an α-amylase that acts in
the lumen of the small intestine and, like salivary
amylase, cleaves α-1,4 linkages between glucose
residues.
b. The products of pancreatic α-amylase are the
disaccharides maltose and isomaltase,
trisaccharides, and small oligosaccharides
containing α-1,4 and α-1,6 linkages.
Digestion by enzymes of intestinal cells:
a. Complexes of enzymes, produced by intestinal
epithelial cells and located in their brush borders,
continue the digestion of carbohydrates
1. Glucoamylase (an α-glucosidase) and
other maltases cleave glucose residues
from the nonreducing ends of
oligosaccharides and also
cleave the α-1,4 bond of maltose, releasing the two
glucose residues.
2. Isomaltase cleaves α-1,6 linkages,
releasing glucose residues from branched
oligosaccharides.
3. Sucrase converts sucrose to glucose
and fructose.
4. Lactase (a β-galactosidase) converts
lactose to glucose and galactose.
ABSORPTION
● Glucose, fructose, and galactose, the final
products generated by digestion of dietary
carbohydrates, are absorbed by intestinal
epithelial cells.
1. They are transported into the cells to
transport proteins, moving down a
concentration gradient.
2. Glucose also moves into cells on a transport
protein that carries sodium ions in addition to
the monosaccharide. This is a secondary
active transport process.
3. The sugars are then passed into the blood
using facilitative transporters on the
serosal side of the intestinal epithelial cells.
FATS
● Triacylglycerol is the primary dietary fat. It is obtained
from the fat stores of the plants and animals that
serve as food.
● The triacylglycerols are emulsified in the intestine by
bile salts and digested by pancreatic lipase to
2-monoacylglycerols and fatty acids, which are
packaged into micelles (solubilized by bile salts) and
absorbed into intestinal epithelial cells, where they
are reconverted to triacylglycerols.
● After digestion and resynthesis, the triacylglycerols
are packaged in chylomicrons, which first enter the
lymph and then the blood.
PROTEINS
● Proteins are digested first by pepsin in the stomach
and then by a series of enzymes in the intestine.
1. The pancreas produces trypsin,
chymotrypsin, elastase, and
carboxypeptidases, which act in the lumen
of the intestine.
2. Aminopeptidases, dipeptidases, and
tripeptides are associated with the
intestinal epithelial cells.
● Proteins are ultimately degraded to a mixture of
amino acids, which then enter intestinal epithelial
cells, where some amino acids are metabolized. The
remainder pass into the blood.
 METABOLISM OF CARBOHYDRATES
GLYCOLYSIS
● Metabolic pathway that glucose is converted
to pyruvate (aerobic condition) or lactate
(anaerobic condition), along with production
of a small quantity of energy.
● Pyruvate kinase is more active in the fed state than in
the fasting state.
● The summary of the reactions of the glycolytic
pathway is that glucose + 2 NAD+ + 2 Pi + 2 ADP
yields 2 pyruvate + 2 NADH + 4 H+ + 2 ATP + 2
H2O.
● It occurs in the cytosol of all cells of the body.

● Rate limiting step:

● Rate limiting step:
Fructose-6-phosphate → Fructose-1,6-bisphosphate
Enzyme: Phosphofructokinase-1
● Steps with ATP production:
1,3-Bisphosphoglycerate → 3-Phosphoglycerate
Enzyme: Phosphoglycerate kinase
Phosphoenolpyruvate → Pyruvate
Enzyme: Pyruvate kinase
● Steps with NADH production
Glyceraldehyde-3-Phosphate
1,3-Bisphosphoglycerate
Enzyme: Glyceraldehyde-3-phosphate dehydrogenase
Isocitrate → α-ketoglutarate
Enzyme: Isocitrate dehydrogenase
● Steps with GTP production:
Succinyl CoA → Succinate
Enzyme: Succinate thiokinase
● Steps with FADH2 production:
Succinate → Fumarate
Enzyme: Succinate dehydrogenase
● Steps with NADH production:
→
Isocitrate → α-ketoglutarate
Enzyme: Isocitrate dehydrogenase
Ketoglutarate → Succinyl CoA
Enzyme: α-ketoglutarate dehydrogenase
Malate → Oxaloacetate
Enzyme: Malate dehydrogenase

● The total energy generated by one round of the cycle,

starting with 1 mole of acetyl-CoA, is approximately 10
KREBS CYCLE
moles of ATP.
● Major energy-producing pathway in the body. The
cycle occurs in mitochondria. ● The NADH and FADH2 (produced by the cycle)
● Foodstuffs feed into the cycle as acetyl-CoA and the donate electrons to the electron transport chain. For
acetyl-CoA is oxidized to carbon dioxide and water in each mole of NADH, approximately 2.5 moles of
order to generate energy. ATP are generated, and for each mole of FADH2,
● The cycle also serves in the synthesis of fatty acids, approximately 1.5 moles of ATP are generated by
amino acids, and glucose. the passage of these electrons to O2 (oxidative
phosphorylation). In addition, GTP is produced when
● All the enzymes of the TCA cycle are in the
succinyl-CoA is cleaved. GTP produces ATP:
mitochondrial matrix except succinate
dehydrogenase, which is in the inner mitochondrial
membrane. OXIDATIVE PHOSPHORYLATION
● ATP is generated as a result of the energy produced
 when electrons from NADH and FADH2 are passed to
molecular oxygen by a series of electron carriers,
collectively known as the electron transport chain.
● The components of the chain include FMN, Fe–S
centers, coenzyme Q, and a series of cytochromes
(b, c1, c, and aa3).
● Protons move back into the matrix through the ATP
synthase complex, causing ATP to be produced from
ADP and inorganic phosphate.
● ATP is transported from the mitochondrial matrix to the
cytosol in exchange for ADP (the ATP– ADP antiport
system).
● The oxidation of 1 mole of NADH generates
approximately 2.5 moles of ATP, whereas the oxidation
of 1 mole of FADH2 generates approximately 1.5
moles of ATP.
● Because energy generated by the transfer of electrons
through the electron transport chain to O2 is used in the
production of ATP, the overall process is known as
oxidative phosphorylation.
The three major stages of electron transport
1. Transfer of electrons from NADH to coenzyme Q
● NADH passes electrons via the NADH
dehydrogenase complex (complex I) to FMN. The
complex is also known as the NADH:CoQ
oxidoreductase.
2. Transfer of electrons from coenzyme Q to
cytochrome c
● Coenzyme Q passes electrons through Fe–S
centers to cytochromes b and c1, which transfer
the electrons to cytochrome c. The protein
complex involved in these transfers is called
complex III, or the cytochrome b-c1 complex.
The complex is also known as CoQ:C1
Oxidoreductase.
3. Transfer of electrons from cytochrome c to oxygen
a. Cytochrome c transfers electrons to the
cytochrome aa3 complex, which transfers the
electrons to molecular oxygen, reducing it to
water. Cytochrome oxidase (complex IV)
catalyzes this transfer of electrons.
i. Cytochromes a and a3 each contain a
heme and two different proteins that
each contain copper.
ii. Two electrons are required to reduce
one atom of oxygen; therefore, for
each NADH that is oxidized, one-half
of O2 is converted to H2O.
b. The energy produced by the transfer of
electrons from cytochrome c to oxygen is
used to pump protons across the inner
mitochondrial membrane.
c. As the protons flow back into the matrix, ATP is
generated.
GLYCOGENESIS
GLYCOGEN
● Large, branched polymer consisting of
D-glucose residues.
● The linkages between glucose residues are
α-1,4 except at branch points where the
linkage is α-1,6.
● One glucose unit, located at the reducing end
of each glycogen molecule, is attached to the
protein glycogenin.
● The glycogen molecule branches like a tree
and has many nonreducing ends at which
addition and release of glucose residues occur
during synthesis and degradation, respectively.
● Liver glycogen is used to maintain blood
glucose levels during fasting or exercise.
● Its breakdown is stimulated by glucagon and
by epinephrine via a mechanism that involves
cyclic adenosine monophosphate (cAMP)
● Muscle glycogen is utilized to generate ATP
for muscle contraction.
● Epinephrine, via cAMP, stimulates muscle
glycogen breakdown.
•Glycogenesis is the formation of glycogen from glucose
•Substrate: Glucose as Glucose-1-phosphate
•Product: Glycogen
•Site: Liver (100g) Muscle (400g)
•Nature: Anabolic
•Rate limiting enzyme: Glycogen synthase
SYNTHESIS
UDP-glucose is the precursor for glycogen synthesis.
1. Synthesis of UDP-glucose
● Glucose enters cells and is phosphorylated to
glucose-6-phosphate by hexokinase (or by
glucokinase in the liver). ATP provides the
phosphate group.
● Phosphoglucomutase converts
glucose-6-phosphate to glucose-1-phosphate.
● Glucose-1-phosphate reacts with UTP, forming
UDP-glucose in a reaction catalyzed by
UDP-glucose pyrophosphorylase. Inorganic
pyrophosphate (PPi) is released in this reaction.
● PPi is cleaved by a pyrophosphatase to 2 Pi.
This removal of the product helps to drive the
process in the direction of glycogen synthesis.
2. Action of glycogen synthase
● Glycogen synthase is the key
regulatory enzyme for glycogen
synthesis. It transfers glucose residues
from UDP-glucose to the nonreducing
ends of a glycogen primer.
● UDP is released and reconverted to UTP
by reaction with ATP.
● The primers, which are attached to
glycogenin, are glycogen molecules
 that were partially degraded in the liver
during fasting or in muscle and liver
during exercise.
3. Formation of branches
● When a chain contains 11 or more glucose
residues, an oligomer, six to eight residues in
length, is removed from the nonreducing end of
the chain. It is reattached via an α-1,6 linkage
to a glucose residue within an α-1,4-linked
chain.
● These branches are formed by the branching
enzyme, a glucosyl 4:6 transferase, that
breaks an α-1,4 bond and forms an α-1,6 bond.
● The new branch points are at least four
residues and an average of 7 to 11 residues
from previously existing branch points.
4. Growth of glycogen chains
● Glycogen synthase continues to add glucose
residues to the nonreducing ends of the newly
formed branches as well as to the ends of the
original chains.
● As the chains continue to grow, additional
branches are produced by the branching
enzyme.
DEGRADATION
1. Action of glycogen phosphorylase
● Glycogen phosphorylase, the key
regulatory enzyme for glycogen
degradation, removes glucose residues,
one at a time, from the nonreducing ends of
glycogen molecules.
● Phosphorylase uses inorganic phosphate
(Pi) to cleave α-1,4 bonds, producing
glucose-1-phosphate.
● Phosphorylase can act only until it is four
glucose units from a branch point.
2. Removal of branches
● The four units remaining at a branch are
removed by the debranching enzyme,
which has both glucosyl 4:4 transferase and
α-1,6-glucosidase activity.
● Three of the four glucose residues that
remain at the branch point are removed as
a trisaccharide and attached to the
nonreducing end of another chain by a 4:4
transferase, which cleaves an α-1,4 bond
and forms a new α-1,4 bond.
● The last glucose unit at the branch point,
which is linked α-1,6, is hydrolyzed by
α-1,6-glucosidase, forming free glucose.
GLUCONEOGENESIS
● Occurs mainly in the liver, is the synthesis of glucose
from compounds that are not carbohydrates.
IMPORTANCE:.
 ● Within the first few hours of fasting,
glycogenolysis is primarily responsible for
maintaining blood glucose levels.
● As a fast progresses and glycogen stores
decrease, gluconeogenesis becomes an important
additional source of blood glucose.
● After about 30 hours, when liver glycogen stores
are depleted, gluconeogenesis becomes the only
source of blood glucose.
● All cells use glucose for energy; however, the
production of glucose during fasting is particularly
important for tissues such as the brain and red
blood cells.
● During exercise, blood glucose levels are also
maintained by liver glycogenolysis and
gluconeogenesis.

REACTIONS
1. Conversion of pyruvate to phosphoenolpyruvate
● In the liver, pyruvate is converted to
phosphoenolpyruvate.
● Pyruvate (produced from lactate, alanine, and
other amino acids) is first converted to
oxaloacetate by pyruvate carboxylase, a
mitochondrial enzyme that requires biotin and
ATP.
● Oxaloacetate cannot directly cross the inner
mitochondrial membrane. Therefore, it is
converted to malate or to aspartate, which
can cross the mitochondrial membrane and
be reconverted to oxaloacetate in the cytosol.
● Oxaloacetate is decarboxylated by
phosphoenolpyruvate carboxykinase to
form phosphoenolpyruvate. This reaction 2. Conversion of fructose 1,6-bisphosphate
requires GTP. to fructose-6-phosphate
● Phosphoenolpyruvate is converted to ● Fructose-1,6-bisphosphate is
fructose 1,6-bisphosphate by reversal of the converted to fructose-6-phosphate
glycolytic reactions in a reaction that releases
inorganic phosphate and is
catalyzed by
fructose-1,6-bisphosphatase.
● Fructose-6-phosphate is
converted to glucose 6-
phosphate by the same isomerase
used in glycolysis.

3. Conversion of glucose-6-phosphate to glucose

● Glucose-6-phosphate releases inorganic
phosphate, which produces free glucose
that enters the blood. The enzyme is
glucose 6-phosphatase.
● Glucose-6-phosphatase is involved both
in gluconeogenesis and glycogenolysis.
Substrate: Glycogen
Product: Glucose-1-phosphate
Site: Liver, Muscle, Brain
Nature: Catabolic
Rate limiting enzyme: Glycogen phosphorylase
PENTOSE PHOSPHATE PATHWAY
● In red blood cells, the pentose phosphate pathway is
the sole source of NADPH for the reduction of oxidized
glutathione catalyzed by glutathione reductase, a
flavoprotein containing flavin adenine dinucleotide
(FAD). Reduced glutathione removes H2O2 in a
reaction catalyzed by glutathione peroxidase, an
enzyme that contains the selenium analog of cysteine
(selenocysteine) at the active site.
PATHWAY
OMEGA OXIDATION
FRUCTOSE METABOLIC CONSEQUENCES
● Diets high in sucrose or in high-fructose syrups (HFS)
used in manufactured foods and beverages lead to large
amounts of fructose (and glucose) entering the hepatic
portal vein.
● Faster glycolysis in the liver than glucose because it
bypasses the regulatory step of phosphofructokinase.
● Fructose flood the pathways in the liver, leading to
increased fatty acid synthesis, esterification of fatty
acids, and secretion of very-low-density lipoprotein
(VLDL), which may raise serum triacylglycerols and
ultimately raise LDL cholesterol concentrations.
METABOLISM OF LIPIDS
BETA OXIDATION OF FATTY ACIDS
● This process is known as beta-oxidation, because the
oxidation and splitting of two carbon units occur at the
beta-carbon atom.
● The oxidation of the hydrocarbon chain occurs by a
sequential cleavage of two carbon atoms.
ALPHA OXIDATION
● It is a process by which fatty acids are oxidized
by removing carbon atoms, one at a time,
from the carboxyl end.
● The process is important in the brain.
● The fatty acid does not need activation.
● Hydroxylation occurs at the alpha-carbon atom
and is then oxidized to alpha-keto acid.
○ The keto acid then undergoes
decarboxylation yielding a molecule of CO2
and a fatty acid with one carbon atom less.
● This process occurs in the endoplasmic
reticulum, does not require CoA, but does not
generate energy.
● Alpha-oxidation is mainly used for fatty acids that
have a methyl group at the beta-carbon, which
blocks
beta-oxidation.
● A major dietary methylated fatty acid is phytanic
acid.
○ It is derived from phytol present in
chlorophyll, milk and animal fats.
● It is a minor pathway taking place in microsomes, with
the help of hydroxylase enzymes involving NADPH and
cytochrome P-450.
● The CH3 group is converted to CH2 OH and
subsequently oxidized with the help of NAD+ to a
COOH group to produce dicarboxylic acids.
● ω-oxidation becomes important when β-oxidation is
defective and dicarboxylic acids (6C and 8C acids) are
excreted in urine causing dicarboxylic aciduria.
STAGES OF FATTY ACID BETA OXIDATION
● The co-enzyme A is a complex molecule containing B
complex vitamin pantothenic acid and a molecule of
beta mercapto ethanolamine.
● This SH group forms thioester bonds in acyl CoA.
● To emphasize the function of the SH group, the CoA is
sometimes written as CoA-SH.
● Fatty acids are activated to their co-enzyme A
(CoA) derivative.
● This activation is taking place in cytoplasm.
● ATP is hydrolyzed to AMP and PPi and the energy
from hydrolysis of PPi drives the reaction forward.
● Thus two high energy bonds are utilized in
this reaction.
● The enzyme is a thiokinase or fatty acyl
CoA synthetase
● Acetyl groups and acyl groups are different
● Three different enzymes, one each for short
chain, medium chain and long chain fatty acids
have been identified.
 ○ Small chain fatty acids may also be
activated by thiophorase enzyme, using
succinyl CoA (see under ketone bodies).
● Fatty acids are activated in the cytoplasm; but
beta oxidation is in mitochondria.
So transport of fatty acids through the
mitochondrial membrane is essential.
● The long chain fatty acyl CoA cannot pass through
the membrane. Therefore a transporter, carnitine,
is involved in transfer of fatty acids.
● Carnitine is beta hydroxy-gamma-trimethyl
ammonium butyrate, (CH3 )3 –N+ –CH2
–CHOH–CH2 –COOH.
○ It is synthesized from lysine and methionine
in the liver and kidney.
● Therefore a transporter, carnitine, is involved in transfer
of fatty acids.
● Carnitine is beta hydroxy-gamma-trimethyl ammonium
butyrate, (CH3 )3 –N+ –CH2 –CHOH–CH2 –COOH.
● It is synthesized from lysine and methionine in the liver
and kidney.
● The enzyme carnitine acyl transferase-I (CAT-I) will
transfer the fatty acyl group to the hydroxyl group
of carnitine to form acyl carnitine (Fig. 12.8)
● The reaction occurs on the cytosolic side of the
inner mitochondrial membrane.
● A protein translocase will carry the acyl carnitine
across the membrane to the matrix of
mitochondria.
● On the matrix side of the membrane another
enzyme, carnitine acyltransferase-II (CAT-II) will
transfer the acyl group back to co-enzyme A
molecule (Fig. 12.8).
● Carnitine is returned to the cytosolic side by
the translocase.
Step 1: FAD Linked Dehydrogenase
● The fatty acyl CoA is dehydrogenated to a trans enoyl
CoA with FAD accepting the hydrogen atoms.
● FADH2 when oxidized in the electron transport chain
will produce 1.5 ATP molecules.
Step 2: Hydration
● This is catalyzed by an enoyl CoA hydratase. This step
forms a beta-hydroxy fatty acyl CoA.
● The L isomer alone is formed during the hydration of
the trans double bond.
Step 3: NAD+ Dependent Dehydrogenase
● The beta-hydroxy fatty acyl CoA is again
oxidized to form beta-keto fatty acyl CoA.
● This dehydrogenase acts only on L isomers.
● The NADH when oxidized in the electron
transport chain will generate 2.5 ATPs.
Step 4: Cleavage
● The beta-keto fatty acyl CoA now undergoes thiolytic
cleavage, splitting off a molecule of acetyl CoA and
leaving behind a fatty acid with 2 carbon atoms less.
Further Cycles
● The newly formed fatty acyl CoA will sequentially
undergo further cycles of steps 1, 2, 3 and 4 of
beta-oxidation until the fatty acid is completely
converted to acetyl.
FORMATION OF KETONE
Acetoacetate
● Primary ketone body
Beta-hydroxybutyrate & Acetone
● Secondary ketone body
● They are synthesized exclusively by the liver
mitochondria
STEPS
STEP 1 :
● 2 molecules of acetyl-CoA are condensed to
form acetoacetyl CoA
STEP 2 :
● 1 more acetyl CoA is added to acetoacetyl CoA to
form HMG CoA (beta hydroxy beta methylglutaryl
CoA)
● The enzyme is HMG CoA synthase
● Mitochondrial HMG CoA is used for ketogenesis
● Cytosolic fraction is for cholesterol synthesis
STEP 3 :
● HMG CoA is lysed to form acetoacetate
● Acetoacetate may also be formed by the
degeneration of carbon skeleton of ketogenic amino
acids like leucine, lysine, phenylalanine and tyrosine.

STEP 4:
● Beta-hydroxybutyrate is formed by reduction of
acetoacetate
● Ratio between acetoacetate and beta hydroxybutyrate is
decided by the cellular NAD:NADH ratio
BIOMEDICAL SIGNIFICANCE OF KETONES
KETOSIS
● Normally the rate of synthesis of ketone bodies by the
liver is such that they can be easily metabolized by the
extrahepatic tissues.
● Hence, the blood level of ketone bodies is < 1 mg/dL
and only traces are excreted in urine (not detectable by
usual tests).
● But when the rate of synthesis exceeds the ability of
extrahepatic tissues to utilize them, there will be
accumulation of ketone bodies in blood.
● This leads to ketonemia, excretion in urine (ketonuria)
and smell of acetone in breath.
● All these three together constitute the condition known
as ketosis.
CAUSES:
Diabetes mellitus
● Untreated diabetes mellitus is the most common cause
for ketosis.
● Even though glucose is in plenty, the deficiency of
insulin causes accelerated lipolysis and more fatty acids
are released into circulation.
● Oxidation of these fatty acids increases the acetyl CoA
pool.
● Enhanced gluconeogenesis restricts the oxidation of
acetyl CoA by TCA cycle, since availability of
oxaloacetate is less.
Starvation
● In starvation, the dietary supply of glucose is decreased.
● Available oxaloacetate is channeled
gluconeogenesis.
● The increased rate of lipolysis is to provide an alternate
source of fuel.
● The excess acetyl CoA is converted to ketone bodies.
● The high glucagon favors ketogenesis.
● The brain derives 75% of energy from ketone bodies
under conditions of fasting.
● Hyperemesis (vomiting) in early pregnancy may also
lead to starvation-like conditions and may lead to
ketosis.
SALIENT FEATURES OF KETOSIS
Metabolic acidosis
● Acetoacetate and beta-hydroxy butyrate
are acids.
● When they accumulate, metabolic
acidosis results.
Reduced buffers
● The plasma bicarbonate is used up for buffering of
these acids.
Kussmaul's respiration
● Patients will have typical acidotic breathing due to
compensatory hyperventilation.
Smell of acetone in patient's breath.
Osmotic diuresis
● Induced by ketonuria may lead to dehydration.
Sodium loss
● The ketone bodies are excreted in urine as their
sodium salt, leading to loss of cations from the
body.
Dehydration
● The sodium loss further aggravates the
dehydration.
Coma
● Hypokalemia, dehydration and acidosis are
contributing to the lethal effect of ketosis.
SYNTHESIS OF FATTY ACIDS
STEPS
Step 1: CarboXylation of Acetyl CoA
● The first step in the fatty acid synthesis is the
carboxylation of acetyl CoA to form malonyl CoA.
● Acetyl CoA carboxylase is not a part of the
multi-enzyme complex. But it is the rate-limiting
enzyme.
● Biotin, a member of B complex vitamins, is
necessary for this reaction
● The enzyme is allosterically regulated, the major
effectors being citrate (positive) and palmitoyl CoA
(negative).
● The reaction is similar to carboxylation of pyruvate
to form oxaloacetate.
● The elongation of the fatty acid occurs by addition
of 2 carbon atoms at a time. But the 2-carbon units
to are added as 3-carbon, malonyl units.
● The whole reaction sequence occurs while the
 intermediates are bound to ACP (acyl carrier
protein).
Step 2: Three C and Two C Units are Added
● Acetyl transacylase
❖ Catalyzes the transfer of the acetyl group (2
carbons) to the cysteinyl SH group of the
condensing enzyme (CE) of the other
monomer of the fatty acid synthase
complex

● Malonyl transacylase
❖ transfers the malonyl group to the SH group
of the ACP of one monomer of the enzyme
❖ One molecule of acetyl CoA (2 carbon) and
one molecule of malonyl CoA (3 carbon)
bind to the multienzyme complex.

Step 3: Condensation
● Acetyl (2C) and malonyl (3C) units are condensed
to form beta-ketoacyl ACP or acetoacetyl ACP (4C).
● During this process one carbon is lost as CO2.
● The enzyme is called condensing enzyme or
ketoacyl synthase.

ELONGATION OF FATTY ACIDS

Step 4: Reduction
● Acetoacetyl ACP is reduced by NADPH dependent
beta ketoacyl reductase to form beta hydroxy fatty
acyl ACP
Step 5: Dehydration
● It is then dehydrated by a dehydratase (DH) to form
enoyl ACP otherwise known as (alpha beta
unsaturated acyl ACP)
Step 6: Second Reduction
● The enoyl ACP is again reduced by enoyl reductase
(ER) utilizing a 2nd molecule of NADPH to form
butyryl ACP
Step 7: Palmitic acid is Released
● Thioesterase or de-acylase activity (TE) releases
palmitate from the multi-enzyme complex
● The end point is Palmitic acid (16 C) in liver and
adipose tissue. But in lactating mammary gland, the
end products are Capric (10 C) and Lauric (12C)
acids.
● Mother's milk contains these medium-chain fatty
acids.
● Cow's milk contains odd numbered fatty acids.
Microsomal system
● microsomal fatty acid elongase system
● Elongates saturated or unsaturated fatty acyl CoA
by successive addition of two-carbon units
● Malonyl CoA is the donor of 2 carbon acetyl groups
● NADPH is required for the reaction
● This system can elongate fatty acids having 10
carbon units onward up to the length of 22 or 24
carbons
● The steps in elongation are similar to de novo
synthesis
STEPS:
1. Acyl CoA (10C in length) + malonyl CoA =
3-ketoacyl CoA (12C). Enzyme is 3-ketoacyl CoA
synthase. 1 molecule of carbon dioxide is released
in this reaction
2. 3-ketoacyl CoA is reduced to 3-hydroxyacyl CoA
Enzyme is 3-ketoacyl CoA reductase NADPH is
needed.
3. 1 water molecule is removed from 3-hydroxyacyl
CoA to make 2-trans enoyl CoA. With the help of
3-hydroxyacyl CoA dehydrase
4. 2-trans enoyl CoA is reduced to acyl CoA (12C).
With the help of transenoyl CoA reductase and
NADPH
● This is repeated till the necessary length is
achieved. Finally CoA is removed from the
molecule.

DESATURATION OF OF FATTY ACIDS

Monounsaturated fatty acids
● can be synthesized from saturated fatty acids by △9
desaturase enzyme system present in the endoplasmic
reticulum.
● The reaction utilizes NADH and molecular O2 and
cytochrome b5.
● Thus, stearic acid is desaturated to form oleic acid.
REGULATION OF FATTY ACIDS
AVAILABILITY OF SUBSTRATE
● Fatty acid synthesis occurs when carbohydrates are
abundant and the level of fatty acids is low.
● The availability of citrate in the cytoplasm is the most
important regulatory factor producing a short-term
effect.
ACETYL COA CARBOXYLASE
● Phosphorylation inactivates acetyl CoA carboxylase
● AMP activated kinase (AMPK)
● phosphorylates acetyl CoA carboxylase and renders it
inactive
● ATP inhibits AMPK and therefore
● Fatty acid synthesis decreases when glucose level and
energy charge is low
● The enzyme is inhibited by palmitoyl CoA, the end
product
● Dephosphorylation of Acetyl CoA carboxylase is
affected by protein phosphatase 1.
INSULIN
● Insulin enhances the uptake of glucose by adipocytes
● Increase the activity of pyruvate dehydrogenase, acetyl
CoA carboxylase and glycerol phosphate
acyltransferase
INSULIN FAVORS LIPOGENESIS
● depresses hormone sensitive lipase
GLUCAGON INHIBITS LIPOGENESIS
● Glucagon & Epinephrine (are lipolytic)
● They inhibit acetyl CoA carboxylase by keeping the
enzyme in the inactive phosphorylated state
● They are secreted when the energy charge is low and
AMP levels are high
ChREBP: MASTER LIPID REGULATOR IN THE LIVER
● Excess glucose is diverted into the lipid synthesis
pathway
Glucose is catabolized to acetyl CoA
● which is used for de novo fatty acid synthesis
ultimately stored as triglycerides in adipose tissue.
● A diet rich in carbohydrates leads to stimulation of both
the glycolytic and lipogenic pathways
● Genes encoding glucokinase (GK) and liver pyruvate
kinase (L-PK) of glycolysis and ATP citrate lyase, ACC
and FAS of lipogenesis regulated by modulation of their
transcription rates
● Contain glucose- or carbohydrate-response elements
(ChoREs) that are responsible for their transcriptional
regulation.
● One transcription factor that exerts control over glucose
and lipid homeostasis is sterol response
element-binding protein (SREBP), in particular
SREBP-1c.
● SREBP controls the expression of a number of genes
involved in lipogenesis and its own transcription is
increased by insulin and repressed by glucagon.
● The carbohydrate responsive element-binding protein
(ChREBP) is identified as a major glucose-responsive
transcription factor and it is required for glucose induced
expression of L-PK and the lipogenic genes ACC and
FAS.
CHOLESTEROL SYNTHESIS, TRANSPORT, EXCRETION
CHOLESTEROL
● Present in tissues and plasma either as a free
cholesterol or cholesterol ester (combination with a
long-chain fatty acid storage form)
● In plasma, both forms are transported in lipoproteins
● It is an amphipathic lipid and a structural component of
membranes
● It is important for the maintenance of the correct
permeability and fluidity and of the outer layer of plasma
lipoproteins
● It is synthesized in in many tissues from acetyl-CoA
● Precursor of all other steroid in the body including:
Corticosteroids. Sex hormones, Bile acids, Vitamin D
● As a typical product of animal metabolism, it occurs in
foods of animal origin such as Egg yolk, meat, liver, and
brain
● Major constituent of gallstones
● chief role in pathologic process in the development of
atherosclerosis of vital arteries
● causes cerebrovascular, coronary and peripheral
vascular disease
FUNCTIONS:
● Cell membranes: Cholesterol is a component of
membranes and has a modulating effect on the fluid
state of the membrane.
● Nerve conduction: Cholesterol is used to insulate nerve
fibers. Bile acids and bile salts are derived from
cholesterol. Bile salts are important for fat absorption.
● Steroid hormones: Glucocorticoids, androgens and
estrogens are from cholesterol.
● Vitamin D3 is from 7-dehydro-cholesterol.
Esterification: The OH group of cholesterol is esterified
to fatty acids to form cholesterol esters. This
esterification occurs in the body by transfer of a PUFA
moiety by lecithin
SYNTHESIS:
1. Synthesis of mevalonate from acetyl-CoA
● BIOSYNTHESIS OF MEVALONATE
● Two molecules of acetyl-CoA condense to form
acetoacetyl-CoA catalyzed by cytosolic thiolase.
● Acetoacetyl-CoA condenses with a further molecule of
acetyl-CoA catalyzed by HMG-CoA synthase to form
HMG-CoA, which is reduced to mevalonate by NADPH
in a reaction catalyzed by HMG-CoA reductase.
● This last step is the principal regulatory step in the
 pathway of cholesterol synthesis and is the site of action
of the most effective class of cholesterol-lowering drugs,
the statins, which are HMG-CoA reductase inhibitors.
● 6 ISOPRENOID UNITS FORM SQUALENE
● Isopentenyl diphosphate is isomerized by a shift
of the double bond to form dimethylallyl
diphosphate, and then condensed with another
molecule of isopentenyl diphosphate to form the
10-carbon intermediate geranyl diphosphate.
● Further condensation with isopentenyl
diphosphate forms farnesyl diphosphate.
● Two molecules of farnesyl diphosphate
condense at the diphosphate end to form
squalene.
● Initially, inorganic pyrophosphate is eliminated,
forming presqualene diphosphate, which is then
reduced by NADPH with elimination of further
inorganic pyrophosphate molecules.
● Farnesyl diphosphate is also an intermediate in
the formation of other important compounds
which contain isoprenoid units such as dolichol
and ubiquinone

2. Formation of isoprenoid units from

mevalonate by loss of CO2
● FORMATION OF ISOPRENOID UNITS
● Mevalonate is phosphorylated sequentially using
ATP by three kinases, and after decarboxylation of
the active isoprenoid unit, isopentenyl diphosphate,
is formed.

3. Formation of cholesterol from lanosterol.

● FORMATION OF CHOLESTEROL
● The formation of cholesterol from lanosterol
takes place in the membranes of the
endoplasmic reticulum and involves changes in
the steroid nucleus and the side chain.
● The methyl groups on C14 and C4 are removed
to form 14-desmethyl lanosterol and then
zymosterol. The double bond at C8—C9 is
subsequently moved to C5—C6 in two steps,
forming desmosterol (24-dehydrocholesterol).
● Finally, the double bond of the side chain is
reduced, producing cholesterol.

Cholesterol synthesis is controlled by regulation of

3. Condensation of six isoprenoid units form
HMG-CoA.
squalene
 ● The liver is regulated partly by cholesterol in diet.
● Cholesterol and metabolites repress transcription of
HMG-CoA reductase mRNA via inhibition of a sterol
regulatory element-binding protein (SREBP)
transcription factor.
● Insulin or thyroid hormone increases HMG-CoA
reductase activity, whereas glucagon or
glucocorticoids decrease it.

Cholesterol is excreted from the body in the bile as

cholesterol or as bile acids (salts)
Cholesterol balance in tissues.
● Maintained between the factors causing gain of
cholesterol (eg. synthesis, uptake via LDL or
scavenger receptors) and the factors causing loss of
cholesterol (eg. steroid synthesis, cholesteryl ester
formation, excretion).
● The activity of the LDL receptor is modulated by
cellular cholesterol levels to achieve this balance.
● Cholesterol is excreted from the body via the bile
either in the unesterified form or after conversion into
bile acids in the liver. Coprostanol is the principal sterol
in the feces; it is formed from cholesterol by the
bacteria in the lower intestine.
● Most (98-99%) of the bile acids are reabsorbed in the
ileum and returned to the liver in the enterohepatic
circulation.

Cholesterol is transported between tissues in plasma

lipoproteins
● Cholesterol is transported in plasma in lipoproteins,
with the greater part in the form of cholesteryl ester,
CLINICAL ASPECTS
and in humans the highest proportion is found in LDL.
Serum Cholesterol Is Correlated With the Incidence of
● In reverse cholesterol transport, HDL takes up
Atherosclerosis & Coronary Heart Disease
cholesterol from the tissues and LCAT then esterifies it
● Elevated levels (>5.2 mmol/L) of cholesterol present in
and deposits it in the core of the particles.
VLDL, IDL, or LDL are associated with
● The cholesteryl ester in HDL is taken up by the liver,
atherosclerosis, whereas high levels of HDL have a
either directly or after transfer to VLDL, IDL, or LDL by
protective effect.
the action of the cholesteryl ester transfer protein.
 ● Atherosclerosis is an inflammatory disease
characterized by the deposition of cholesterol and
cholesteryl ester from the plasma lipoproteins into the
artery wall and is a major cause of heart disease.
Diet Can Play an Important Role in Reducing Serum
Cholesterol
● Most beneficial = substitution in the diet of
polyunsaturated and monounsaturated fatty acids for
saturated fatty acids.
● Plant oils such as corn oil and sunflower seed oil
contain a high proportion of ω6 polyunsaturated fatty
acids, while olive oil contains a high concentration of
monounsaturated fatty acids. ω3 fatty acids found in
fish oils are also beneficial.
● On the other hand, butter fat, beef fat, and palm oil
contain a high proportion of saturated fatty acids.
● One of the mechanisms by which unsaturated fatty
acids lower blood cholesterol levels is by the
upregulation of LDL receptors on the cell surface,
causing an increase in the catabolic rate of LDL, the
main atherogenic lipoprotein.
● In addition, ω3 fatty acids have anti-inflammatory
and triacylglycerol-lowering effects.
● Saturated fatty acids also cause the formation of
smaller VLDL particles that contain relatively more
cholesterol, and they are utilized by extrahepatic
tissues at a slower rate than are larger
particles—tendencies that may be regarded as
atherogenic.
Lifestyle Affects the Serum Cholesterol Level
● Additional factors considered to play a part in coronary
heart disease include high blood pressure, smoking,
male gender, obesity (particularly abdominal obesity),
lack of exercise, and drinking soft as opposed to hard
water.
● Factors associated with elevation of plasma-free fatty
acids (FFAs) followed by increased output of
triacylglycerol and cholesterol into the circulation in
VLDL include emotional stress and coffee drinking.
● Premenopausal women appear to be protected against
many of these deleterious factors = related to the
beneficial effects of estrogen.
● There is an association between moderate alcohol
consumption and a lower incidence of coronary heart
disease.
● Due to elevation of HDL concentrations resulting from
increase synthesis of apo A-I and changes in activity of
cholesteryl ester transfer protein.
● Red wine is particularly beneficial = content of
antioxidants.
● Regular exercise lowers plasma LDL but raises HDL.
Triacylglycerol concentrations are also reduced, due
most likely to increased insulin sensitivity, which
enhances the expression of lipoprotein lipase.
When Diet Changes Fail, Hypolipidemic Drugs Can
Reduce Serum Cholesterol and Triacylglycerol
● STATINS
❖ Highly efficacious in lowering plasma
cholesterol and preventing heart disease.
❖ Act by inhibiting HMG-CoA reductase
and upregulating LDL receptor activity.
❖ Examples: Atorvastatin, simvastatin,
fluvastatin, and pravastatin.
● EZETIMIBE
❖ Reduces blood cholesterol levels by inhibiting the
absorption of cholesterol by the intestine via
blockage of uptake by the
❖ Niemann-Pick C-like 1 protein.
❖ Other drugs used include fibrates such as clofibrate,
gemfibrozil, and nicotinic acid, which act mainly to
lower plasma triacylglycerols by decreasing the
secretion of triacylglycerol and cholesterol containing
VLDL by the liver.
❖ PCSK9 reduces the number of LDL receptors
exposed on the cell membrane
❖ Effect of raising blood cholesterol levels, thus drugs
that inhibit its activity are potentially antiatherogenic
and two such compounds, alirocumab and
evolocumab, have recently been approved for use
and others are currently in development.
METABOLISM OF PROTEINS
BIOSYNTHESIS OF NUTRITIONALLY NON ESSENTIAL
AMINO ACIDS
20 amino acids
● Nutritionally essential:
❖ 8 amino acids must be present in the human diet.
❖ Body cannot produce on its own.
● Nutritionally nonessential:
❖ 12 amino acids, while metabolically essential, need
not be present in the diet.
 ALANINE AND ASPARTATE
● Transamination of pyruvate forms alanine.
● Transamination of oxaloacetate forms aspartate.

GLUTAMATE
● Precursor of the “glutamate family” of amino acids.
● Formed by the reductive amidation of the citric acid
cycle intermediate α-ketoglutarate, a reaction
catalyzed by mitochondria glutamate
dehydrogenase.
● The reaction both strongly favors glutamate
synthesis and lowers the concentration of cytotoxic ASPARAGINE
ammonium ion. ● The conversion of aspartate to asparagine,
catalyzed by asparagine synthetase, where
glutamine provides nitrogen.
● Bacteria asparagine synthetases can, however,
also use ammonium ion. The reaction involves the
intermediate formation of aspartyl phosphate
● The coupled hydrolysis of PPi to Pi by
pyrophosphatase, EC 3.6.1.1, ensures that
the reaction is strongly favored.

GLUTAMINE
● The amidation of glutamate to glutamine catalyzed
by glutamine synthetase involves the intermediate
formation of γ-gutamy phosphate.
● Following the ordered binding of glutamate and ATP,
glutamate attacks the γ-phosphorus of ATP, forming
γ-glutamyl phosphate and ADP. NH4+ then binds,
and uncharged NH3 attacks γ-glutamyl phosphate.
Release of Pi and of a proton from the γ-amino group
of the tetrahedral intermediate then allows release of
the product, glutamine.
 to tyrosine.
● If the diet contains adequate quantities of the
nutritionally essential amino acid
phenylalanine, tyrosine is nutritionally
nonessential.
● However, since the phenylalanine
SERINE
hydroxylase reaction is irreversible, dietary
● Oxidation of the α-hydroxyl group of the glycolytic
tyrosine cannot replace phenylalanine.
intermediate 3-phosphoglycerate, catalyzed by
● Catalysis by this mixed-function oxidase
3-phosphoglycerate dehydrogenase, converts it to
incorporates one atom of O2 into the para position
3-phosphohydroxypyruvate.
of phenylalanine and reduces the other atom to
● Transamination and subsequent dephosphorylation
water. Reducing power, provided as
then form serine.
tetrahydrobiopterin, derived ultimately from NADPH
● Provides the carbon skeleton and homocysteine the
sulfur for cysteine biosynthesis.

GLYCINE
● Glycine aminotransferases can catalyze the
synthesis of glycine from gyoxyate and glutamate or
alanine.
● Unlike most aminotransferase reactions, it is
strongly favored for glycine synthesis.
● Additional important mammalian routes for glycine
formation are from choline and from serine.
PROLINE
● The initial reaction of proline biosynthesis converts
the γ-carboxyl group of glutamate to the mixed acid
anhydride of glutamate γ-phosphate.
● Subsequent reduction forms glutamateγ-semialdehyde,
which following spontaneous cyclization is reduced to
l-proline.
CYSTEINE
● Cysteine formed from methionine = nutritionally
essential.
● Following conversion of methionine to homocysteine,
homocysteine and serine form cystathionine, whose
hydrolysis forms cysteine and homoserine.
TYROSINE
● Phenylalanine hydroxylase converts phenylalanine
HYDROXYPROLINE & HYDROXYLYSINE
● Occur principally in collagen.
● Phenylalanine hydroxylase converts phenylalanine to
tyrosine. Since the reaction catalyzed by this mixed
function oxidase is irreversible, tyrosine cannot give
rise to phenylalanine.
● Neither dietary hydroxyproline nor hydroxylysine is
incorporated into proteins because no codon or tRNA
dictates their insertion into peptides.
● Peptidyl hydroxyproline and hydroxylysine are
formed by hydroxylation of peptidyl proline or lysine
in reactions catalyzed by mixed-function oxidases
that require vitamin C as cofactor.
● In scurvy, a nutritional disease that results from a
deficiency of vitamin C, impaired hydroxylation of
peptidyl proline and peptidyl lysine results in a failure
to provide the substrates for cross-linking of maturing
collagens.

VALINE, LEUCINE, & ISOLEUCINE
● While leucine, valine, and isoleucine are nutritionally
essential amino acids, tissue aminotransferases
reversibly interconvert three amino acids and their
corresponding α-keto acids.
●These α-keto acids thus can replace
their corresponding amino acids in the
diet.
SELENOCYSTEINE
● 21st Amino Acid
● An essential active site residue in several
mammalian enzymes, arises by
cotranslational insertion from a previously
modified tRNA.
CATABOLISM OF PROTEINS AND ALPHA AMINO ACIDS
● In normal adults, nitrogen intake matches nitrogen
excreted.
● Positive nitrogen balance, an excess of ingested over
excreted nitrogen, accompanies growth and
pregnancy.
● Negative nitrogen balance, where output exceeds
intake, may follow surgery, advanced cancer, and the
nutritional disorders kwashiorkor and marasmus.
● Genetic disorders that result from defects in the
genes that encode ubiquitin, ubiquitin ligases, or
deubiquitinating enzymes that participate in the
degradation of certain proteins include Angelman
syndrome, juvenile Parkinson disease, von
Hippel-Lindau syndrome, and congenital
polycythemia.
● Ammonia, which is highly toxic, arises in humans
primarily from the α-amino nitrogen of amino acids.
● Tissues therefore convert ammonia to the amide
nitrogen of the nontoxic amino acid glutamine.
● Subsequent deamination of glutamine in the liver
releases ammonia, which is efficiently converted to
urea, which is not toxic.
● However, if liver function is compromised, as in
cirrhosis or hepatitis, elevated blood ammonia levels
generate clinical signs and symptoms.
● Each enzyme of the urea cycle provides examples of
metabolic defects and their physiologic consequences.
In addition, the urea cycle provides a useful molecular
model or the study of other human metabolic defects.
PEPTIDASES AND PROTEASES
● The relative susceptibility of a protein to degradation
is expressed as its half-life (t ½), the time required to
lower its concentration to half of its initial value.
● Half-lives of liver proteins range from under 30
minutes to over 150 hours.
● Typical “housekeeping” enzymes such as those of
glycolysis, have t ½ values of over 100 hours. By
contrast, key regulatory enzymes may have t ½
values as low as 0.5 to 2 hours.
● PEST sequences, regions rich in proline (P),
glutamate (E), serine (S), and threonine (T), target
some proteins for rapid degradation.
● Intracellular proteases hydrolyze internal peptide
bonds.
● The resulting peptides are then degraded to amino
acids by endopeptidases that hydrolyze internal
peptide bonds, and by aminopeptidases and
carboxypeptidases that remove amino acids
sequentially from the amino- and carboxyl-termini,
respectively.
ATP-INDEPENDENT DEGRADATION
● Degradation of blood glycoproteins follows loss of a
sialic acid moiety from the nonreducing ends of their
oligosaccharide chains.
● Asialoglycoproteins are then internalized by liver-cell
asialoglycoprotein receptors and degraded by
lysosomal proteases.
● Extracellular, membrane-associated, and long-lived
intracellular proteins are also degraded in lysosomes
by ATP-independent processes.
ATP & UBIQUITIN-DEPENDENT DEGRADATION
● Degradation of regulatory proteins with short half-lives
and of abnormal or misfolded proteins occurs in the
cytosol, and requires ATP and ubiquitin.
● Named based on its presence in all eukaryotic cells,
ubiquitin is a small (8.5 kDa, 76 residue) polypeptide
that targets many intracellular proteins for degradation.
● The primary structure of ubiquitin is highly
conserved. Only 3 of 76 residues differ between
yeast and human ubiquitin.
● Soluble proteins undergo polyubiquitination, the
ligase-catalyzed attachment of four or more
additional ubiquitin molecules.
● Subsequent degradation of ubiquitin-tagged proteins
takes place in the proteasome, a macromolecule that
also is ubiquitous in eukaryotic cells.
● For degradation, a protein thus must first enter the
central pore. Entry into the core is regulated by the
two outer rings that recognize polyubiquitinated
proteins.
INTERORGAN EXCHANGE FOR MAINTENANCE OF
CIRCULATING AMINO ACID

PURELY KETOGENIC:
● Leucine

KETOGENIC AND GLUCOGENIC

● Lysine
● Isoleucine
● Phenylalanine
● Tyrosine
● Tryptophan
PURELY GLUCOGENIC
● All 14 remaining amino acids

BIOSYNTHESIS OF UREA
● Urea biosynthesis occurs in four stages:
❖ (1) transamination,
❖ (2) oxidative deamination of glutamate,
❖ (3) ammonia transport,
❖ (4) reactions of the urea cycle

● The expression in the liver of the RNAs for all the

enzymes of the urea cycle increased several fold in
starvation, probably secondary to enhanced protein
● Muscle generates half of total free amino acids and
degradation to provide energy.
liver is the site for urea cyle and removal of
● RATE LIMITING ENZYME: Carbamoyl phosphate
nitrogen.
synthetase
● Alanine is a key gluconeogenic amino acid (Figure
● Arginine is the precursor of Urea
28–6). The rate of hepatic gluconeogenesis from
alanine is far higher than from all other amino acids.
● The capacity of the liver for gluconeogenesis from
alanine does not reach saturation until the alanine
concentration reaches 20 to 30 times its normal
physiologic level.
FATE OF AMINO ACIDS
 ➢ β-Alanyl Dipeptides
➢ γ-Aminobutyrate
PORPHYRINS AND BILE PIGMENTS
● Heme is synthesized from porphyrins and iron, and
the products of degradation of heme are the bile
pigments and iron.
● The biochemistry of the porphyrins and of heme is
basic to understanding the varied functions of
hemoproteins, and the porphyrias, a group of
diseases caused by abnormalities in the pathway
of porphyrin biosynthesis.
● A much more common clinical condition is
jaundice, a consequence of an elevated level of
plasma bilirubin, due either to overproduction of
bilirubin or to failure of its excretion.
BIOSYNTHESIS OF UREA
● Involves both cytosolic and mitochondrial
reactions and intermediates.
● Occurs in most mammalian cells except mature
erythrocytes, which lack mitochondria.
● Porphyrins are cyclic compounds formed by the
linkage of four pyrrole rings through methyne
(——HC—) bridges. Various sidechains can
replace the eight numbered hydrogen atoms of
the pyrrole rings.
STEPS:
1. Carbamoyl phosphate synthetase I initiates urea
biosynthesis.
2. Carbamoyl phosphate plus ornithine forms citrulline.
3. Citrulline plus aspartate forms argininosuccinate.
4. Cleavage of argininosuccinate forms arginine &
fumarate.
5. Cleavage of arginine releases urea & reforms
ornithine.
6. Carbamoyl phosphate synthetase I is the
pacemaker enzyme of the urea cycle.
● Mitochondrial reactions: Reactions 1 and 2
● Cytosol reactions: Reactions 3,4,5
● Substances that need a carriers: CO2, NH4,
Citrulline and Ornithine
SPECIALIZED PRODUCTS
❖ L-α-AMINO ACIDS
➢ Alanine
➢ Arginine
➢ Cysteine
➢ Glycine
➢ Histidine
➢ Methionine
➢ Serine
➢ Tryptophan
➢ Tyrosine
➢ Phosphoserine,
Phosphothreonine,
& Phosphotyrosine
➢ Sarcosine (N-Methylglycine)
➢ Creatine & Creatinine
❖ NON–α-AMINO ACIDS
➢ β-Alanine & β-Aminoisobutyrate ● It involves both cytosolic and mitochondrial reactions
 and intermediates.

● Humans express two isozymes of ALA synthase.

○ ALAS1 is ubiquitously expressed
throughout the body
○ ALAS2 is expressed in erythrocyte precursor
cells.
● Formation of δ-aminolevulinate is rate-limiting for
porphyrin biosynthesis in mammalian liver (Figure
31–3).

● Following the exit of δ-aminolevulinate into the

cytosol, the reaction catalyzed by cytosolic ALA
dehydratase (EC 4.2.1.24; porphobilinogen synthase)
condenses two molecules of ALA, forming
porphobilinogen:
● A zinc metalloprotein, ALA dehydratase is
sensitive to inhibition by lead, as can occur in
lead poisoning.
IMPORTANT NOTES:
BILIRUBIN FORMATION
● Human adults normally destroy about 200 billion
erythrocytes per day. A 70-kg human therefore turns
over approximately 6 g of hemoglobin daily. All
products are reused.
● The globin is degraded to its constituent amino acids,
and the released iron enters the iron pool.
● The iron-free porphyrin portion of heme is also
degraded, mainly in the reticuloendothelial cells of
the liver, spleen, and bone marrow.
● The catabolism of heme from all heme proteins
takes place in the microsomal fraction of cells by
heme oxygenase, EC 1.14.18.18.
● The iron of the heme that reaches heme oxygenase
has usually been oxidized to its ferric form (hemin).
● Conversion of one mole of heme-Fe 3+ to
biliverdin, carbon monoxide, and Fe 3+ consumes
three moles of O 2 , plus seven electrons provided
by NADH and NADPH–cytochrome P450
reductase:
 ● Despite its high affinity for heme-Fe 2+, the
carbon monoxide produced does not
severely inhibit heme oxygenase.
● In humans, biliverdin reductase (EC
1.3.1.24) reduces the central methylene
bridge of biliverdin to a methyl group,
producing the yellow-pigment bilirubin
(Figure 31–11):
● Since 1 g of hemoglobin yields about 35 mg of
bilirubin, human adults form 250 to 350 mg of
bilirubin per day.
● This is derived principally from hemoglobin, and also
from ineffective erythropoiesis and from catabolism
of other heme proteins.
● Conversion of heme to bilirubin by reticuloendothelial
cells can be observed visually as the purple color of
the heme in a hematoma slowly converts to the
yellow pigment of bilirubin.
SUMMARY OF RATE LIMITING ENZYMES:
● Glycolysis: PHOSPHOFRUCTOKINASE-1
● Gluconeogenesis: FRUCTOSE-1,6-BIPHOSPHATE
● Glycogenesis: GLYCOGEN SYNTHASE
● Glycogenolysis:GLYCOGEN PHOSPHORYLASE
● HexoseMonophosphateShunt:
GLUCOSE-6-PHOSPHATE DEHYDROGENASE
● TCA Cycle: ISOCITRATE DEHYDROGENASE
● Lipogenesis: ACETYL-CoA CARBOXYLASE
● Lipolysis: CARNITINE PALMITOYL TRANSFERASE
● Ketogenesis: HMG-CoA SYNTHASE
REFERENCES
Textbook of Biochemistry for Medical Students, 9th ed
Harper's lllustrated Biochemistry, 32md ed
POINTERS
Pointers from doc Apiong
1. Dont further memorize the steps, MEMORIZE ONLY THE
1ST STEP, SUBSTRATE, PRODUCT AND RATE LIMITING
ENZYMES
2. Product sa HMS
3. ATPs of glycolysis, glucose, NADH, FADH
4. 4 complexes
5. Citric acid cycle
6. Shuttles
7. GIVE EMPHASIS glycolysis, urea cycle, hmp, beta
oxidation
Pointers from Doc Cantila:
1. Products
2. Rate limiting enzymes
Pointers from doc Litao
-Metabolism of carbs, proteins and amino acids- take note of
the products produced, used, and net
-most important carbohydrate is glucose
problem in the metabolism of fatty acid leads to obesity,
diabetes, fatty liver disease
-clinical cases
NAFLD (non-alcoholic fatty liver disease)
MAFLD (metabolic dysfunction associated fatty liver disease)
Pointers from doc murillo
1. Pathways Pointers from Doc Aspera
2. Enzymes
3. Rate limiting steps DEFINITION of
4. Other names of cofactors Bioenergetics
5. Products of pathways Free energy
Entropy
Pointers from Doc sumndad Enthalpy
1. Study substrates and products for each pathway
2. Fxn of each pathway Glycolysis & TCA Pathway
3. When ma use ang specific pathway example: first 24hrs, Rate limiting steps
unsay gamiton? Steps produce ATP & NADH
TCA poisons( Not sure)
4. Why man taas oxidation sa TCA? Complex I, III and IV
5. Stages for each pathway
6. Net gain atp for each pathway Aerobic ATP produce
7. LO 19-22 just read harpers Anerobic ATP produce
8. Beta oxidation products specifically palmitate
Biproducts of each reactions
9. Gross vs net gain
10. Implications if naay enzymes deficiency or inhibited
11. Cofactors in each cycle esp vitamins

GROUP 8: Doc Fuentes

POINTERS
1. Identify rate limiting steps
2. Glycolysis (reversible enzymes)
3. Glycolysis and Gluconeogenesis
4. Pathway where Pentose Phosphate Pathway inserts
5. Beta-Oxidation Rate limiting Steps
6. NADH and ATP produce every cycle
7. Co-Factors
8. ETC sequence
9. What inhibits ETC (medicine, toxins etc.)
10. Familiarize biosynthesis of Heme

Pointers from Doc Cababaros

1) Compute BMI
2) BMI Classification
3) Amino Acid Classification
4) All Reactions: How many ATP used & produced, Subtrate,
Enzyme, product & Rate limiting Rx