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Biochemistry 2.

July 28, 2011


Dra. Balcueva

Introduction to Metabolism
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OUTLINE
I.
II.
III.
IV.
V.
VI.
VII.

Learning Objectives
Metabolism
Metabolic pathways
Glucose metabolism
Protein metabolism
Lipid metabolism
Metabolic pathways may be studied at different levels of organization
A.
Integration of metabolism at the tissue level & organ level
B.
Integration of metabolism at the cellular level
VIII. Metabolites must be regulated in a concerted manner
IX.
Metabolic fuel reserves are mobilized in the fasting state
X.
In the fed state
XI.
Patterns of metabolic regulation

I.
A.

B.

LEARNING OBJECTIVES

General Objectives
To explain thoroughly how cells carry out and regulate complex
reaction sequences.
Specific Objectives
1. To be able to differentiate between anabolic and catabolic
pathways
2. To be able to explain briefly how carbohydrates, lipids and
proteins are metabolized
3. To be able to correlate relationships between each
pathways

Intermediary Metabolism
o Reactions involving the low molecular weight molecules
that are metabolites in the degradation and/or
biosynthesis of biopolymers.

Energy metabolism
o Part of intermediary metabolism
o pathways that store or generate metabolic energy
o Most organisms derive both the raw materials and the
energyfrom organic fuel molecules such as glucose.
o reducing equivalents released by CAC stored in NAD and
FADH2

II. METABOLISM

Link Anabolism to Catabolism


Eg. Citric Acid Cycle (actually catabolic but intermediates
can be used as precursor of other reactions

Network of chemical reactions carried out by living cells


Thousands of reactions occur SIMULTANEOUSLY
Controlled so unwanted ACCUMULATIONS/DEFICIENCIES of
intermediate products do not occur
Causes of accumulation/deficiencies:
o Nutritional, coenzyme, cofactor deficiency
o Hormonal imbalance
o Presence of drugs and toxins
Includes:
1. Interconversion of chemical compounds in the body
2. Pathways taken by molecules
3. Interrelationships between the pathways
4. Regulating mechanisms

Categories:

Catabolism
o From complex to simpler organic molecules
o Often exergonic (produces energy)
o Eg: Degradation of CHON to AA
Triglycerides to fatty acids
Glucose to pyruvate

Anabolism
o Synthesis of simple to complex organic molecules for the
maintenance of growth and reproduction
o Endergonic in nature
o Eg: Glycogenlolysis

Amphibolic

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III. METABOLIC PATHWAYS

Sequences of reactions that include the reactants,


intermediate, products and the enzymes involved
4 major groups of biomolecules
o Carbohydrates
o Proteins- involve enzymes. (required to synthesize new
products)
o Fats
o Nucleotides
Acetyl-CoA common product
o goes to CAC to give off ATP
o consumed with release of 2 CO2
o
cant be utilized once used

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Introduction to Metabolism

July 28,2011

C.
D.

E.

F.

IV. GLUCOSE METABOLISM

Also called hexose monophosphate shunt/pathway or


HMS/H MP for short
o Another source of reducing equivalents but instead
NADPH is used for biosynthesis
o Source of ribose for nucleotide and nucleic acid synthesis
o For RBC maintenance
o Liver and skeletal muscle: reduction of glutathione
Triacylglycerol (TAG) pathway
o Triose phosphate glycerol moiety of triacylglycerols
Amino acid synthesis
o Via pyruvate
o Via intermediates of citric acid cycle
Steroid synthesis
o Since acetyl-CoA is a precursor of fatty acids and
cholesterol
Glycogenesis
o Formation of glycogen
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
Normal blood glucose 5.5 mmol or 110 mg/decimeter
Anaerobic glycolysis produces 2 ATP (product: lactate)
Aerobic glycolysis (normal) produces 38 ATP
G6PD deficiency NADPH deficient (pentose phosphate
pathway); hereditary disease where RBC hemolyse
Gluconeogenesis pathway: non-carbohydrate precursors from
glucose
Pyruvate + amino acid Aspartate
-ketoglutarate + amino acid Glutamate

V. PROTEIN METABOLISM

Glucose in the form of polysaccharide in diet

Pathways present:
A. Glycolysis
o Can occur anaerobically (oxygen absent) but instead of
glucose, the product will be lactate
o Linked to oxidative phosphorylation and thus, also
producing ATP
B. Pentose phosphate pathway
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Amino group of amino acid is always eliminated (not stored in


the body->excreted via UREA)
Carbon skeleton of amino acid is recycled via
o Oxidation to CO2 via citric acid cycle
o Forms glucose (gluconeogenesis)
o Form ketone bodies (can be a source of fuel for the brain)

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Introduction to Metabolism

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DEAMINATION: ammonia is converted to its non-toxic form


which is urea and then excreted outside as urine
protein intake urea kidney damage
2 types:
o Essential amino acid supplied via diet
o Non-essential can be formed from metabolic
intermediates by transamination

VI. LIPID METABOLISM

Fatty Acids
o Exist in diet as triglycerides
o Stored in Adipose Tissue
o Sources

Dietary lipid

De novo synthesis from acetyl-CoA derived from


CHON
o Undergoes B-oxidation to form Acetyl-CoA
o 3 fates of acetyl-CoA

Oxidize to CO2 + water via citric acid cycle

As precursor for cholesterol/other steroids

Form as ketone bodies in the liver

Esterification with glycerol to form triacylglycerol

VII. METABOLIC PATHWAYS MAY BE STUDIED AT


DIFFERENT LEVELS OF ORGANIZATION

Tissue and organ level nature of substrates entering and


metabolites leavingtissues and organs = defined
Subcellular level each cell organelle has specific roles that
form part of a subcellular pattern of metabolic pathways

A. Tissue & Organ Level


*Blood Circulation Integrates Metabolism
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Amino acids and glucose- absorbed via the hepatic portal vein
Liver
o Regulates blood concentration of water-soluble
metabolites via:

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
Skeletal muscle (for muscle contraction)
o Fuel: glucose (storage form: glycogen)
o Product: lactate and CO2 (anaerobically)
o Muscle protein from plasma amino acids: 50% body mass,
a possible source of energy during starvation
Lipids

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Introduction to Metabolism

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B.

In diet, mainly triacylglycerol (TAG)


Hydrolyzed to monoacylglycerols and fatty acids in the gut
then re-esterified in the intestinal mucosa
o Packaged with protein and secreted into the lymphatic
systemand into the bloodstream as chylomicrons
o 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


o Other major source of long-chain fatty acids is lipogenesis
from carbohydrate, in adipose tissue and the liver
Adipose tissue triacylglycerol
o main fuel reserve of the body
o release glycerol and free fatty acids via Hydrolysis
Fatty acids
o transported bound to serum albumin
o not taken-up by brain or erythrocytes
o esterified to triacylglycerols for storage or oxidized as a
fuel
o Partial oxidation leads to ketone body production
Ketone bodies - act as a fuel in prolonged fasting and starvation
Very Low Density Lipoprotein (VLDL)
o triacylglycerol arising from lipogenesis, free fatty acids,
and chylomicron remnants

Subcellular Level
Cytosol
Glycolysis
Gluconeogenesis
Pentose phosphate pathway
Fatty acid synthesis
Protein synthesis in ribosome
catabolism

VIII. METABOLITES MUST BE REGULATED IN A


CONCERTED MANNER

Non-equilibrium Reactions Are Potential Control Points


Flux-Generating Reaction Is the First Reaction in a Pathway That
Is Saturated with Substrate
Allosteric & Hormonal Mechanisms Are Important in the
Metabolic Control of Enzyme-Catalyzed Reactions

IX. METABOLIC FUEL RESERVES ARE MOBILIZED IN


THE FASTING STATE

July 28,2011

Important to ensure an appropriate supply of the products of


that pathway
Achieved by control of one or more key reactions in the
pathway, catalyzed by regulatory enzymes

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Matrix / Inner Membrane


B-oxidation of fatty acids
Citric acid cycle (Krebs)
Synthesis of ketone bodies
Oxidative phosphorylation
Electron transport chain

In fasting state
o concentration of glucose in the portal blood falls
o insulin decreases
o skeletal muscle and adipose tissue take up less glucose
o increase in secretion of glucagon inhibits glycogen
synthetase, and activates glycogen phosphorylase in the
liver
Fasting state in adipose tissue
o decrease in insulin and increase in glucagon results in
inhibition of lipogenesis, inactivation of lipoprotein lipase,
and activation of intracellular hormone-sensitive lipase
o leads to release from adipose tissue of increased amounts
of glycerol and free fatty acids
Fasting state in Muscle
o preferentially takes up and metabolizes free fatty acids
Fasting state in Liver
o greater capacity for B oxidation
o fasting becomes more prolonged, it forms more acetylCoA
o acetyl-CoA is used to synthesize the KETONE BODIES
Prolonged Starvation
o glucose may represent less than 10% of whole body
energy-yielding metabolism

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liver and muscle glycogen would be exhausted after about


18 h fasting
o increase in the net rate of protein catabolism to provide
amino acids, not only as substrates for gluconeogenesis,
but also as the main metabolic fuel of all tissues
DEATH results when essential tissue proteins are catabolized
and not replaced
Cachexia
o release of cytokines in response to tumors and a number
of other pathologic conditions
o increase in the rate of tissue protein catabolism, as well as
a considerably increased metabolic rate, so they are in a
state of advanced starvation
Type I Diabetes Mellitus (IDDM Insulin Dependent Diabetes
Mellitus)
o 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
o increased lipolysis in adipose tissue, and the resultant free
fatty acids are substrates for ketogenesis in the liver
o Utilization ofketone bodies in musclemay be impaired
because of the lack of oxaloacetate
o In uncontrolled diabetes, the ketosis may be severe
enough to result in pronounced acidosis
o Coma results from acidosis and increased osmolality of
extracellular fluid

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


States

Erythrocytes
o lack mitochondria rely on (anaerobic) glycolysis and the
pentose phosphate pathway

Brain
o metabolize ketone bodies to meet about 20% of energy
requirements
o remainder must be supplied by glucose

In pregnancy
o fetus requires a significant amount of glucose and
synthesis of lactose in lactation

Reasons for multistep pathway:


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

XI. PATTERNS OF METABOLIC REGULATION

X. IN THE FED STATE

Glucose major fuel for oxidation in most tissues


Increase in the respiratory quotient (ratio of carbon dioxide
produced/oxygen consumed)
Glucose uptake is controlled by insulin
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
GLUT 4 glucose transporter in muscles and adipose tissues;
responds to insulin secretion by migration to plasma membrane
Hexokinase liver enzyme with high Km
Glucose 6-phosphatase liver enzyme that hydrolyses G6PO4
and release glucose into the blood

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.
Covalent modification alters catalytic rate by attachment to
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

catalyzed by protein phosphatases


Supply of substrate ATP or ADP
Hormones: insulin and glucagon

SAMPLE QUESTIONS: MODIFIED TRUE/FALSE

In a fasting state skeletal muscle and adipose tissue take up more


glucose

Glycogen is the main fuel reserve of the body

Gluconeogenesis is the conversion of glycogen back to glucose.


ANSWERS:
1.
False,takes up less glucose
2.
False, Adipose tissue triacylglycerol
3.
False,Glycogenesis

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