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BIOMOLECULES AND METABOLISM 3. Metabolism and Its Control

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BCH 1002 Biochemical Aspects of Health and Disease BIOMOLECULES AND METABOLISM 3. Metabolism and Its Control Prof. K. M. Chan Dept. of Biochemistry – PowerPoint PPT presentation

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Title: BIOMOLECULES AND METABOLISM 3. Metabolism and Its Control


1
BIOMOLECULES AND METABOLISM3. Metabolism and Its
Control
BCH 1002 Biochemical Aspects of Health and Disease
  • Prof. K. M. Chan
  • Dept. of Biochemistry
  • Chinese University
  • Rm 513B, Basic Medical Sciences Building
  • Tel 3163-4420
  • Email kingchan_at_cuhk.edu.hk

2
Contents
  • Anabolism, catabolism, reducing power and energy
    production
  • Enzyme actions
  • Glycolysis Krebs cycle
  • B oxidation and fat metabolism
  • Regulation of metabolism by hormones

3
3.1 Aabolism, catabolism, reducing power and
energy (ATP) production
  • Living processes are complex of anabolic
    (biosynthesis) and catabolic (disintegration)
    reaction pathways that use carbohydrates, lipids,
    and proteins as energy sources and biosynthetic
    precursors. The processes are precisely regulated
    by the following ways.
  • Compartmentation different organs have different
    functions, and different pathways take place in
    various organelles in the cells.
  • Each step in the pathways requires specific
    enzyme, co-factors and optimal pH (buffered) amd
    is tightly controlled by various factors.

4
3.1.1 Catabolism has three stages
  • Nutrient molecules (proteins, polysaccharides and
    fats from food) are hydrolyzed to their building
    block units by digestions.
  • Building block units are converted to easily
    oxidized forms (primarily acetyl CoA).
  • Acetyl CoA is completely oxidized to form CO2 and
    H2O. Energy is captured when ATP synthesis is
    linked to the electron transport pathway using
    ATP synthase.

5
Catabolism processes
FOOD
Proteins
Carbohydrates
Fats
Fatty acids and glycerol
Glucose
Amino acids
ATP
Glycolysis
Pyruvate
ATP
Acetyl CoA
Oxidative phosphorylation
Krebs (Citric acid) cycle
6
3.1.2 Anabolism
  • Large complex molecules are synthesized from
    smaller precursors.
  • Building block molecules (amino acids, sugars and
    fatty acids) are produced or acquired from the
    diet.
  • Because anabolic processes include the synthesis
    of polysaccharides and proteins from sugars and
    amino acids, the biosynthetic pathways increase
    order and complexity, they require inputs of free
    energy (ATP and NADPH).

http//www.accessexcellence.org/RC/VL/GG/ecb/ATP_A
DP.html
7
3.1.3. ATP energy and Acetyl Coenzyme A (acetyl
CoA)
  • ATP plays an extraordinary role within cells
    currency or input of energy.
  • Hydrolysis of ATP provides an immediate and
    direct input of free energy to drive a variety of
    endergonic (energy requiring) biochemical
    reactions.
  • Chemical coupling allows the cell to get the
    energy produced by catabolism.
  • Thioester is also important in energy harvesting
    pathways for breakdown of molecules.
  • Acetyl CoA carries one acetyl group for further
    catabolism of carbohydrates.

CH3
Coenzyme A S C O
8
3.1.4 Reducing power
  • Both energy capturing and releasing processes
    consist largely of redox reactions.
  • Electron donor (reducing agent)
  • Electron acceptor (oxidizing agent)

½ O2
2 e-
NAD H 2 e-
NADH
ATP
FADH2
FAD 2H 2 e-
Cu Fe3
Cu2 Fe2
9
http//en.wikipedia.org/wiki/ImageNADplus.png
NAD Nicotinamide Adenine Dinucleotide
http//www.estrellamountain.edu/faculty/farabee/bi
obk/BioBookEnzym.html
10
3.1.5 Division of labor in our body
  • Liver for metabolism stomach and duodenum for
    digestion.
  • Intestine for absorption.
  • Circulation for transport (water distribution
    between plasma and interstitial fluid
    compartments).
  • Renal system for excretion (control of body fluid
    and electrolyte balance)
  • Muscle plays an important part to burn the energy
    from food when fed or from fat when starved.
  • Importance of nutrients, exercise and sport
    (control of body composition and energy
    expenditure).
  • The best way to keep your body in good shape is
    to do exercise.

11
3.2 Enzymatic Control of Metabolism
http//www.estrellamountain.edu/faculty/farabee/bi
obk/BioBookEnzym.html
12
Interconversion of the macronutrients
  • Protein, carbohydrate and fat are energy
    producing macronutrients
  • Pathways are regulated at the following levels
  • certain regulatory enzymes by substrate
    availability,
  • allosteric mechanisms, and
  • covalent modification such as phosphorylation.

13
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15
3.3 Carbohydrate metabolism and energy production
  • Glycolysis (in cytoplasm)
  • Krebs cycle (in matrix inside mitochondria)
  • Aerobic and anaerobic metabolism
  • Gluconeogenesis

16
3.3.1 GLYCOLYSIS
  • Glucose can also be available from food intake.
  • Glucose is also stored as glycogen
    (glycogenesis).
  • After gluconeogenesis, glucose is converted from
    glycogen in liver or muscle for glycolysis.
  • Glycolysis is the break down of a 6 C glucose
    sugar to two 3C pyruvate.

17
Central role of liver in metabolism
  • Glucose entering the hepatocyte is phosphorylated
    by glucokinase to glucose-6-phosphate (G-6-P).
  • Other monosaccharides are also made to G-6-P via
    gluconeogenesis, then glucose can be stored as
    glycogen.
  • When we need energy, glycolysis converts G-6-P to
    pyruvate and acetyl coA to enter Citric acid
    cycle to produce ATP energy via oxidative
    phosporylation (aerobic metabolism).

18
Glycolysis break down of glucose in cytoplasm
UDP-glucose
Glucose-1-phosphate
Glycogen
Lactate
Lactate Dehydrogenase
Glucose-6-phosphate
Hexokinase
Glucose
ATP
ADP
Fructose-6-phosphate
6 C
ADP
Pyruvate
ATP
Fructose-1, 6-biphosphate
Dihydroxyacetone phosphate (DHAP)
Glycerol
ATP
Glyceraldehyde-3-phosphate
ADP
3 C
NAD Pi
H2O
Phospho-enol-pyruvate
ATP
ADP
NADH H
Glycerate-3-phosphate
Glycerate-2-phosphate
Glyceraldehyde-1, 3-bisphosphate
ATP
ADP
H2O
19
http//www.accessexcellence.org/RC/VL/GG/ecb/outli
ne_glycolysis.html
20
  • Pyruvate is transported across the inner
    mitochondrial membrane and oxidized within the
    matrix to acetyl CoA via TCA (Krebs) cycle.
  • Acetyl Co A can also be produced fromßoxidation
    of fatty acids in the mitochondria.
  • From which the NADH produced in the mitochondria
    is used for oxidative phosphorylation in the
    inner membrane of mitochondria to make ATP energy
    using water and oxygen.

21
Glycolysis
Fat, triacylglycerol
Carbohydrate, Glycogen and glucose (6C)
Protein
Fructose
Amino acids
Triose P (3C)
Glycerol 3-P
Fatty Acids Cholesterol
Phosphoenolpyruvate(PEP)
Cysteine
Alanine
Pyruvate (3C)
PhenylalanineTyrosine Leucine
Acetoacetate
Serine
Histidine
Acetyl CoA (2C)
Oxaloacetate (4C)
Citrate (6C)
Glutamate
Krebs Cycle (Citric acid cycle)
Fumarate (4C)
Proline
Ketoglutarate (5C)
Succinyl CoA (4C)
Hydroxylproline
Valine
22
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23
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24
3.3.2 Importance of Krebs Cycle
  • Kreb cycle (Citric acid cycle or TCA cycle) is a
    amphibolic pathway oxidative catabolism and
    provide precursor molecules for anabolism,
    particularly gluconeogenesis.
  • Energy (2 ATPs per cycle) will be produced from
    succinyl Co A. Other compounds produce NADH and
    FADH2 for oxidative phosphorylation in the
    mitochondria to make 26 more ATP.

25
3.3.3 Aerobic and anerobic metabolism
  • Glucose 6 O2 ? 6 CO2 6 H2O
  • Glucose 2ADP 2 Pi ? 2 Lactate 2ATP
  • Glucose 6 O2 30 ADP 32 Pi? 6 CO2 6 H2O
    30 ATP
  • In glycolysis, initially 2 ATPs are used one for
    hexokinase to phosphrylate glucose to G-6-P,
    another to make Fructose 6 Phosphate to Fructose
    1,6, biphosphate.
  • This 6 C sugar is further divided into 2 3C
    sugars each producing 2 ATP to make a total of 4
    ATP.
  • Net ATP production is 2 ATP from making glucose
    to pyruvate without using oxygen (anerobic).

26
  • Acetyl CoA (2C from pyruvate, 3C) reacts with
    oxaloacetate (4C), citrate (6C) is formed to
    produce 3 NADH and FADH2.
  • The cycle goes on from citrate to isocitrate
    (6C), then forming ketoglutarate (5C),
    succinyl-CoA (4C), succinate (4C) , fumarate and
    Malate to Oxaloacetate (4C) again.
  • The 10 NADH and 2 FADH2 made from Kreb cycle are
    used for electron transport to generate proton
    gradient across inner membrane for ATP synthase
    to produce 26 ATP with oxidative phosphorylation.
    2 ATP are made from TCA cycle and 2 ATP from
    glycolysis, 26 ATP are from oxidative
    phosphorylation to make a total of 30 ATP from
    one glucose.

27
3.3.4 Oxidative Phosphorylation takes place in
mitochondria for more ATP production
  • Glycolysis takes place in the cytoplasm after
    glycolysis, pyruvate is added with CoA using NAD
    to become Acetyl CoA, CO2 and NADH.
  • Acetyl CoA is the fuel for Krebs Cycle to take
    place in the matrix.
  • Oxidative phosphorylation depends on electron
    transfer and the respiratory chain linking to TCA
    cycle create proton gradient across the inner
    membrane of mitochondria.
  • The proton gradient powers the synthesis of ATP
    using ATP Synthase
  • When these steps are blocked or uncoupled by
    uncoupling proteins, no ATP made but only heat
    energy produced.

28
Krebs Cycle in matrix
Glycolysis in cytoplasm
Matrix
Inner mitochondria membrane
Electron transport chain and oxidative
phosphorylation
H
H
H
H
H
H
Oxidative phosphorylation
H
Cytochrome B, Cytochrome C, Fe-S proteins, etc.
ATP Synthase
e-
Electron Transport Chain
H
H
H

2 H ½ O2 ? H2O
NADH
H
Uncoupling Proteins
ATP production
NAD
H
e.g. in brown fats for heat generation in small
mammals.
Matrix
29
Overview of oxidative phosphorylation
30
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31
3.3.5 Gluconeogenesis
  • Occurs within mitochondria
  • Lactate is made to pyruvate, but this is not the
    reverse of glycolysis
  • Pyruvate carboxylase converts pyruvate to
    Oxaloacetate with CO2
  • PEPCK (PEP carboxykinase) converts oxaloacetate
    to PEP (Phosphoenol pyruvate to G-3-P, F-6-P to
    G-6-P.
  • Glucose-6-phosphatase converts G-6-P to glucose
    in endoplasmic reticulum

32
The Cori Cycle
  • Skeletal Muscle
  • Liver

Lactate
Lactate
blood
LDH, Lactate Dehydrogenase
LDH, Lactate Dehydrogenase
Pyruvate
Pyruvate
Glycolysis
Gluconeogenesis
Glucose 6-phosphate
Glucose 6-phosphate
Glucose 6-phosphatase
blood
Hexokinase
Glucose
Glucose
33
Metabolism in liver (amino acid for
gluconeogenesis)
  • Amino acids in the liver can also be converted to
    pyruvate which is converted to glucose or acetyl
    coA.
  • Acetyl Co A can be made to fatty acid and
    triacylglycerols and stored as fat.
  • Fatty acids in the liver can be made to lipids
    for storage or converted to acetyl CoA via
    ßoxidation when needed.

34
3.4 REGULATION OF METABOLISM BY HORMONES
  • Feeding and Fasting
  • The Pancreatic Islet Hormones
  • Regulation of Fatty Acid Metabolism
  • Diabetes Mellitus

35
3.4.1 Feeding and Fasting
  • As glucose moves via the blood to the liver,
    insulin from the ßcells in the pancreas is
    released to promote glucose uptake by muscle and
    adipose (for fat storage), and formation of
    glycogen in liver. Insulin also induce protein
    synthesis.
  • When the nutrient flow from intestine diminishes
    (fasting), blood glucose and insulin drop to
    normal and glucagon is released to prevent
    hypoglycemia by promoting glycogenolysis and
    gluconeogenesis in the liver.
  • Insulin can depress glycagon in acells. They have
    opposing effects on blood glucose levels.

36
FASTING
Well-fed
Glucose
Glucose
- INSULIN
Glucagon -
G-6-P
G-6-P
Fructose-6-P
Fructose-6-P
Fructose-1, 6- bis-P
Fructose-1, 6- bis-P
Cortisol
-
PEP (3C)
PEP


Oxaloacetate
PEPCK
-

Pyruvate
Pyruvate
37
3.4.2 The Pancreatic Islet Hormones
F cell secretes pancreatic polypeptides for
digestion in duodenum
Hyperglycemia (high blood glucose) stimulates
Exocrine Acini
Pancreas
Beta cell secretes insulin
Hepatic artery
Spleen
Abdominal aorta
Alpha cell secretes glucagon
Duodenum
Delta cell secretes somatostatin (inhibits growth
hormone)
Hypoglycemia (low blood glucose) stimulates
38
Feedback Regulation of the Secretion of Glucagon
and Insulin
39
Insulin
  • Increase glucose uptake in cells.
  • Convert glucose to glycogen (glycogenesis).
  • Increase amino acid uptake and protein synthesis.
  • Promote lipogenesis.
  • Slow down gluconeogenesis and glycogenolysis.
  • Blood glucose level drops
  • Hypoglycemia inhibits release of insulin.

40
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41
Glucagon
  • Acts on hepatocytes.
  • Converts glycogen to glucose (glycogenolysis).
  • Form glucose from lactic acid and amino acids
    (gluconeogenesis).
  • Glucose released from liver to make blood glucose
    increase to normal.
  • Hyperglycemia inhibits release of glucagon.

42
http//www.medbio.info/Horn/Time203-4/homeostasis
_2.htm
43
http//www.medbio.info/Horn/Time203-4/homeostasis
_2.htm
44
http//www.medbio.info/Horn/Time203-4/homeostasis
_2.htm
45
http//www.medbio.info/Horn/Time203-4/homeostasis
_2.htm
46
3.5.4 Diabetes Mellitus
  • Caused by deficiency of insulin secretion or
    actions
  • Type I diabetes (10) is insulin-dependent
    (IDDM), starts early in life and could become
    very severe. Due to insufficient insulin
    secretion and thus injection of insulin is
    required to save the patients life.
  • Type II diabetes (90) is non-insulin dependent,
    NIDDM, which is slow to develop with milder
    symptoms. Insulin is produced but the cells are
    not responding (insulin resistant), causing many
    complications including obesity.

47
Biochemical complications of diabetes mellitus.
  • Both types of diabetes fail to uptake glucose,
    leading to hyperglycemia. Other symptoms of
    diabetes include thirst and frequent urination.
  • In IDDM, excessive glucagon level (due to lower
    insulin level) also reduces the level of F-2,6-BP
    in the liver, and inhibits glycolysis.
  • Gluconeogenesis and glycogen breakdown are also
    induced.
  • NIDDM produces excessive amount of glucose in
    blood leading to glucosuria.
  • Excessive glucose is thus produced into the blood
    leading to hyperglycemia (gt 10 mM), even with
    glucose excreted in urine (hence named mellitus).

48
Tutorial Questions
  • Compare gluconeogenesis and glycogenolysis, and
    explain how insulin affects these processes.
  • Explain the consequences of using low
    carbohydrate and high protein diet for weigh loss
    plan.
  • What is the role of leptine on dieting?
  • Why untreated diabetes may die?
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