Biocehemistry 2.

1 24 July 2012
Introduction to Metabolism Dr. Balcueva

OUTLINE
A. Learning Objectives Catabolic Anabolic
B. Metabolism
GLYCOLYSIS aerobic: glucose to GLYCOGENESIS synthesis of
C. Metabolic Pathways
pyruvate to acetyl CoA; glycogen from glucose
D. Carbohydrate Metabolism
anaerobic: glucose to lactate GLUCONEOGENESIS synthesis of
E. Lipid Metabolism
β-OXIDATION fatty acids to acetylCoA; glycogen from pyruvate
F. Amino Acid Metabolism
makes NADH/H+ and FADH2 for PALMITATE BIOSYNTHESIS
G. Metabolic Pathways may be Studied at Different Levels of
chemiosmotic production of ATP synthesis of fatty acid from
Organization
CITRIC ACID CYCLE oxidation of acetyl acetyl CoA
H. Metabolites Must be Regulated in a Concerted Manner
CoA producing NADH/H+ and FADH2 NONESSENTIAL AMINO ACID
I. Metabolic Fuel Reserves are Mobilized in the Fasting
for chemiosmotic production of ATP; BIOSYNTHESIS aminotransferase
State
all three food groups converge here reactions from α-ketoacids
J. In the Fed State
ELECTRON TRANSPORT CHAIN PURINE AND PYRIMIDINE
K. Patterns of Metabolic Regulation
electrons passed down to oxygen; NUCLEOTIDE BIOSYNTHESIS ring
L. Clinical Correlation
proton gradient across mitochondrial structures from nitrogen donors
LEARNING OBJECTIVES inner membrane proton gradient PROTEIN BIOSYNTHESIS
General Objective: trapped to make ATP from ADP and Pi translation
To explain thoroughly how cells carry out and regulate complex (chemiosmotic coupling) NUCLEIC ACID BIOSYNTHESIS
reaction sequences AMINO ACID CATABOLISM replication, transcription
redistribution or reduced nitrogen;
Specific Objectives: elimination of excess by urea cycle
1. To be able to differentiate between anabolic and catabolic
pathways. • Intermediary Metabolism
2. To be able to explain briefly how carbohydrates, lipids and - Applied to reactions involving the low molecular weight
proteins are metabolized
molecules that are metabolites in the degradation and/or
3. To be able to correlate relationships between each
pathways. biosynthesis of biopolymers
- “between substrate and product”
METABOLISM
• Entire network of chemical reactions carried out by living cells.
• Energy Metabolism
• Living cells carry out thousands of reactions simultaneously
• Each reaction sequence is controlled so that unwanted - Part of the intermediary metabolism consisting of pathways that
accumulations or deficiencies of intermediate products do not store or generate metabolic energy
occur - Most organisms derive both the raw materials and the energy
• Metabolism includes: from organic fuel molecules such as glucose.
a. interconversion of chemical compounds in the body - reducing equivalents released by Citric Acid Cycle stored in NAD
b. pathways taken by molecules and FADH2
c. interrelationships between the pathways
d. regulating mechanisms METABOLIC PATHWAYS
• divided into 3 categories: - Sequences of reactions that include the reactants, intermediates,
a. Catabolic products and the enzymes involved.
- Process related to degradation of complex substances - 4 major groups of biomolecules whose metabolic pathways are
to liberate smaller molecules and energy; considered separately:
- Exothermic, commonly involving oxidative reactions a. carbohydrates – Main source of energy in the body in
producing reducing equivalent the form of glucose.
- e.g. Degradation of CHON to AA; Triglycerides to fatty b. proteins
acids; Glucose to pyruvate c. fats
b. Anabolic d. nucleotides
- Processes concerned primarily with synthesis of • Acetyl-CoA is the common product of the metabolism of all
complex organic molecules needed for cell products of digestion, which then goes to Kreb’s cycle to give
maintenance, growth and reproduction; are off ATP
endothermic • consumed with release of 2 CO2
- e.g. glycogenolysis • cannot be utilized once used
c. Amphibolic
- Act as links between anabolism and catabolism; they
are at the “crossroad” between the 2 pathways;
e.g. citric acid cycle (actually catabolic but intermediates can be used
as precursor of other reactions)

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 Biocehemistry 2.1 24 July 2012
Introduction to Metabolism Dr. Balcueva

Metabolic Process - Source of ribose for nucleotide and nucleic acid synthesis
o depends on the nature of the diet - For RBC maintenance
o requirement for metabolic fuel is relatively constant (physical - Liver and skeletal muscle: reduction of glutathione
activity increases metabolic rate by 40-50% over the basal - Alternative pathway for glycolysis
metabolism) C. Triacylglycerol (TAG) pathway
o Need to form glycogen and triacylglycerides to provide for energy - Triose phosphate → glycerol moiety of triacylglycerols
in between meals. D. Amino acid synthesis
• Obesity – if intake of metabolic fuels is greater than o Via pyruvate and intermediates of citric acid cycle (α-
expenditure ketoglutarate, and oxaloacetate)
• Emaciation – if intake is consistently lower than expenditure; E. Steroid synthesis
may lead to wasting  death o Since acetyl-CoA is a precursor of fatty acids and cholesterol
F. Glycogenesis
o Formation of glycogen (storage for glucose in the liver and
skeletal muscle)
o The pathway when there is too much glucose
o Glycogenolysis – opposite of glycogenesis which forms glycogen
back to glucose; pathway when there is little amount of glucose

Metabolic Fuels
 Fed state – metabolic fuel is glucose
 Fasting state – glycogen, fatty acids amino acids,
ketone bodies (glycogen in liver will not supply muscles with
energy for physical activities, but can regulate blood glucose
levels)
 Major Hormones that control utilization of fuel:
- Insulin (beta cells), stimulated by high blood glucose level
- Glucagon (alpha cells), stimulated by low blood glucose level

CARBOHYDRATE METABOLISM
• Glucose is a major fuel of most tissues
Pathways present:
A. Glycolysis
- Converted to pyruvate acetyl CoA  CO2 + H2O
- Can occur anaerobically (oxygen absent) but instead of
glucose, the product will be lactate Gluconeogenesis: synthesis of glucose from non-carbohydrate
- Linked to oxidative phosphorylation and thus, also sources (lactate, amino acids, glycerol)
producing ATP (Aerobic tissues metabolize pyruvate to acetyl-CoA Liver maintains blood glucose levels by
 enter the citric acid cycle for complete oxidation to CO2 and H2O, a. Glycogenolysis
linked to the formation of ATP) b.Gluconeogenesis
B. Pentose phosphate pathway Pyruvate – Main product of aerobic glycolysis
- Also called hexose monophosphate shunt/pathway or HMS/H Lactate – Main product of anaerobic glycolysis
MP for short
- Another source of reducing equivalents but instead NADPH is
used for fatty acid synthesis

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 Biocehemistry 2.1
Introduction to Metabolism
LIPID METABOLISM
Figure 1.2 overview of fatty acid metabolism showing the major
pathways and end products.
The ketone bodies are acetoacetate, 3-hydroxybutyrate, and
acetone.
• Lipid metabolism is concerned mainly with Fatty acids and
Cholesterol
• Dietary lipid or de novo synthesis from acetyl-CoA (derived
from carbohydrate or amino acids: source of long-chain fatty
acids
• Fatty acids may be:
o oxidized to acetyl-CoA (β-oxidation)
o Esterified with glycerol, forming triacylglycerol (fat) as the
body's main fuel reserve.
• Acetyl-CoA formed by β-oxidation may undergo three fates:
a. As with acetyl-CoA arising from glycolysis, it is
oxidized to CO2 + H2O via the citric acid cycle, w/
reducing equivalents
b. It is the precursor for synthesis of cholesterol and
other steroids.
c. In the liver, it is used to form ketone bodies
(acetoacetate and 3 hydroxybutyrate) that are
important fuels in prolonged fasting.
AMINO ACID METABOLISM
Amino acids – for protein synthesis and synthesis of non-protein
nitrogen derivatives
Fates of amino acids:
a. Oxidized to CO2 and H2O – carbon skeleton
b. Gluconeogenesis – non-glucose source: alanine
c. Form ketone bodies
 Amino group of amino acid is always eliminated (not stored in
the body->converted to UREA then excreted in URINE)
 2 types:
o Essential amino acid – supplied via diet
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24 July 2012
Dr. Balcueva
o Non-essential – can be formed from metabolic
intermediates by transamination
DEAMINATION: ammonia is converted to its non-toxic form which
is urea and then excreted outside as urine
o ↑protein intake – ↑urea = kidney damage
o Carbon skeleton of amino acid is recycled via:
 Oxidation to CO2 via citric acid cycle
 Forms glucose (gluconeogenesis)
 Form ketone bodies (can be a source of fuel for
the brain)
Figure 2.3 Overview of amino acid metabolism showing the major pathways and end
products.
METABOLIC PATHWAYS MAY BE STUDIED AT DIFFERENT LEVELS OF
ORGANIZATION
• Tissue and organ level – nature of substrates entering and
metabolites leaving tissues and organs = defined
• Subcellular level – each cell organelle has specific roles that
form part of a subcellular pattern of metabolic pathways
A. Tissue and Organ Level: Blood Circulation Integrates
Metabolism
 Amino acids and glucose- absorbed via the hepatic portal vein
 Liver
o regulates blood concentration of water-soluble
metabolites via (especially vital for brain and RBC):
 Glycogenesis
 Lipogenesis
 Glycogenolysis
 Gluconeogenesis
o synthesizes major plasma proteins (albumin)
o deaminates amino acids to urea
 Kidney
o Where urea from liver is transported and then excreted
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 Biocehemistry 2.1 24 July 2012
Introduction to Metabolism Dr. Balcueva

 Skeletal muscle (for muscle contraction)

o Fuel: glucose (forming CO2; storage form: glycogen)
o Product: lactate(anaerobically)
o Synthesizes muscle protein from plasma amino acids: 50%
body mass, a possible source of energy during starvation
 Lipids
 In diet, mainly triacylglycerol (TAG)
 Hydrolyzed to monoacylglycerols and fatty acids in the gut
then re-esterified in the intestinal mucosa
 Packaged with protein and secreted into the lymphatic
system and into the bloodstream as chylomicrons
 Chylomicrons
largest of the plasma lipoproteins
contain other lipid-soluble nutrients
not taken up directly by the liver
metabolized by tissues that have lipoprotein lipase
remnants are cleared by the liver
 Other major source of long-chain fatty acids is lipogenesis
from carbohydrate, in adipose tissue and the liver
 Adipose tissue triacylglycerol
 main fuel reserve of the body
 release glycerol and free fatty acids via Hydrolysis
Figure 3.4 Transport & fate of major carbohydrate and amino acid
(glycerol is a substrate for gluconeogenesis)
substrates and metabolites. Note that there is little free glucose in
 Fatty acids muscle , since it is rapidly phosphorylated upon entry
 transported bound to serum albumin
 not taken-up by brain or erythrocytes
 esterified to triacylglycerols for storage or oxidized as a B. Subcellular Level: Glycolysis Occurs in the Cytosol and Citric
fuel Acid Cycle in the Mitochondria
 Partial oxidation leads to ketone body production
(ketogenesis)
o Ketone bodies - act as a fuel in prolonged fasting and
starvation; used as fuel by extrahepatic tissues
including the brain but not the erythrocytes
 Very Low Density Lipoprotein (VLDL)
o triacylglycerol arising from lipogenesis, free fatty acids,
and chylomicron remnants

 Compartmentalization of pathways permits regulation and

integration of metabolism.

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 Biocehemistry 2.1 24 July 2012
Introduction to Metabolism Dr. Balcueva

Cytosol Mitochondria - decrease in insulin and increase in glucagon results in

Glycolysis Citric Acid Cycle inhibition of lipogenesis, inactivation of lipoprotein lipase,
Pentose Phosphate Pathway Electron Transport Chain and activation of intracellular hormone-sensitive lipase
Lipid synthesis ATP Synthesis - leads to release of increased amounts of glycerol and free
Protein synthesis Ketogenesis fatty acids from adipose tissue
Gluconeogenesis B oxidation o Fasting state in Muscle:
(lactate/pyruvate  oxaloacetate as - preferentially takes up and metabolizes free fatty acids
precursor for glucose synthesis) o Fasting state in Liver:
Glycogenesis - greater capacity for B –oxidation
Glycogenolysis - fasting becomes more prolonged, it forms more acetyl-
CoA
 In ER membrane, there are enzymes for TAG - acetyl-CoA is used to synthesize the KETONE BODIES
synthesis. o Prolonged Starvation
- glucose may represent less than 10% of whole body
METABOLITES MUST BE REGULATED IN A CONCERTED MANNER energy-yielding metabolism
- liver and muscle glycogen would be exhausted after about
 Important to ensure an appropriate supply of the products of 18 h fasting
that pathway - increase in the net rate of protein catabolism to provide
 Achieved by control of one or more key reactions in the pathway, amino acids, not only as substrates for gluconeogenesis,
catalyzed by regulatory enzymes but also as the main metabolic fuel of all tissues
 Non-equilibrium Reactions Are Potential Control Points - DEATH results when essential tissue proteins are
 Flux-generating reaction is the first reaction in a pathway that is catabolized and not replaced
saturated with substrate (Km is lower than normal substrate o Cachexia
concentration) - release of cytokines in response to tumors and a number
 Allosteric & Hormonal Mechanisms are important in the of other pathologic conditions
metabolic control of enzyme-catalyzed reactions - increase in the rate of tissue protein catabolism, as well as
a considerably increased metabolic rate, so they are in a
METABOLIC FUEL RESERVES ARE MOBILIZED IN THE FASTING STATE state of advanced starvation
o Type I Diabetes Mellitus (IDDM – Insulin Dependent Diabetes
Mellitus)
- hyperglycemic, partly as a result of lack of insulin and in
the absence of insulin there is increased gluconeogenesis
from amino acids in the liver
- increased lipolysis in adipose tissue, and the resultant free
fatty acids are substrates for ketogenesis in the liver
- Utilization of ketone bodies in muscle may be impaired
because of the lack of oxaloacetate
- In uncontrolled diabetes, the ketosis may be severe
enough to result in pronounced acidosis (DKA or Diabetic
Ketoacidosis -> medical emergency)
- Coma results from acidosis and increased osmolality of
extracellular fluid

 Supply of Metabolic Fuels Is Provided in Both the Fed & Fasting

States
1. Erythrocytes
o lack mitochondria – rely on (anaerobic) glycolysis and
the pentose phosphate pathway
2. Brain
In fasting state: o metabolize ketone bodies to meet about 20% of
- concentration of glucose in the portal blood falls energy requirements; remainder must be supplied by
- insulin decreases glucose
- skeletal muscle and adipose tissue take up less glucose 3. In pregnancy
- increase in secretion of glucagon inhibits glycogen o fetus requires a significant amount of glucose and
synthetase, and activates glycogen phosphorylase in the synthesis of lactose in pregnancy and lactation
liver
o Fasting state in adipose tissue:

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 Biocehemistry 2.1 24 July 2012
Introduction to Metabolism Dr. Balcueva

IN THE FED STATE Reasons for multistep pathway:

• Fed State - glucose is the major fuel
• Increase in the respiratory quotient (ratio of carbon dioxide
produced/oxygen consumed)
• Glucose uptake is controlled by insulin in muscle cell and
adipose tissue
• As insulin secretion falls in the fasting state, so the receptors
are internalized again, reducing glucose uptake.
• Uptake of glucose into the liver is independent of insulin
o Insulin INDEPENDENT – liver and pancreas
o Insulin DEPENDENT – muscle cells and adipose
tissue
• GLUT 4 - glucose transporter in muscles and adipose tissues;
responds to insulin secretion by migration to plasma
membrane
• Hexokinase - liver enzyme with high Km but low affinity for
glucose
• Glucose 6-phosphatase - liver enzyme that hydrolyses
G6PO4 release glucose into the blood
• Erythrocytes - completely dependent on glucose for fuel
(anaerobic glycolysis and pentose phosphate pathway)
• Brain - uses mostly glucose for fuel; also some ketone bodies
• ANAEROBIC glycolysis – lactate
• AEROBIC glycolysis – pyruvate
• Pancreas and Liver - independent of Insulin

1. Limited reaction – specificity of enzymes; each active site
catalyzes only a single step of the pathway
2. To control energy input and output – energy flow is mediated
by energy donors and acceptors
3. Catabolism of metabolic fuels yield 3 types of compounds
that mediate the release of energy:
a. acetyl CoA
b. nucleoside triphosphate (ATP)
c. reduced coenzymes (NADH,FADH)
4. Some compounds can be substrates or products of more
than 1 enzyme so they can have 2 or more metabolic
functions.
5. To establish control points
a. balance of energy supply and demand in living
cells
b. ability to respond to internal signals or change in
the environment
Metabolic Regulation
• Most pathways are irreversible under physiologic
conditions
• When a metabolite enters the pathway each step occurs in
sequence w/out backing up or wasting cellular material or
energy
• Reactions are regulated to proceed in only 1 direction

PATTERNS OF METABOLIC REGULATION

1. Allosteric modification
o Feedback inhibition – when the product controls the rate
of its own synthesis
o Feedforward activation – when a metabolite produced
early in the pathway activates an enzyme that catalyzes a
reaction further down the pathway.
2. Covalent modification – alters catalytic rate by attachment to
Why does reaction in the body do not occur at once?
some group by a covalent bond (usually a phosphate group
o Phosphorylation:
 activates enzymes regulating catabolic pathways
 inhibits enzymes regulating anabolic pathways
 catalyzed by protein kinases
o Dephosphorylation
 inhibits enzymes regulating catabolic pathways
 activates enzymes regulating anabolic pathways
“E”nergy is released in several stops, so that it can be stored by
 catalyzed by protein phosphatases
NAD, FAD
3. Supply of substrate ATP or ADP
4. Hormones: insulin and glucagon

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 Biocehemistry 2.1 24 July 2012
Introduction to Metabolism Dr. Balcueva

CLINICAL CORRELATION  Diabetes mellitus - glucose is not utilized by the cells

 Cachexia - in prolonged starvation, adipose tissue reserves are because of receptor resistance to insulin (Type II) or lack
depleted, muscle tissues are catabolized and used as fuel. of insulin due to destruction of B-cells of the pancreas
(Type I)

SUMMARY:

 Most of the products of digestion of fat, proteins and carbs are

metabolized to a common metabolite, acetyl-CoA, before
undergoing oxidation in the citric acid cycle.
 Acetyl-CoA is the precursor of long chain fatty acid synthesis
and steroids, including ketone bodies and cholesterol
 Glucose provides carbon skeletons for the glycerol of
triacylglycerols and non-essential amino acids.
 Pathways are compartmentalized.
 Dietary carbohydrates and amino acids in excess can be used
for fatty acid (triacylglycerol synthesis)
 In fasting and starvation, glucose must be provided for the
brain and RBC; in early fasting state, this is supplied from
glycogen reserves. In order to spare glucose, muscle and other
tissues do not take up glucose when insulin secretion is low;
they utilize fatty acids as fuel.
 Amino acids can also be used for gluconeogenesis
(glyceroltriacylglycerol)
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