BIOMOLECULES AND METABOLISM 3. Metabolism and Its Control

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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 [phone]
• Email kingchan_at_cuhk.edu.hk

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Contents

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

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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.

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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.

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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
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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
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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
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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
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http//en.wikipedia.org/wiki/ImageNADplus.png
NAD Nicotinamide Adenine Dinucleotide
http//www.estrellamountain.edu/faculty/farabee/bi
obk/BioBookEnzym.html
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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.

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3.2 Enzymatic Control of Metabolism
http//www.estrellamountain.edu/faculty/farabee/bi
obk/BioBookEnzym.html
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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.

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3.3 Carbohydrate metabolism and energy production

• Glycolysis (in cytoplasm)
• Krebs cycle (in matrix inside mitochondria)
• Aerobic and anaerobic metabolism
• Gluconeogenesis

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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.

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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).

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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
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http//www.accessexcellence.org/RC/VL/GG/ecb/outli
ne_glycolysis.html
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• 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.

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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
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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.

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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).

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• 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.

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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.

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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
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Overview of oxidative phosphorylation
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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

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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
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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.

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3.4 REGULATION OF METABOLISM BY HORMONES

• Feeding and Fasting
• The Pancreatic Islet Hormones
• Regulation of Fatty Acid Metabolism
• Diabetes Mellitus

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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.

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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
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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
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Feedback Regulation of the Secretion of Glucagon
and Insulin
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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.

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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.

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http//www.medbio.info/Horn/Time203-4/homeostasis
_2.htm
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http//www.medbio.info/Horn/Time203-4/homeostasis
_2.htm
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http//www.medbio.info/Horn/Time203-4/homeostasis
_2.htm
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http//www.medbio.info/Horn/Time203-4/homeostasis
_2.htm
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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.

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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).

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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?