Metabolism: An Overview: Prof. Dr. Gerhard Grüber

Metabolism: An overview
Prof. Dr. Gerhard Grüber

Nanyang Technological University
School of Biological Sciences
Singapore 637551
GGrueber@ntu.edu.sg
BS2003 - Biochemistry II
1. We will provide our lectures electronically in time, so that you can decide to study its
contexts every Tuesday from 8:30-10:30 a.m. or maybe together with your colleagues at any
time with a fresh cup of tea or coffee and social distance. During the Covid19 pandemic we
realized, that technical problems occurred in a number of the streamline presentations or
meetings. We will announce the uploading of each e-lecture.
2. The Tutorials will start by the 16th of August online. More details will follow.
3. Practical Courses (week 8 + 9): The beauty of principles in carbohydrate catabolism and
All I have to know about lipids and fatty acids
4. Coffee-online session via Teams, where you can address additional questions
related to BS2003 or your general studies. We will update you soon about the respective
schedule and IT-issues.
Assessment Components:
1. Laboratories-written report 50%
2. Closed-book exam 50%; exams may be conducted in-person or in
e-mode
Learning Outcome
Identify the classes of organic molecules in our food.
Describe the metabolic processes of proteins, carbohydrates, fatty- and nucleic acids.
Classify the key catalysts, involved in metabolic processes.
Transfer of these enzymatic reactions to related organic reactions
Discuss the link of pathways in the digestions and synthesis of amino-, fatty- and nucleic
acids as well as carbohydrates.
Prof. Dr. G. Grüber Dr. A. Grüber

Coordinator Gruber@ntu.edu.sg
GGrueber@ntu.edu.sg
Recommended textbooks
Voet & Voet: Biochemistry 3rd edition, John Wiley & Sons
Mathews, van Holde, Ahern: Biochemistry 4th edition
Berg, Tymoczko & Stryer: Biochemistry 5th edition, Spectrum
Horton, Moran, Scrimgeour, Perry & Rawn: Principles of

Biochemistry - 4th edition
Essentials and Beauty of Biochemistry

Metabolism (from Greek: , "change") is the set of life-sustaining chemical reactions in
organisms. The three main purposes of metabolism are:
a) the conversion of food to energy to run cellular processes;
b) the conversion of food/fuel to building blocks for proteins, lipids, nucleic acids, and some
carbohydrates;
c) and the elimination of metabolic wastes.
Metabolism consists of literally hundreds of enzymatic reactions organized into discrete pathways.
These pathways proceed in a stepwise fashion, transforming substrates into end products through
many specific chemical intermediates. The course will give an understanding about the anabolic
and catabolic processes that satisfy the metabolic needs of the biological cell.
This course deals with the basic principles, pathways and regulation of metabolism required to
understand modern biological sciences. The lectures will cover introduction to metabolism and
regulation and enzyme catalysis, carbohydrate-, lipid-, amino acid- and nucleotide metabolism,
citric acid cycle, oxidative phosphorylation and photosynthesis.
Metabolic Fuels and Dietary Components
In order to survive, humans must meet two basic metabolic

requirements: We must be able to synthesize everything our
cells need that is not supplied by our diet, and we must be
able to protect our internal environment from toxins and
changing conditions in our external environment. In order to
meet these requirements, we metabolize our dietary
components through four basic types of pathways: fuel
oxidative pathways, fuel storage and mobilization
pathways, biosynthetic pathways, and detoxification or
waste disposal pathways.
The foods in our diet are the fuels that supply us with
An overview of the general
energy in the form of calories. metabolic routes for dietary
Our diet also must contain the compounds we cannot components in the body. The types
synthesize, as well as all the basic building blocks for of pathways are named in red.
compounds we do synthesize in our biosynthetic pathways.

For example, we have dietary requirements for some amino
acids, but we can synthesize other amino acids from our
fuels and a dietary nitrogen precursor. The compounds 4
Store
glucose glycogen
required in our diet for biosynthetic pathways include certain →
amino acids, vitamins, and essential fatty acids.

Detoxification pathways and waste disposal pathways are
metabolic pathways devoted to removing toxins that can be
present in our diets or in the air we breathe, introduced into
our bodies as drugs, or generated internally from the
metabolism of dietary components. Dietary components that
have no value to the body and must be disposed of are called
xenobiotics (from the Greek word "xenos" meaning stranger,
guest).
C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

Carbohydrates: Monosaccharides
Monosaccharides exist in solution mainly as ring structures in which the

carbonyl (aldehyde or ketone) group has reacted with a hydroxyl group in the
same molecule to form a five- or six-membered ring (see Fig. right). The oxygen
that was on the hydroxyl group is now part of the ring, and the original carbonyl
carbon, which now contains an OH group, has become the anomeric carbon
atom. A hydroxyl group on the anomeric carbon drawn down below the ring is
in the position; drawn up above the ring, it is in the position. In the actual
three-dimensional structure, the ring is not planar but usually takes a chair
conformation in which the hydroxyl groups are located at a maximal distance
from each other.
C, G C2
In solution, the hydroxyl group on the anomeric carbon spontaneously changes * -

anomeric
carbons
from the to the position through a process called mutarotation. When the
ring opens, the straight-chain aldehyde or ketone is formed. When the ring
closes, the hydroxyl group may be in either the or the position. This process
occurs more rapidly in the presence of cellular enzymes called mutarotases.
However, if the anomeric carbon forms a bond with another molecule, that
bond is fixed in the or position, and the sugar cannot mutarotate. Enzymes
are specific for or bonds between sugars and other molecules and react with
only one type.
Mutarotation of glucose in solution, with percentages of each form at equilibrium.

Carbohydrates
A disaccharide contains two monosaccharides joined by an O-glycosidic bond.
Lactose, which is the sugar in milk, consists of galactose and glucose linked
through a (1 4) bond formed between the OH group of the anomeric carbon
of galactose and the hydroxyl group on carbon 4 of glucose.
Oligosaccharides contain from 3 to roughly 12 monosaccharides linked

together. They are often found attached through N- or O-glycosidic bonds to
proteins to form glycoproteins. Polysaccharides contain tens to thousands of
monosaccharides joined by glycosidic bonds to form linear chains or branched
structures. Starch is an example of a branched polymer of glucosyl residues
linked through (1 4) and (1 6) bonds.
The hydroxyl group on the anomeric carbon of a monosaccharide can react also
with an NH group of another compound to form a N-glycosidic bond. N-
glycosidic bonds are found in nucleosides and nucleotides. For example, in the
adenosine moiety of adenosine triphosphate (ATP), the nitrogenous base adenine
is linked to the sugar ribose through a -N-glycosidic bond.

The three key polymers made from glucose monosaccharides
Hard to digest because of B (1-4) bonds .
→
Cellulose is a structural polysaccharide that is found in the cell wall of plants.
It is a linear molecule composed of -glucose subunits (1-4 arrangement).
Because it is composed of -glucose, it is indigestible for most animals (lack
the enzyme required to break it down)
Starch is an energy storage polysaccharide found in plants.

It is composed of -glucose subunits (1-4 arrangement) and exists in one of
two forms amylose or amylopectin
Amylose is a linear (helical) molecule while amylopectin is branched
(contains additional 1-6 linkages)
Amylose is harder to digest and less soluble, however, as it takes up less
space, is the preferred storage form in plants.
Glycogen is an energy storage polysaccharide formed in the liver in animals.

It is composed of -glucose subunits linked together by both 1-4 linkages and
1-6 linkages (branching).
It is akin to amylopectin in plants, but is more highly branched (1-6 linkages
occur every ~10 subunits as opposed to ~20).
Molecular images of the polymers
Cellulose Amylose Amylopectin Glycogen
https://ib.bioninja.com.au/standard-level/topic-2-molecular-biology/23-carbohydrates-and-lipids/sugar-polymers.html
Energy content of food constituents
Stored metabolic fuel in a 70-kg person
Two important advantages for storing energy in the form of fatty

acids: 1. The carbon in fatty acids (mostly CH2-groups) is almost
completely reduced compared to the carbon in sugars or amino
acids. Therefore, oxidation of fatty acids will yield more energy in
form of ATP than any other form of carbon. 2. Fatty acids are not
generally as hydrated as monosaccharides are, and thus they can
7
pack more closely in storage tissues.
1-Palmitoyl-2,3-dioleoyl-glycerol
Chemically fatty acids

,
are in their reduced form
therefore oxidation of
F- A willyield more ATP .
Voet, Voet: BIOCHEMISTRY 3rd edition

Garett & Grisham: Biochemistry 4th edition
Saturated fatty acids and unsaturated fatty acids
(A) The carbons are either numbered starting with the carboxyl
group or given Greek letters starting with the carbon next to the
carboxyl group. The methyl (or carbon at the end of the chain
is always called the -carbon, regardless of the chain length.
The symbol 18:0 refers to the number of carbon atoms (18) and
the number of double bonds (0). In the unsaturated fatty acids
shown, not all of the carbons are numbered, but note that the
double bonds are cis and spaced at three-carbon intervals. Both
3 and 6 fatty acids are required in the diet.
(B) Cis- and trans double bonds in fatty acid side chains. Note
that the cis double bond causes the chain to bend. The double
bonds in most naturally occurring fatty acids are in the cis
configuration (Fig. right). The designation cis means that the
hydrogens are on the same side of the double bond and the acyl
chains are on the other side. In trans-fatty acids, the acyl
chains are on opposite sides of the double bond. Margarine and
the fat used in preparing French fries are probably the major
sources of trans-fatty acids found in humans. Trans-fatty acids
are produced by the chemical hydrogenation of polyunsaturated
fatty acids in vegetable oils and are not a natural food product.
The melting point of a fatty acid increases with chain length
and decreases with the degree of unsaturation. Thus, fatty acids
with many double bonds, such as those in vegetable oils, are
liquid at room temperature; and saturated fatty acids, such as
those in butterfat, are solids. Lipids with lower melting points
are more fluid at body temperature and contribute to the fluidity
of our cellular membranes.
* Double bond → lower melting temp
* Length ✗ melting point .

Amino acids and peptide formation
Max.
Absorption
(nm)
Trp 280
Tyr 274
Phe 257
The planar peptide group. Three bonds separate sequential -carbons in a polypeptide
chain. The N- and -C bonds can rotate with bond angles designated and
respectively. The peptide C-N bond is not free to rotate. Other single bonds in the backbone
may also be rotationally hindered, depending on the size and charge of the rest (R) groups.
In the conformation shown, and are 180° (or -180°). As one looks out from the -
carbon, the and angles increase as the carbonyl or amide nitrogens (respectively) rotate
clockwise.
t
charged residues can be protonated or deprotonated .

David L. Nelson, Michael M. Cox: Lehninger Principles of Biochemistry, 4th edition
The Acidic and Basic Amino Acids
The charge on amino acids at physiologic pH is a function of

their pKa for dissociation of protons from the -carboxylic
acid groups, the -amino groups, and the side chains. The
titration curve of histidine illustrates the changes in amino acid
structure that occurs as the pH of the solution is changed from
<1 to 14 by the addition of hydroxide ions ((OH ) Fig. right).
At low pH, all groups carry protons; amino groups have a
positive charge, and carboxylic acid groups have zero charge.
As the pH is increased by the addition of hydroxide ions, the
proton dissociates from the carboxylic acid group, and its
charge changes from zero to negative one with a pKa of
approximately 2, the pH at which 50% of the protons have
dissociated.
The histidine side chain is an imidazole ring with a pKa of
approximately 6 that changes from a predominantly protonated
positively charged ring to an uncharged ring at this pH. The
amino group on the -carbon titrates at a much higher pH
(between 9 and 10), and the charge changes from positive one
to zero as the pH rises. The pH at which the net charge on the
molecules in solution is zero is called the isoelectric point
(pI). At this pH, the molecules will not migrate in an electric
field toward either a positive pole (cathode) or a negative pole ~
(anode), because the number of negative charges on each

Overall charge 0
molecule is equal to the number of positive charges.
.

Dissociation of the side chains of the amino acids
As the pH increases, the charge on the side chain goes from 0 to or from + to 0.
The pKa is the pH at which half the molecules of an amino acid in solution have
side chains that are charged. Half are uncharged.

pH Scale
0
1
Battery acid
Increasingly Acidic
2 Gastric juice, lemon juice
H
H
[H ] [OH ]
3 Vinegar, wine,
H
H OH
OH H H cola
H H
Acidic 4 Tomato juice

solution Beer
5 Black coffee
Rainwater
6 Urine
OH
OH Saliva
H H OH
Neutral 7 Pure water
OH OH
H
[H ] [OH ] Human blood, tears
H H
8 Seawater
Neutral
Inside of small intestine
solution
Increasingly Basic
9
[H ] [OH ]
10
OH
Milk of magnesia
OH
OH H OH
11
OH OH
OH
Household ammonia
H
12
Basic
Household
solution 13 bleach
Oven cleaner
14
© 2017 Pearson Education, Ltd.
Levels of structure in a protein
Protein structure is described in terms of four different levels: primary, secondary, tertiary, and
quaternary. The primary structure of a protein is the linear sequence of amino acids in the
polypeptide chain. The secondary structure consists of local regions of polypeptide chains
formed into structures that are stabilized by a repeating pattern of hydrogen bonds, such as the
regular structures called -helices and -sheets. The rigidity of the peptide backbone determines
the types of secondary structure that can occur. The tertiary structure involves folding of the
secondary structural elements into an overall three-dimensional conformation. In globular
proteins such as myoglobin, the tertiary structure generally forms a densely packed hydrophobic
core with polar amino acid side chains on the outside. Some proteins exhibit quaternary
structure, the combination of two or more subunits, each composed of a polypeptide chain.

Enzymes as catalysts
Reaction in the enzyme active catalytic site (Fig. right). (A)

The enzyme contains an active catalytic site, shown in dark
red, with a region or domain where the substrate binds. The
active site also may contain cofactors, nonprotein
components that assist in catalysis. (B) The substrate forms
bonds with amino acid residues in the substrate-binding site.
Substrate binding induces a conformational change in the
active site. (C) Functional groups of amino acid residues and
cofactors in the active site participate in forming the
transition-state complex, which is stabilized by additional
noncovalent bonds with the enzyme, shown in red. (D)
Because the products of the reaction dissociate, the enzyme
returns to its original conformation.
Enzymes are proteins that act as catalysts, compounds that increase the rate
of chemical reactions (Fig. right). Enzyme catalysts bind reactants
(substrates), convert them to products, and release the products. Many
enzymes increase the rate of a chemical reaction by a factor of 1011 or
higher. To appreciate an increase in reaction rate by this order of magnitude,
consider a room-sized box of golf balls that by releasing energy and
turning brown. The 12 ft × 12 ft × 8 ft box contains 380,000 golf balls. If the
rate of the reaction in the absence of enzyme were 100 golf balls per year, the
presence of 1 molecule of enzyme would turn the entire box of golf balls
brown in 1 second (assuming a 1011 increase in reaction rate).

Antibiotic penicillin is a transition-state analog
The antibiotic penicillin is an example of a transition-state

analog that binds very tightly to glycopeptidyl
transferase, an enzyme required by bacteria for synthesis
of the cell wall (Fig. right). The enzyme normally cleaves
the peptide bond between two D-alanine residues in a
polypeptide. Penicillin contains a strained peptide bond
within the -lactam ring that resembles the transition state
of the normal cleavage reaction, and thus penicillin binds
very readily in the enzyme active site. As the bacterial
enzyme attempts to cleave this penicillin peptide bond,
penicillin becomes irreversibly covalently attached to the
active-site serine, thereby inactivating the
enzyme.

Coenzymes in Catalysis
Coenzymes (cofactors) are complex nonprotein organic molecules that participate in catalysis by providing functional groups, much like
the amino acid side chains. In the human, they are usually (but not always) synthesized from vitamins. Each coenzyme is involved in
catalyzing a specific type of reaction for a class of substrates with certain structural features. Coenzymes can be divided into two general
classes: activation-transfer coenzymes and oxidation reduction coenzymes.
1. Activation-Transfer Coenzymes
The activation-transfer coenzymes usually participate directly in catalysis by forming a
covalent bond with a portion of the substrate; the tightly held substrate moiety is then
activated for transfer, addition of water, or some other reaction. The portion of the
coenzyme that forms a covalent bond with the substrate is its functional group. A separate
portion of the coenzyme binds tightly to the enzyme.
Thiamine pyrophosphate (TPP, see Fig. below), Coenzyme A (CoA), biotin, and
pyridoxal phosphate are examples of activation-transfer coenzymes synthesized from
vitamins.
Thiamine pyrophosphate (TPP)
Never forget me!

Coenzymes in Catalysis
2. Oxidation Reduction Coenzymes

A large number of coenzymes are involved in oxidation reduction reactions catalyzed by enzymes categorized as
oxidoreductases. When a compound is oxidized, it loses electrons. As a result, the oxidized carbon has fewer H
atoms or gains an O atom. The reduction of a compound is the gain of electrons, which shows in its structure as
the gain of H or loss of O. Some coenzymes, such as nicotinamide-adenine dinucleotide (NAD+) and flavin
adenine dinucleotide (FAD), can transfer electrons together with hydrogen and have unique roles in the
generation of ATP from the oxidation of fuels.
simultaneously .
oxidation Ee reduction takes place

have donor Ee
acceptor ]
I need to
Nicotinamide-adenine dinucleotide (NAD+)

Regulation Matches Function
In the human body, thousands of diverse enzymes are regulated to

fulfill their individual functions without waste of dietary
components. Changes in the rate of a metabolic pathway occur
because at least one enzyme in that pathway, the regulatory enzyme,
has been activated or inhibited, or the amount of enzyme has
increased or decreased. Regulatory enzymes usually catalyze the
rate-limiting, or slowest, step in the pathway, so that increasing or
decreasing their rate changes the rate of the entire pathway (Fig.
right). The mechanisms used to regulate the rate-limiting enzyme in
a pathway reflect the function of the pathway.
The flux of substrates down a metabolic pathway is analogous to
cars traveling down a highway (Fig. right). The rate-limiting enzyme
is the portion of the highway that is narrowed to one lane by a
highway barrier. This single portion of the highway limits the rate at
which cars can arrive at their final destination miles later. Cars will
back up before the barrier (similar to the increase in concentration of a
precursor when a rate-limiting enzyme is inhibited). Some cars may
exit and take an alternate route (similar to precursors entering another
metabolic pathway). Moving the barrier just a little to open an
additional lane is like activating a rate-limiting enzyme: It increases
flow through the entire length of the pathway.

The Michaelis-Menten Equation
The velocity of all enzymes is dependent on the concentration of

substrate. This dependence is reflected in conditions such as
starvation, in which several pathways are deprived of substrate. In
contrast, storage pathways (e.g., glucose conversion to glycogen in
the liver) and toxic waste disposal pathways (e.g., the urea cycle,
which prevents NH4+ toxicity by converting NH4+ to urea) are
normally regulated to speed up when more substrate is available.
The Michaelis-Menten equation describes the response of an
enzyme to changes in substrate concentration (Fig. right). This
equation relates the initial velocity (vi) to the concentration of
substrate [S] and the two parameters Km and Vmax. The Vmax of the
enzyme is the maximal velocity that can be achieved at an infinite
concentration of substrate, and the Km of the enzyme for a substrate
is the concentration of substrate required to reach ½Vmax. The
graph of the Michaelis-Menten equation is a rectangular
hyperbola that approaches a finite limit.

Regulation of enzyme activity
1. Allosteric regulation (Feedback control)

2. Regulation by covalent modification
3. Regulation by proteolytic cleavage
4. Regulation by isoenzymes
5. Regulation by availability
6. Regulation by compartmentation
7. Hormonal regulation
Two types of allosteric interaction
Heterotropic interaction (heteroallostery): when effector molecules are

different from the substrate molecules.
Homotropic interaction (homoallostery): when binding of one substrate
molecule to an active site alters the binding properties of the other
(identical) substrate molecules in the same enzyme.
Hemoglobin, although not an enzyme, is a classic example of homotropic
allosteric interaction.
Allosteric interaction
Allosteric interaction represents a sigmoid plot between the

rate of reaction and the substrate concentration.
has only one binding site .
Mb →
y
1st site
↳ 4 binding site SObinding to the
Hb has
increased binding
.
this can trigger

slow but
might be
3 sites positive cooperation

to the other
.
0
sigmoid curve .
Alteration in one hemoglobin subunit before O2 binding
oxygen enters
the heme /iron
> Before
in its planar form
slightly on top
.
is
Alteration in one hemoglobin subunit after O2 binding
enters heme is lying

> Once Oxygen ,
axis
planar
.
within the

Regulation by covalent modification
Catalytic activities of enzymes are altered by reversible, covalent

changes to specific amino acid side chains in the enzyme. Common used
modifications are:
Phosphorylation of -OH groups of Ser, Thr or Tyr.
Attachment of AMP to a similar -OH group.
Attachment of ADP-ribosyl group to Arg, Gln or Cys.
Methylation of Glu.
Reduction of cysteine disulfide bonds.
Covalent modification itself is an enzymatic reaction.

In general, by covalent modification, an enzyme is made
either completely active or completely inactive.


Enzyme regulation by compartmentation
ENDOPLASMIC RETICULUM (ER) Nuclear
Smooth ER envelope
Nucleolus NUCLEUS
Flagellum Rough ER
Chromatin
Centrosome
Plasma
membrane
CYTOSKELETON:
Microfilaments
Intermediate Ribosomes
filaments (small brown
Microtubules dots)
Golgi apparatus
Microvilli
Peroxisome
Lysosome
© 2017 Pearson Education, Ltd. Mitochondrion
Regulation by compartmentation
Many enzymes are regulated by localizing them in specific compartments

within a cell.
pH-rate profiles for pepsin and HIV protease

Pepsin (pepsis
the chief cells of the stomach lining. The enzyme
uses a catalytic aspartate in its active site.

Coffee break
Energy-related organelles
S. S. Mader, Inquiry Into Life

Overview of metabolism
The metabolic map shown here is

the basic road map for this course.
It reveals the central pathways and
some intermediates. The catabolic
pathway (red) proceed downward
and anabolic pathways (blue)
p r o c e e d u p w a r d .
Mathews, van Holde, Ahern: Biochemistry 3rd edition

Integration of metabolism among major organs
Each organ has unique metabolic

needs, which must be coordinated in a
variety of organs to maintain a
constant supply of energy while
preserving some energy for the future.
The body uses the nervous system and
hormonal signals to differentially
stimulate and inhibit biochemical
pathways. The main signals used to
regulate metabolism are insulin,
glucagon, catecholamine, gluco-
corticoids, and growth hormone (in
children).
The liver actively provides the
quick fuel (glucose) the body needs,
whereas adipose tissue provides long-
term energy storage. Finally, skeletal
muscle and the rest of the body
constantly demand the energy.
L. W. Janson & M. E. Tischler, THE BIG PICTUTE: MEDICAL BIOCHEMISTRY 1st edition
Transport and fate of major carbohydrates and amino acids
Transport and fate of major lipid substrates and metabolites
In most tissues, lipids serve a primary

role as the components of biological
membranes.
In adipose tissues, triglycerides (TG)
are the major storage form of
biological energy. Lipolysis of
triglycerides mobilizes fatty acids that
generate energy through -oxidation
and produces the substrates necessary
for ketone body synthesis, an essential
fuel source during prolonged
starvation.
The consumption of dietary
cholesterol and fats has a large impact
on lipid metabolism through the
generation of plasma lipoproteins
[chylomicrons and low-density
lipoproteins (LDL) via very-low-
density lipoproteins (VLDL)].
Energy relationship between the pathways of catabolism and anabolism
Metabolism serves two fundamentally different purposes: the generation of energy to drive vital
functions and the synthesis of biological molecules. To achieve these end, metabolism consists
largely of two contrasting processes; catabolism and anabolism. Both processes occur
simultaneously in the cell and are controlled (i) by the tight and separate regulation of both
catabolism and anabolism, so that metabolic needs are served in an immediate and orderly
fashion. (ii) Competing metabolic pathways are often localized within different cellular
compartments. Isolating opposing activities within distinct
compartments, such as separate organelles, avoids interference between them.

NADH and NADPH as sources of free energy
Never forget me!
The structures and reaction of nicotinamide-adenine dinucleotide (NAD+)

and nicotinamide adenine dinucleotide phosphate (NADP+).

ATP serves in a cellular energy cycle
ATP is the energy currency of the cell. It

provides the energy that drives the manifold
activities of all living cells-the synthesis of
complex biomolecules, the osmotic work
involved in transporting substances into cells,
the work of cell motility, and the work of muscle
contraction. These diverse activities are all
powered by energy released in the hydrolysis of
ATP to ADP and inorganic phosphate (Pi). There
is an energy cycle in cells where ATP serves as
the vessel carrying energy from photosynthesis
or catabolism to the energy-requiring processes
unique to living cells.
The structure of ATP indicating its relationship to ADP, AMP, and adenosine.
Never forget me!

Corresponding pathways of cata- and anabolism differ in regulation
(a) (b)
A second reason for different pathways serving the opposite metabolic directions is that such pathways
must be independently regulated. If catabolism and anabolism passed along the same set of metabolic
tracks, equilibrium considerations would dictate that slowing the traffic in one direction by inhibiting a
particular enzymatic reaction would necessarily slow traffic in the opposite direction. Independent
regulation of anabolism and catabolism can be accomplished only if these two contrasting processes move
along different routes or, in the case of shared pathways, the rate-limiting steps serving as the points of
regulation are catalyzed by enzymes that are unique to each opposing sequence.
The figure above shows two possible arrangements of opposing catabolic and anabolic sequences
between A and P. (a) The parallel sequences proceed via independent routes. (b) Only one reaction has
two different enzymes, a catabolic one (E3) and its anabolic counterpart (E6). These provide sites for
regulation.

Multienzyme systems carrying out a metabolic pathway
The individual metabolic pathways consist of

sequential enzymatic steps. Several types of
organization are possible. (a) The enzyme of
some multienzyme systems may exist as
physically separate, soluble entities, with
diffusing intermediates. In other instances, (b)
the enzymes of a pathway are collected to form
a discrete multienzyme complex, and the
substrate is sequentially modified as it is passed
along from enzyme to enzyme. This type of
organization has the advantage that
intermediates are not lost or diluted by diffusion.
(c) In a third pattern of organization, the
enzymes common to a pathway reside together
as a membrane-bound system. In this case the
enzyme partners (and perhaps the substrates as
well) must diffuse in just the two dimensions of
the membrane to interact with their neighbors.

Metabolic pathways are compartmentalized within cells
Each compartment is dedicated to specialized

me t a boli c fun ction s, and th e enz yme s
appropriate to these specialized functions are
confined together within the organellar
membrane. Thus, the flow metabolic
intermediates in the cell is specially as well as
chemically segregated. For example, the 10
enzymes of glycolysis are found in the cytosol,
but pyruvate, the product of glycolysis, is fed
into the mitochondria. These organelles contain
the citric acid cycle enzymes, which oxidize
pyruvate to CO2.
Compartmentalization of glycolysis, the

TCA cycle, and oxidative phosphorylation

State of reduction of carbon atoms in biomolecules
of
-
loss e
More reduced state s Less reduced state
Fats Carbohydrates Carbonyls Carboxyls

Carbon
dioxide
In living systems most of the energy needed to drive biosynthetic reactions is derived from the oxidation of
organic substrates. Oxygen, the ultimate electron acceptor for aerobic organisms, is a strong oxidant; it has the
tendency to attract electrons, becoming reduced in the process, e.g.:
C6H12O6 + 6 O2 2 + 6 H2O -2823 KJ/mol
The substrates of catabolism - proteins, carbohydrates, and lipids - are good sources of chemical energy, because
the carbon atoms in these molecules are in a relatively reduced state. In the oxidative reactions of catabolism,
reducing equivalents are released from these substrates, often in the form of hydride ions (a proton coupled
with two electrons, H:-). These hydride ions are transferred in enzymatic dehydrogenase reactions from
substrates to NAD+ molecules, reducing them to NADH. A second proton accompanies these reactions,
appearing in the overall equation as H+.

Biochemical reaction types
There is no metaphysics in biochemistry - the chemistry of living systems follows the

same chemical and physical laws as the rest of nature. The complexity of these
biochemical pathways may at first glance seem overwhelming, but only five general
types of chemical transformations are commonly used in cells:
Nucleophilic substitution
Nucleophilic additions
Carbonyl condensations
Eliminations
Oxidations and reductions
Much of the chemistry in biological molecules is the chemistry of the carbonyl group (C=O) because the vast majority
of biological molecules contains them. And most of the chemistry of carbonyl groups involves nucleophiles (Nu:) and
electrophiles. Recall that a nucleophile is a - substance with a negatively polarized, electron-rich
atom that can form a bond by donating a pair of electrons to an electron-poor atom. An electrophile is an -
substance with a positively polarized, electron-poor atom that can form a bond by accepting a pair of electrons
from an electron-rich atom. Carbonyl groups are polar, with the electron-poor C-atom bearing a partial positive
charge and the electron-rich O-atom bearing a partial negative charge.
Never forget me!

Carbonyl carbons are very common

electrophiles in biochemistry reactions.
Other common electrophiles are
protonated imines, phosphate groups,
and protons.
Never forget me!

Oxyanions, carbanions, deprotonated

amines, and the imidazole side chain
of histidine are common nucleophiles
in biochemical reactions.
Never forget me!

The formation and function of molecules depend on
chemical bonding between atoms
Atoms with incomplete valence shells can share or transfer valence electrons with certain other atoms
This usually results in atoms staying close together, held by attractions called chemical bonds
Animation: Covalent Bonds

Ionic Bonds
Atoms sometimes strip electrons from their bonding partners

An example is the transfer of an electron from sodium to chlorine
After the transfer of an electron, both atoms have charges and are called ions
Both atoms also have complete valence shells
Animation: Ionic Bonds

Quiz
1. Name the three principal modes of enzyme organization in metabolic pathway?
(a) The enzyme may exist as physically separate, soluble entities

(b) The enzymes of a pathway are collected to form a discrete multienzyme complex
(c) The enzymes common to a pathway reside together as a membrane-bound system.
2. What are the advantages of compartmentalizing particular metabolic pathways

within specific organelles?
1) Otherwise uncontrolled behaviour is regulated.
2) diffusion is restricted, product of one reaction is released
close to the next enzyme in a pathway;
3) selective permeability of the membrane can control the rate of
movements of metabolites;
4) ion-gradients formed by certain enzymatic reaction can
influence other enzymatic reactions.
Quiz
3. What are the five general types of chemical transformations commonly used in cells?
Nucleophilic additions
Carbonyl condensations
Eliminations
Oxidations and reductions
Quiz
the following amino acid substitutions at this position could lead to a permanent alteration in
normal enzyme activity?
Thank you!

Metabolism: An Overview: Prof. Dr. Gerhard Grüber

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Metabolism: An Overview: Prof. Dr. Gerhard Grüber

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Metabolism: An overview

Prof. Dr. Gerhard Grüber

Prof. Dr. G. Grüber Dr. A. Grüber

Mathews, van Holde, Ahern: Biochemistry 4th edition

Berg, Tymoczko & Stryer: Biochemistry 5th edition, Spectrum

Horton, Moran, Scrimgeour, Perry & Rawn: Principles of

Essentials and Beauty of Biochemistry

In order to survive, humans must meet two basic metabolic

compounds we do synthesize in our biosynthetic pathways.

amino acids, vitamins, and essential fatty acids.

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

Monosaccharides exist in solution mainly as ring structures in which the

In solution, the hydroxyl group on the anomeric carbon spontaneously changes * -

Mutarotation of glucose in solution, with percentages of each form at equilibrium.

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

Oligosaccharides contain from 3 to roughly 12 monosaccharides linked

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

Starch is an energy storage polysaccharide found in plants.

Glycogen is an energy storage polysaccharide formed in the liver in animals.

Molecular images of the polymers

Cellulose Amylose Amylopectin Glycogen

Stored metabolic fuel in a 70-kg person

Two important advantages for storing energy in the form of fatty

Chemically fatty acids

Voet, Voet: BIOCHEMISTRY 3rd edition

* Length ✗ melting point .

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

The charge on amino acids at physiologic pH is a function of

(anode), because the number of negative charges on each

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

Acidic 4 Tomato juice

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

Reaction in the enzyme active catalytic site (Fig. right). (A)

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

The antibiotic penicillin is an example of a transition-state

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

Thiamine pyrophosphate (TPP)

Never forget me!

2. Oxidation Reduction Coenzymes

oxidation Ee reduction takes place

Nicotinamide-adenine dinucleotide (NAD+)

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

In the human body, thousands of diverse enzymes are regulated to

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

The velocity of all enzymes is dependent on the concentration of

C. M. Smith, A. D. Marks & M. A. Liebermann , 7th edition

1. Allosteric regulation (Feedback control)

Heterotropic interaction (heteroallostery): when effector molecules are

Allosteric interaction represents a sigmoid plot between the

has only one binding site .

this can trigger

3 sites positive cooperation

enters heme is lying

1. Allosteric regulation (Feedback control)

Catalytic activities of enzymes are altered by reversible, covalent

Covalent modification itself is an enzymatic reaction.

1. Allosteric regulation (Feedback control)

1. Allosteric regulation (Feedback control)

Many enzymes are regulated by localizing them in specific compartments

pH-rate profiles for pepsin and HIV protease

1. Allosteric regulation (Feedback control)