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Medical Biochemistry

For Dentistry Students

SGS 246

Bioenergetics &

Metabolism

by

Prof. Dr. Aisha Eid (M.D.)

Prof. Dr. Yasser Nassar (M.D.) Prof. Dr. Samar Marzouk (M.D.)

(2015-2016)

(2)

Preface

This is a summary book for the course of biochemistry. It provides comprehensive information about the metabolic pathways of different biomolecules. It also throws light on the significance of biomolecules in energy production, their medical and clinical relevance, as well as discussing the diseases resulting from their impaired metabolism.

(3)

CONTENTS

Page

INTRODUCTION TO METABOLISM 4

BIOENERGETICS 6

CARBOHYDRATE METABOLISM 10

BLOOD GLUCOSE 38

GLUCOSURIA 41

INSULIN AND DIABETES MELLITUS 42

LIPID METABOLISM 46

PROTEIN METABOLISM 58

NUCLEOPROTEIN METABOLISM 66

HEME METABOLISM 69

PLASMA ENZYMES OF CLINICAL SIGNIFICANCE 72

NPN COMPOUNDS 72

SALIVA 73

MINERALS 74

VITAMINS 78

(4)

Introduction to Metabolism

Once foods have been ingested, there follows a large number of biochemical reactions inside the living cell referred to as metabolism.

Two metabolic processes are recognized: anabolism and catabolism.

Anabolism (constructive metabolism):

It is the process of synthesis of macromolecules from simple ones: it is required for the growth of new cells and the maintenance of all tissues.

Catabolism (destructive metabolism):

It is the breaking down of large molecules into smaller ones.

Catabolism of the main metabolites occurs at three stages:

 Stage I: Digestion: Hydrolysis of polysaccharides into monosaccharides, triacylglycerols into glycerol and fatty acids, proteins into amino acids. No free energy is obtained in this stage.

 Stage II: Conversion of monosaccharides, glycerol, fatty acids and amino acids into active acetate (acetyl CoA). This process produces some energy. Some free energy is obtained in this stage.

 Stage III: Oxidation of active acetate into CO2 and H2O and reduced coenzymes (hydrogen carriers). This stage produces the maximum amount of energy via the resispiratory chain.

The maximum amount of free energy is obtained in this stage.

Metabolism is carried out by chemical substances called enzymes, which are biological catalysts made by the body.

(5)

Breakdown of food occurs at three stages:

CHO lipids proteins Stage I

(digestion)

ENERGY

monosacchs glycerol & FAs, AAs

Stage II

ENERGY

Acetyl CoA

ENERGY

Stage III

CO2 & H2O + CoEnz H

+

(6)

Bioenergetics

Definition of Energy:

Energy is the capacity to perform work. Two types of energy are considered in our body:

a) Heat energy: serves to maintain body temperature.

b) Free energy: used for performance of work e.g. mechanical work (muscle contraction), electrical work (nerve impulses), chemical work and osmotic work.

All organisms depend on energy from food for life. Food energy is expressed in calories. Carbohydrates have an average value of 4.1 calories per gram, proteins have 4.7 calories per gram, and fats have an average of 9.3 calories per gram.

Kinetics of Chemical reactions:

The chemical reactions taking place in tissues undergoing both degradation in catabolism and resynthesis in anabolism are either:

 Exergonic reactions: which occur during catabolism, liberate, or give off, energy from within the system of reacting substances.

 Endergonic reactions: which occur during anabolism, require energy from the outside.

 Isothermic reactions: in which no energy change occurs.

In keeping with the laws of thermodynamics, organisms can neither create nor destroy energy but can only transform it from one form to another.

Source of energy:

Breakdown of different chemical bonds contained in oxidizable foodstuff.

Chemical bonds are classified according to energy levels into:

Energy Levels of Chemical Bonds

Low energy bonds High energy bonds

On hydrolysis they give <7Kcal/mol. On hydrolysis they give >7Kcal/mol.

Designed as (-) Designed as (~)

(7)

Low energy bonds:

1. Phosphate ester bonds, e.g. G-6-P.

2. Glycosidic bonds in carbohydrates.

3. Peptide bonds in proteins.

4. Carboxyl ester bonds in triacylglycerols.

High energy bonds:

1. High energy phosphate bonds, e.g ATP, ADP, GTP, creatine phosphate 2. High energy sulfur bonds, e.g. acyl CoA, S adenosyl methionine.

Collection and Storage of Energy:

Free energy produced during catabolism of foodstuffs (stages II and III) is collected and stored in high energy phosphate bonds in the form of Adenosine triphosphate and creatine phosphate.

Currency of energy:

Adenosine triphosphate (ATP) is the currency of energy through which chemical energy is exchanged in all living cells.

ATP contains two high-energy phosphate bonds.

Cleaving one phosphate group from ATP liberates 7.3 kcal/mol.

ATP is produced in exergonic reactions and consumed in endergonic reactions.

Storage form of energy:

Creatine phosphate is the storage form of energy in skeletal muscle tissue.

Surplus ATP is converted to creatine phosphate in a reversible reaction catalyzed by the enzyme creatine kinase (CK) or creatine phosphokinase (CPK):

CPK

Creatine + ATP Creatine phosphate + ADP High energy phosphate bond is stored in creatine phosphate, and

converted to ATP when the latter is needed in energy-requiring reactions

Mechanism of collection of released energy:

Released energy is collected in the form of high energy phosphate bonds (ATP) at two levels:

1. Substrate level oxidative phosphorylation reactions.

2. Electron transport chain (respiratory chain) level.

(8)

1. Substrate Level Oxidative Phosphorylation:

Here while the substrate undergoes direct oxidation, energy (> 7 Kcal) is produced and directly captured to form a high energy phosphate bond in ATP molecule.

2. Electron transport chain (ETC) or Respiratory Chain Level Oxidative Phosphorylation:

This includes two processes:

a- Oxidation by the electron transport chain (ETC) or the respiratory chain.

b- Phosphorylation (ATP synthesis).

-During the oxidation of carbohydrates, fats and proteins, the metabolic intermediates of reactions donate hydrogen atoms (or electrons) to hydrogen carriers or coenzymes (NAD or FAD), forming reduced coenzymes (NADH or FADH2).

-These reduced coenzymes further give their hydrogen (or electrons) to a series of hydrogen (or electron) carriers called the electron transport chain (ETC) or the respiratory chain which is located on the inner mitochondrial membrane.

Function of ETC:

1) Oxidation:

The function of ETC is the transfer of hydrogen (or electrons) from the metabolic intermediates of various reactions, and its delivery to oxygen to form water.

Energy is liberated during electron transfer.

This occurs at complexes I, III, and IV.

2) Phosphorylation:

Oxidation of 2H+ to form water is accompanied by or coupled to formation of ATP (liberated energy during the electron transfer of 8 kcal/mole is collected in the form of ATP).

This is doneby complex V (ATP synthase).

(9)

Oxidation of foodstuffs metabolic intermediates 2 H+

H2O

ETC NADH (or FADH2) (Energy)

3 ATP (or 2 ATP)

It is to be noted that:

1. Oxidation of NADH+H+ by the ETC produces 3 ATP.

2. Oxidation of FADH2 by the ETC produces 2 ATP.

3. ETC shows that there are two processes:

 oxidation (2H+→H2O), and

 phosphorylation (formation of ATP).

Uncoupling oxidative phosphorylation:

The processes of oxidation and phosphorylation are tightly coupled, i.e.

occur hand in hand.

If these two processes are uncoupled, the process of oxidation will proceed without phosphorylation (no ATP production), and thus the energy of the reaction will be dissipated or lost in the form of heat.

Uncouplers:

These are substances which uncouple respiratory chain oxidation from phosphorylation, e.g. thyroxine, dicumarol and calcium ions.

ETC or Respiratory Chain

FAD

FADH2 FAD

Complex V

(10)

Metabolism

Although the three major foodstuffs—proteins, carbohydrates, and fats—

have different chemical compositions and follow independent biochemical pathways, at a certain stage in metabolic reactions, they all form carbon compounds. These compounds follow the same pattern of oxidative reactions that eventually yield carbon dioxide and water for excretion from the body. Each step involves a number of highly complex biochemical reactions.

CARBOHYDRATE METABOLISM

Dietary Carbohydrates:

 Monosaccharides:

These include glucose, fructose and galactose which are present in fruits and honey and obtained by hydrolysis of different oligo- and polysaccharides.

 Disaccharides:

These include sucrose (table sugar), lactose (in milk) and maltose (produced by hydrolysis of starch).

 Polysaccharides:

Mainly starch which is present in potatoes, rice, corn and wheat.

Cellulose is present in the cell wall of some plants, but is not digested by humans due to the absence of the cellulase enzyme which hydrolyzes it.

Digestion of Carbohydrates:

 In the mouth:

Salivary amylase

Starch Dextrin + Maltose

 In the stomach:

Salivary amylase acts for a very short time till the gastric HCL (due to drop of pH) inhibits the enzyme. HCL partially hydrolyzes carbohydrates to monosaccharides.

 In the small intestines:

Pancreatic and intestinal enzymes hydrolyze the oligo- and polysaccharides as follows:

(11)

Pancreatic amylase

Starch maltose + isomaltose

Maltase

Maltose 2 glucose

Lactase

Lactose glucose + galactose

Sucrase

Sucrose glucose + fructose

Absorption of monosaccharides:

Different monosaccharides, ingested in diet and resulting from the process of digestion, can be absorbed through three main mechanisms:

1. Simple diffusion:

It depends on the concentration gradient of sugars between the intestinal lumen and mucosal cells. Fructose and pentose are absorbed by this mechanism.

2. Facilitated transport:

It requires a transporter. Glucose, Fructose and galactose are partially absorbed by this mechanism.

3. Active transport (cotransport):

This is an active mechanism which needs energy derived from the hydrolysis of ATP. By this process, glucose and galactose are actively transported against their concentration gradients.

Fate of absorbed monosaccharides:

At the liver, fructose and galactose are converted to glucose.

Fate of glucose:

A. Uptake by different tissues

B. Utilization by the tissues in the form of:

1. Oxidation to produce energy:

- Major pathways (glycolysis & Krebs' cycle).

- Minor pathways (hexose monophosphate pathway & uronic acid pathway)

2. Conversion to other substances:

 Carbohydrates:

- Ribose and deoxyribose (for structure of RNA and DNA).

- Galactose in lactose of milk and glycolipids.

(12)

- Fructose in semen.

 Lipids: Glycerol-3 P for formation of triacylglycerols.

 Proteins: Non-essential amino acids which enter in formation of proteins.

C. Storage of excess glucose:

Excess glucose is stored as glycogen in liver and muscles.

D. Excretion in urine:

Normally, there is no glucose detectable in urine.

If the blood glucose exceeds the renal threshold (180 mg/dL), which is the maximum capacity of the kidneys to reabsorb glucose from the glomerular filtrate, it will be excreted in urine.

(13)

Glucose Oxidation

Glucose is the major source of energy for all cells.

Extracting Energy from Glucose:

There are 3 major biochemical processes that occur in cells to progressively breakdown glucose with the release of various packets of energy:

 Glycolysis (occurs in the cytoplasm).

 Krebs' cycle (takes place in the matrix of the mitochondria and results in a great release of energy).

 Electron transport chain.

GLUCOSE OXIDATION

(14)

GLYCOLYSIS

It is a series of biochemical reactions by which glucose is converted to:

 Pyruvate (in aerobic conditions)or

 Lactate (in anaerobic conditions).

Site: cytosol of every cell. Physiologically it occurs in muscles, during exercise (due to lack of oxygen) and in RBCs (no mitochondria).

Steps:

Phase one

:

In this phase 1 molecule of glucose (C6) is converted to 2 molecules of glyceraldehyde 3-phosphate (C3) as follows:

ATP ATP

Glucose (C6) 2 Glyceraldehyde 3 P (C3) These steps require energy, in the form of 2 ATPs / glucose molecule.

(15)

Phase two

: in this phase the 2 molecules of glyceraldehyde 3-P are converted to 2 molecules of pyruvate (aerobic) or lactate (anaerobic):

2 ATP

Glyceraldehyde-3 P (C3) Pyruvic Acid(C3)

NADH + H+

NAD+

Overall, glycolysis can thus be summarized as follows:

Glucose 2 Pyruvic Acid + 2 net ATP + 4 hydrogens (2 NADH2) Or:

2 Lactic Acid + 2 net ATP Lactic Acid

Ҳ2

NADH+H+

NAD+

Lactate

Lactate

dehydrogenase

(16)

Regulation of Glycolysis:

It can be noted that all reactions of glycolysis are reversible except those catalyzed by:

1. Glucokinase (or hexokinase) (GK) 2. Phosphofructokinase (PFK)

3. Pyruvate kinase (PK)

Glycolysis is regulated by factors which control the activity of the key enzymes which catalyze the 3 irreversible reactions.

A. Regulation according to energy requirements of cell:

Each cell regulates glycolysis according to the rate of utilization and thus availability of ATP:

i) High levels of AMP (indicating decreased ATP availability):

activates glycolysis (by activating PFK).

ii)High levels of ATP (indicating little utilization of ATP):

inhibits glycolysis (i.e. inhibits PFK and PK).

B. Regulation by hormones:

Postprandial hyperglycemia causes increased secretion of insulin and decreased secretion of glucagon and adrenaline (anti-insulin hormones).

i) Insulin:

-It stimulates all the pathways of glucose utilization.

-It stimulates glycolysis by activating all the glycolytic key enzymes.

ii) Anti-insulin hormones (Glucagon and adrenaline):

-It inhibits glycolysis by acting as inactivator of glycolytic key enzymes.

N.B.: It can thus be noted that activity of the 3 key enzymes and consequently glycolysis:

-increases during carbohydrate feeding -decreases during starvation

Importance of Glycolysis:

1. Glycolysis provides the mitochondria with pyruvic acid, an important source of oxaloacetate, which is the primer of the Krebs' cycle.

2. Glycolysis provides dihydroxyacetone phosphate which is convertible to glycerol 3-phosphate that is important for lipogenesis.

3. Energy production:

Glycolysis liberates only a small part of energy from glucose, however:

a. It is very important during severe muscular exercise, where oxygen supply is often insufficient to meet the demands of aerobic metabolism.

b. It provides all energy required by the R.B.Cs. (due to lack of mitochondria).

(17)

Energy yield of glycolysis

: A. In absence of oxygen:

 2 ATP are consumed for conversion of glucose to Fructose 1,6 P.

 2 ATP are produced during conversion of glyceraldehydes 3-P to pyruvate.

 Since 1 glucose molecule gives 2 molecules of G 3-P, then the total number of ATP produced is 4.

Therefore net gain of ATP in absence of oxygen is: 4-2=2 ATP.

B. In presence of oxygen:

 2 ATP are produced directly (as in absence of oxygen), and

 6 ATP are produced indirectly: (from the oxidation of 2 NADH2

through the respiratory chain)

Therefore net gain of ATP in presence of oxygen is: 2+6= 8 ATP.

3ATP 3ATP

2ATP 2ATP

Net ATP production = 10 ATP – 2 ATP = 8 ATP (In Presence of Oxygen)

(18)

The Transition Reactions

These link glycolysis to the Krebs Cycle

Alternate Fates of Pyruvate

A.

Oxidative Decarboxylation: B. Carboxylation:

forms Acetyl CoA forms Oxaloacetate A. Oxidative decarboxylation of pyruvate:

Puruvate dehydrodenase complex irreversibly converts pyruvate into acetyl CoA:

Pyruvic acid (3C)+NAD++Coenzyme A Acetyl CoA(2C)+CO2+ NADH+ H+

-NAD+ is converted into NADH+H+. Those hydrogens go through oxidative phosphorylation and produce 3 more ATP.

This process is a prelude to the Kreb's Cycle.

B. Carboxylation of pyruvate to oxaloacetate:

Pyruvate carboxylase converts pyruvate to oxaloacetate.

Pyruvic acid (3C) + CO2 + ATP Oxaloacetic acid (4C) + ADP + Pi

Finally, comes the Krebs' Cyclewhich starts by condensation of acetyl- CoA and oxaloacetate to form a tricarboxylic acid called citric acid. That is why it is also called tricarboxylic acid cycle (TCA) or citric acid cycle.

2 CoenzymeA

NADH+H

NADH+H

(19)

Krebs' Cycle (Citric Acid Cycle)

(Tricarboxylic Acid "TCA" Cycle)

-This cycle is a series of biochemical reactions that are responsible for complete oxidation of organic substances (carbohydrates, fats and proteins) to form : CO2 + H2O + Energy.

-During oxidation in the cycle, hydrogens are transferred to NAD+ and FAD then to the respiratory chain for ATP synthesis.

Site:

In the mitochondria of every cell.

Steps:

Acetyl CoA

+ oxaloacetate citric acid

-Krebs’ cycle begins by the condensation of acetyl-CoA with oxaloacetate to form citrate.

-Citrate then passes through a series of biochemical reactions to reforma new oxaloacetate molecule.

-The new oxaloacetate molecule can bind to another acetyl CoA to start the process all over again.

-During one cycle the following is produced:

 2 CO2

 3 NADH2

 1 FADH2

 1 ATP

2 CO2 3 NADH2

FADH2 ATP oxaloacetate

(20)

Energy yield of Krebs' cycle:

I. One mole of acetyl CoA by going through Krebs' cycle produces 12 ATPs as follows:

-1 ATP (substrate level oxidative phosphorylation).

-1 FADH2 → 2 ATP (respiratory chain level oxidative phosphorylation).

-3 NADH+H+→9 ATP(respiratory chain level oxidative phosphorylation) II. Conversion of pyruvate to acetyl CoA produces:

-1 NADH+H+→3 ATP(respiratory chain level oxidative phosphorylation) Thus net ATP gain from oxidation of 1 pyruvate molecule is:

12 + 3 = 15 ATP

III. Since 1 glucose molecule through glycolysis gives 2 pyruvate molecules, therefore 1 glucose molecule yields:

15 × 2 = 30 ATP.

Complete oxidation of glucose in presence of oxygen (i.e. glycolysis + conversion of pyruvate to acetyl co A + Krebs’cycle) gives:

 Glycolysis: 8 ATP

 Conversion of pyruvate to acetyl CoA: 2×3 = 6 ATP

Oxidation of acetyl CoA through Krebs’cycle = 2×12 =24 ATP

 Total ATP yield = 8+6+24 = 38 ATP.

oxaloacetate

2 ATP 3ATP

3 ATP

3 ATP 3 ATP

NADH

puruvate CO2

Glucose

CO2

× 2

CO2 Citrate

(21)

Energy gain (yield) from complete oxidation of one molecule of glucose (under aerobic conditions)

Glucose (C6)

-2ATP

+4ATP 8 ATP 2NADH 6ATP

2 Pyruvate(C3)

1NADH 3ATP x2 6ATP

2 Acetyl CoA (C3)

1 ATP

3NADH 9ATP x2 24ATP 1FADH2 2ATP

CO

2

+ H

2

O

8 + 6 + 24 = 38 ATP I. Glycolysis

III. Krebs' Cycle II. Transition Reaction

Total gain (yield) of ATP 38 ATP

(22)

Importance of Krebs' cycle:

1. Energy production: 1 acetyl CoA yields 12 ATP.

2. It is the final common metabolic pathway for complete oxidation of acetyl CoA which results from the partial oxidation of carbohydrates, fats and proteins (amino acids).

3. Interconversion of carbohydrates, fats and proteins (gluconeogenesis, lipogenesis, and formation of non-essential amino acids).

Regulation of Krebs' cycle:

1. Regulation according to energy status of the cell:

 High NADH/NAD and ATP/ADP (denoting that there is no need for further energy production) inhibit the cycle, and vice versa.

 Krebs' cycle is only aerobic, since under anaerobic conditions the respiratory chain is inhibited leading to increased NADH/NAD ratio which inhibits the cycle.

2. Regulation according to availability of substrate:

 High concentrations of acetyl CoA and oxaloacetate produce activation of the cycle.

 High concentrations of intermediate metabolic products of the cycle (citrate & succinyl Co A) produce feedback inhibition of the cycle.

(23)

Minor Pathways of Glucose Oxidation

These pathways occur in certain organs, and their main importance is not the production of energy. They include:

-Hexose monophosphate pathway (HMP shunt).

-Uronic acid pathway.

Hexose Monophosphate Pathway (HMP shunt) Pentose Phosphate Pathway

Pentose Shunt

It is an alternative pathway for oxidation of glucose which involves pentoses as intermediates.

Site: It occurs in the cytoplasm of many cells e.g. liver, adipose tissue, adrenals, ovaries, testis, red blood cells and retina of the eye.

Steps:

Overall the steps can be summarized as follows:

Glucose-6-P dehydrogenase

6 Glucose-6-P 6 Ribose-5-P 12 NADP+ 6 CO2 12 NADPH+H+

Importance of HMP shunt:

1. Provides the body with ribose-5-phosphate (R-5-P):

R-5-P is important for synthesis of nucleotides and nucleic acids.

Ribose of diet is excreted in urine, as there is no pentokinase for its phosphorylation.

2. It is the main source of NADPH:

NADPH act as a coenzyme for many reductases, hydroxylases and NADPH oxidase which catalyze several important biochemical reactions, e.g.:

i) Fatty acid synthesis and hence lipogenesis:

Thus HMP is very important in liver, adipose tissue and lactating mammary gland.

ii) Steroid synthesis:

HMP is active in adrenal cortex, testis, ovaries and placenta.

iii) Important for vision:

Retinal reductase (which uses NADP as hydrogen carrier) converts retinal into retinol which is important for vision, that is why HMP is active in the eye.

(24)

3) Importance of HMP in Red Blood Cells:

-H2O2 produced through certain biochemical reactions is a powerful oxidant and produces damage of cellular DNA, proteins and phospholipids of the cell membrane.

-Glutathione reductase and glutathione peroxidase are important for removal of this H2O2 .

glutathione peroxidase

H2O2 2 H2O

2 G-SH G-S-S-G

NADP+ NADPH, H+ glutathione reductase

-RBCs are liable for oxidative damage by H2O2 due to their role in oxygen transport. H2O2 produces oxidative damage in the form of:

a-Oxidation of Fe2+ iron of Hb to form Fe3+ iron in met Hb, which is incapable of carrying oxygen.

b. Lipid peroxidation which increases cell membrane fragility.

-Thus exposure of RBCs to oxidizing agents produces their lysis and development of anemia and jaundice.

-HMP is very important in RBCs for production of NADPH, which in turn provides reduced glutathione for removal of H2O2 and thus protects the cell from the oxidative damage.

Favism:

-This is a genetic condition due to deficiency of glucose-6-phosphate dehydrogenase (G6PD), which is the key enzyme catalyzing the rate limiting reaction of the HMP.

-There is impaired HMP in the RBCs, and the red cell capacity to protect itself from oxidative damage is markedly decreased (due to decreased production of NADPH).

-Eating Fava beans (which contain oxidizing agents), or administration of certain drugs (e.g. aspirin, sulfonamides or primaquin) which stimulate production of H2O2, produce lysis of the fragile red cells.

Regulation of HMP:

Insulin, produced in response to hyperglycemia, increase glucose oxidation by HMP (by acting as inducer of synthesis of G6PD).

(25)

Uronic Acid Pathway

This pathway converts glucose to glucuronic acid then UDP- glucuronic acid, the active donor of glucuronate.

Site:

cytosol of liver cells.

Importance of Uronic Acid Pathway:

1.Synthesis of glycosaminoglycans (GAGs).

2.Conjugation with certain compounds rendering them more water soluble, thus helping in their excretion, e.g.:

a) Steroid hormones.

b)Bilirubin, which is excreted in bile in the form of bilirubin diglucuronide.

(26)

Glycogen Metabolism

Glycogen is the main storage form of carbohydrates in animal tissue.

It is present mainly in the form of:

1. Liver glycogen:

-It forms 8-10% of the wet weight of the liver.

-It is mainly concerned with the maintenance of blood glucose, especially between meals.

-Liver glycogen is depleted after 12-18 hours fasting.

2. Muscle glycogen:

-It forms only 2% of the wet weight of muscle. However, due to the greater mass of muscles, its glycogen store is three to four times more than that of liver.

-Its main function is to supply glucose within muscles during contraction.

-Muscle glycogen is only depleted after prolonged exercise.

Glycogen metabolism includes:

 Glycogenesis: synthesis of glycogen from glucose.

 Glycogenolysis: breakdown of glycogen to glucose-1-phosphate.

 Gluconeogenesis: synthesis of glucose or glycogen from non- carbohydrate precursors.

(27)

Glycogenesis and Glycogenolysis

Site: cytoplasm of liver and muscle cells.

I. Glycogenesis (Glycogen Synthesis)

The key enzyme of glycogenesis is glycogen synthase.

Steps:

Glycogen Phosphorylase

Glycogen Synthase

+ Branching Enzyme

Glucose

Glucose-6-phosphatase in liver in muscle

(28)

hexokinase mutase

Glucose Glucose 6P Glucose 1P ATP ADP

UTP Pi

UDP-glucose

UDP

Glucose +

Glycogen primer chain elongation chain branching Glycogen

synthase

Branching enzyme

(29)

II. Glycogenolysis (Glycogen Degradation)

The key enzyme of glycogenolysis is glycogen phosphorylase.

Steps:

A. Shortening of chains:

Glycogen phosphorylase acts on the 1,4-glucosidic linkage of glycogen leading to sequential cleavage of G-1-P residues

C. Conversion of G-1-P to G-6-P: This is done by phosphoglucomutase enzyme.

N.B: Muscles cannot supply blood glucose due to their lack of the enzyme Glucose-6-phosphatase.

In muscles: G-6-P is oxidized by glycolysis to provide energy during muscle contraction.

In liver: due to presence of the enzyme G-6-phosphatase, G-6-P can be converted to glucose. Free glucose is released to the blood, as the main function of liver glycogen is to maintain the blood glucose level especially during fasting or carbohydrate deficiency.

G-6-phoshatase (in liver)

Glucose-6-P Glucose blood Glucose

Mutase Pi Glucose-1-P

Glucose residues joined by α-1,4- glucosidic linkage

Glucose residues joined by α-1,6- glucosidic linkage

debranching enz transferase

phosphorylase

Glycogen Phosphorylase

(30)

Regulation of Glycogenesis vs. Glycogenolysis:

The key enzymes are:

-Glycogen synthase (for glycogenesis)

-Glycogen phosphorylase (for glycogenolysis) Regulation of these enzymes occurs via:

I. Covalent modification (phosphorylation and dephosphorylation) II. Hormonal regulation

III.Allosteric regulation

IV.According to the nutritional status

Regulation of Glycogenesis:

I. Covalent modification (phosphorylation and dephosphorylation):

Glycogen synthase is present in two forms:

1. a-form: it is the active form and it is dephorylated.

2. b-form: it is the inactive form and it is phosphorylated.

II. Hormonal regulation:

A. Insulin stimulates glycogenesis in both liver and muscle by:

-Activation of phosphodiesterase decrease levels of cAMP.

-Activation of protein phosphatase.

B. Glucagon (in liver) and epinephrine (in liver and muscles) inhibit glycogenesis by activation of adenyl cyclase generating cAMP.

C. Growth hormone and glucocorticoids:

These increase gluconeogenesis and thus increase production of G-6-P.

Elevated levels of G-6-P allosterically activates glycogen synthase and accordingly stimulate glycogenesis.

III. Allosteric regulation:

Allosteric modifiers lead to conformational changes in the glycogen synthase enzyme protein which affect its activity and regulation, eg:

Glucose-6-phosphate (excess substrate) and ATP:

-Allosterically activate synthase leading to increased glycogenesis.

(31)

Regulation of Glycogenesis:

Regulation of Activity of Glycogen Synthase

ATP

5'-AMP

PPi H2O

Protein kinase

3',5'-cAMP

Adenyl cyclase

Insulin Glucagon or

Epinephrine

phosphdiesterase

+ +

Glycogen Synthase (a) (Active)

Glycogen Synthase (b) (Inactive)

ATP ADP

Phosphatase

Pi H2O

+ +

P

؛

Insulin cAMP

- +

Glycogen G6P

ATP

- +

(32)

Regulation of Glycogenolysis:

Regulation of Activity of Glycogen Phosphorylase:

ATP

5'-AMP

PPi H2O

Protein kinase

I. Covalent modification (phosphorylation and dephosphorylation):

Glycogen phosphorylase is present in two forms:

1. a-form: it is the active form and it is phosphorylated.

2. b-form: it is the inactive form and it is dephosphorylated.

II. Hormonal regulation:

A. Insulin inhibits glycogenolysisin both liver and muscle by:

-Activation of phosphodiesterase, which in turn decreases cAMP.

-Activation of protein phosphatase.

3',5'-cAMP

Adenyl cyclase

Insulin Glucagon or

Epinephrine

phosphdiesterase

+ +

Phosphorylase (b) (Inactive)

Phosphorylase (a) (Active)

ATP ADP

Phosphatase

Pi H2O

+ +

P

؛

Insulin cAMP

- + G6P

ATP -

(33)

B. Glucagon (in liver) and epinephrine (in liver and muscles) stimulate glycogenolysis by:

-Activation of adenyl cyclase thus increasing cAMP level.

III. Allosteric regulation:

Allosteric modifiers lead to conformational changes in the glycogen phosphorylase enzyme protein which affect its activity and regulation, eg:

ATP and G6P: allosterically inhibit glycogen phosphorylase.

Ca+2 ions:

-Allosterically activate glycogen phosphorylase leading to glycogen breakdown (glycogenolysis)

-Muscle contraction leads to release of Ca+2. Calcium release activates phosphorylase ensuring release of glucose from glycogen for ATP generation for ensuing cycles of muscle contraction.

Regulation of glycogenesis and glycogenolysis according to the nutritional status:

A. In the well fed state:

There is excess of substrate (Glucose-6 P) and surplus of energy (ATP).

-Both G6P and ATP allosterically activate glycogen synthase leading to increased glycogenesis to store the excess G6P, and, at the same time allosterically inhibit glycogen phosphorylase thus decreasing glycogenolysis.

Thus there is inhibition of glycogenolysis and activation of glycogenesis to store the excess blood glucose.

B. During starvation:

Here there are decreased levels of G6P and ATP, thus glycogenesis is inhibited while glycogenolysis is activated to supply blood glucose.

(34)

Muscle glycogen and blood glucose:

Muscle glycogen can be converted to blood glucose via:

1. During muscle exercise by an indirect pathway (Cori's Cycle).

2. During starvation by Glucose- Alanine Cycle , as follows:

Glycogen storage diseases:

These are due to inherited deficiencies of specific enzymes of glycogen metabolism.The most common of which is Von Gierke's disease which is due to deficiency of G-6-phosphatase enzyme. It is characterized by:

-enlargement of liver and kidneys -hypoglycemia

-hyperlipemia

-hypercholestorelemia.

Glycogen

glycolysis gluconeogenesis

glycogenolysis 6 P

Glycogen

transamination gluconeogenesis

glycogenolysis 6 P

(35)

Gluconeogenesis

It is the synthesis of glucose from non-carbohydrate precursors. These precursors are metabolic intermediates.

Importance:

The main function of gluconeogenesis is to supply blood glucose in case of carbohydrate deficiency (fasting, starvation and low carbohydrate diet) for more than 18 hours.

Site:

Mainly in cytosol of liver cells and to a lesser extent in kidneys.

Steps:

-It occurs by reversal of glycolysis.

-The three irreversible reactions in glycolysis catalyzed by the three glycolytic key enzymes are reversed by four key enzymes of gluconeogenesis as follows:

Glycolytic key enzymes Gluconeogenic key enzymes

1. Glucokinase 1. Glucose-6-phosphatase

2. Phosphofructokinase 2. Fructose-1,6-biphosphatase 3. Pyruvate kinase 3. Puruvate carboxylase

4. Phosphoenolpyruvate carboxykinase

I. Pyruvate kinase reaction is rerversed by 2 enzymes through 2 reactions:

a. Pyruvate carboxylase

b. Phosphoenol pyruvate carboxykinase (PEP-carboxykinase)

ATP ADP+Pi GTP GDP

Pyruvate Oxalo

-acetatate PEP

Pyruvate

carboxylase PEP-carboxykinase

Cytosol Mitochondria

(36)

II. Phosphofructokinase is reversed by Fructose-1,6-biphosphatase:

Fructose-6-phosphate+ATP Fructose-1,6-biphosphate+ADP

III. Glucokinase is reversed by glucose-6-phosphatase:

Glucose +ATP Glucose-6-P+ADP

Glucogenic Precursors:

They give directly or indirectly pyruvate, oxaloacetate or any intermediates of glycolysis or Krebs' cycle. They include:

1. Lactate:

It is released by R.B.Cs. and by skeletal muscles during exercise, then transferred to the liver to form pyruvate then glucose.

2. Glycerol:

It is produced from digestion of fats and from lipolysis. It gives glucose as follows:

ATP ADP

Glycerol Glycerol-3-P

Glucose Dihydroxy acetone-P

3. Glucogenic amino acids:

Proteins are considered as one of the main sources of blood glucose especially after 18 hours due to depletion of liver glycogen, by:

-deamination to form pyruvic acid or oxaloacetic.

-deamination to give intermediates of Krebs' cycle which go through the cycle eventually yielding oxaloacetic acid.

Both pyruvic acid and oxaloacetic may follow the gluconeogenic pathway to give glucose.

phosphofructokinase

Fructose-1,6-biphosphatase

Glucose-6-phosphatase Glucokinasee

dehydrogenase Glycerokinase

Reversal of glycolysis

Glucose

(37)

4. Propionyl CoA:

Many amino acids may give propionyl CoA through their catabolism.

Also the last 3 carbons of odd chain fatty acids form propionyl CoA and thus give glucose. This is uncommon in humans.

CO2

Propionyl CoA Methyl malonyl CoA

Glucose Succinyl CoA

Regulation of gluconeogenesis:

The gluconeogenic regulatory key enzymes are those which reverse the glycolytic key enzymes.

Glycolysis and gluconeogenesis are reciprocally controlled:

I. Insulin: (secreted after carbohydrate meal):

-decreases the activity of gluconeogenic key enzymes -stimulates the activity of glycolytic key enzymes

Thus insulin decreases gluconeogenesis leading to decreased blood glucose.

II. Anti-insulin hormones:

Glucagon, epinephrine, glucocorticoids & growth hormone:

(secreted during fasting, stress or severe muscular exercise):

-increase the activity of key enzymes of gluconeogenesis.

Thus anti-insulin hormones increase gluconeogenesis leading to increased blood glucose.

Through Krebs' cycle Reversal of glycolysis

Carboxylase

isomerase

Glucose

(38)

Blood Glucose

Concentration of bloog glucose:

Normal fasting blood glucose (8-12 hrs. after the last meal) is 70-105 mg/dL.

It increases after meals but returns to fasting level within 2 hrs.

Sources of blood glucose:

1. Dietary carbohydrates.

2. Glycogenolysis (during fasting for less than 18 hrs.).

3. Gluconeogenesis (during fasting for more than 18 hrs.).

Regulation of Blood Glucose:

Four factors are important for regulating blood glucose level:

I. Gastrointestinal tract.

II. Liver III. Kidney.

IV.Hormones.

I. Gastrointestinal tract:

1. It controls the rate of glucose absorption. The maximum rate of glucose absorption is 1 gm/kg body weight/ hour. An average person weighing 70 gm will absorb 70 gm glucose/ hour.

2. Glucose given orally stimulates more insulin than intravenous glucose. This may be due to secretion of glucagon-like substance by intestines. This stimulates B-cells of pancreas to secrete more insulin. This is called anticipatory action.

II. Liver: (Role of liver in carbohydrate metabolism):

The liver is the main blood glucostat, i.e. it tries to maintain blood glucose level within normal as follows:

A. If blood glucose level increases, the liver controls this elevation and decreases it through:

1. Oxidation of glucose via major and minor pathways.

2. Glycogenesis.

3. Lipogenesis.

B. If blood glucose level decreases, the liver controls this drop and increases it through:

1. Glycogenolysis.

2. Gluconeogenesis.

(39)

III. Kidney:

All glucose in blood is filtered through the kidneys, it then completely returns to the blood by tubular reabsorption via a phosphorylation mechanism.

If blood glucose exceeds a certain limit (called renal threshold), it will pass in urine causing glucosuria.

Renal threshold: it is the maximum rate of reabsorption of glucose by the renal tubules. Normally the renal threshold for glucose is 180 mg/100mL.

IV. Hormones:

A. Insulin (the only hypoglycemic hormone):

Insulin is a protein hormone, secreted by the B-cells of the islets of Langerhans of the pancreas.

Action of insulin:

Insulin decreases blood glucose level by the following mechanisms:

1. Stimulates the oxidation of glucose. It stimulates glycolysis by inducing the synthesis and activating all the glycolytic key enzymes (GK, PFK & PK).

2. It stimulates glycogenesis by enhancing the glycogen synthase activity.

3. It inhibits glycogenolysis by inhibiting the glycogen phosphorylase activity (through its effect on cAMP).

4. It inhibits glyconeogenesis. This is achieved through its suppressive effect on the key enzymes of gluconeogenesis (enzymes of reversal of glycolysis).

5. It stimulates lipogenesis by oxidation of glucose which supplies active acetate, glycerol-3-phosphate, NADPH and ATP.

B. Anti-Insulin Hormones: (hyperglycemic hormones):

1. Growth Hormone and glucocorticoids:

It elevates the blood glucose level by stimulating gluconeogenesis.

2. Thyroxine:

It elevates the blood glucose level by:

 Increasing the rate of absorption of glucose from intestines.

 Stimulating gluconeogenesis and glycogenolysis.

 Inhibiting glycogenesis.

3. Epinephrine (adrenaline):

It increases the blood glucose level by increasing glycogenolysis in both liver and muscles.

4. Glucagon:

It increases the blood glucose level by increasing glycogenolysis in liver.

(40)

Mechanism of Blood Glucose Regulation (Glucose Homeostasis)

The blood glucose level is regulated by the balance between the action of insulin and anti-insulin hormones (hyperglycemic hormones).

After a carbohydrate meal:

The blood glucose level increases, stimulating the secretion of insulin which tends to decrease the blood glucose level by its various actions.

During fasting:

The blood glucose level is low; this stimulates the secretion of the anti- insulin hormones (hyperglycemic hormones) which by their various mechanisms lead to increasing the blood glucose level.

Thus it is clear that there are certain factors which add glucose to the blood, while there are opposing factors which remove glucose from the blood.

The net result is a condition of glucose equilibrium, or what we call the homeostatic mechanism.

Abnormalities of Blood Glucose Level

These may be in the form of:

1. Hyperglycemia: (Diabetes Mellitus):

It is due to decreased insulin secretion and/or hypersecretion of anti- insulin hormones.

2. Hypoglycemia:

-It is the decrease in blood glucose level below the fasting level.

At a level of 50mg/dL convulsions occur and at a level of 30 mg/dL coma and death result.

-Hypoglycemia is more dangerous than hyperglycemia because glucose is the only fuel to the brain.

Causes:

i. Excess insulin:

a) Overdose of insulin.

b) Tumor of B-cells of pancreas (insulinoma).

ii. Hyposecretion of anti-insulin hormones:

This may be due to hypo-functions of the pituitary gland, adrenals and thyroid gland. In all these conditions, insulin acts unopposed causing lowering of blood glucose

iii. Liver disease:

In this case, hypoglycemia is due to decreased glycogen stores and impaired gluconeogenesis.

(41)

Glucosuria

Definition:

Glucosuria is presence of detectable amounts of glucose in urine (>30 mg/dL).

Causes:

A. Hyperglycemic glocusuria:

It occurs when blood glucose level exceeds the renal threshold (180mg/dL). It is caused by:

1. Diabetes mellitus.

2. Emotional or stress glucosuria (epinephrine glucosuria):

In cases of emotional stress there is increased epinephrine secretion. This leads to hyperglycemia which if exceeds the renal threshold leads to glucosuria.

3. Alimentary glucosuria;It is due to increased rate of glucose absorption as in cases of gastrectomy or gastrojejunostomy.

B. Normoglycemic or renal glucosuria:

1. Congenital renal glucosuria (diabetes innocens):

It is due to congenital defect in renal tubular reabsorption of glucose.

2. Acquired renal disease (e.g. nephritis).

3. Pregnancy glucosuria:

It appears during pregnancy and disappears later on after labour.

(42)

INSULIN AND DIABETES MELLITUS

Insulin is a polypeptide hormone formed of 51 amino acids, arranged into two chains A and B, A chain is formed of 21 amino acids, and B chain is formed of 30 amino acids. The two chains are connected together by two disulfide bonds.

Insulin hormone is secreted by the B cells of the pancreatic islets. It is secreted as a single polypeptide called proinsulin in which the two chains are connected by a connecting peptide (C peptide), then by the action of a certain peptidase the C-peptide is removed

The increase in plasma glucose concentration is the most potent stimulator for insulin secretion.

DIABETES MELLITUS (DM) Definition:

Diabetes is a metabolic disease characterized by increased blood glucose level (hyperglycemia) and decreased glucose tolerance. In diabetes there is a disturbance in the metabolism of carbohydrate, lipid and protein due to decrease insulin / anti-insulin ratio.

Types of DM:

1) Primary types: due to decrease in insulin secretion or action.

2) Secondary types: due to hypersecretion of anti-insulin hormones.

(43)

Primary types of DM:

I) Type I or Insulin dependent diabetes mellitus (IDDM).

II) Type II or Non-insulin dependent diabetes mellitus (NIDDM).

Type I (IDDM) Type II (NIDDM)

Other terms: Juvenile onset DM Old onset DM

Incidence: 10% 90%

Age: Under 20 years Above 40 years

Onset: Rapid Slow

Cause: Autoimmune or viral disease leads to

destruction of the B cells of the pancreas.

Defect in insulin secretion or insulin resistance.

Level of blood insulin:

Low or absent Insulin usually present Treatment: Insulin injection Oral hypoglycemic drugs

Metabolic changes in DM:

All the metabolic changes are due to decrease in the insulin / anti-insulin ratio, which produces changes reversal to insulin action:

1) Changes in carbohydrate metabolism:

- Decrease glucose uptake, glucose oxidation and glycogenesis.

- Increase glycogenolysis and gluconeogenesis.

- This leads to hyperglycemia glucosuria (when renal threshold of glucose exceeds 180 mg/dl) polyuria loss of electrolytes dehydration polydepsia (feeling of thirst).

2) Changes in lipid metabolism:

- Decrease lipogenesis and increase lipolysis.

- This leads to weight loss, increase free fatty acids in blood, fatty liver, hypercholesterolemiam ketosis and may be coma.

3) Changes in protein metabolism:

- Decrease protein synthesis and increase protein catabolism.

- This leads to increased sensitivity to infection and delayed healing of wounds.

Diagnosis of DM:

The following tests are done for diagnosis and control of DM :

1) Fasting and two hours postprandial (2PP) plasma glucose levels:

Normal fasting level 70-105 mg/dL (diabetic above 140 mg/dL).

Normal 2PP level < 140 mg/dL (diabetic above 200 mg/dL).

(44)

2) Oral Glucose Tolerance Test (OGTT):

After 8- 12 hours fasting, blood and urine samples are taken, then the patient is given 75 g glucose in a cup of water, blood and urine samples are taken every ½ hour for 3 hours. Blood glucose is measured and urine samples are examined for the presence of glucose and acetone.

Fasting level: Normal: <100 mg/dl.

Diabetic: > 126 mg/dl.

Return to fasting level: Normal: at 2 hours.

Diabetic:>2hours.

Urine samples: Normal : samples are free from glucose or acetone.

Diabetic: samples may contain glucose and / or acetone.

0 50 100 150 200 250

Fasting 30 min 1 hour 2 hours 3 hours Normal Diabetic

3) Measurement of glycosylated- Hb (HbA1c):

It is considered a good test for follow up of diabetic patients.

Controlled cases of DM have 4-8% glycosylated –Hb, and this percent increases proportional to the blood glucose level.

Complications of DM:

Most of the complications are due to the damage of the vascular system, which is initiated by hyperglycemia. The common complications are:

1) Retinopathy (eye disease).

2) Nephropathy (kidney disease).

3) Neuropathy (nerve disease).

F 1 h 2 h 3 h

(45)

4) Cardiovascular diseases, such as hypertension, heart attack, heart failure, stroke and problems caused by poor circulation e.g.

gangrene.

5) Diabetic coma: there are two types of diabetic coma, hyperglycemic coma and hypoglycemic coma.

Hyperglycemic coma Hypoglycemic coma Cause: Usually due to ketosis and

acidosis caused by severe uncontrolled DM.

Usually due to overdose of insulin or oral hypoglycemic drugs.

Respiratory rate:

Hyperventillation Normal respiratory rate Pulse: Weak rapid pulse Strong rapid pulse Skin: Dry skin (dehydration) Excessive sweating Urine: Excess amounts of glucose

and acetone

Free from glucose or acetone Treatment: Intravenous administration

of insulin together with glucose.

Glucose administration

(46)

LIPID METABOLISM

Dietary lipids:

lipids in the diet are triacylglycerols (mainly), phospholipids, cholesterol esters and fat-soluble vitamins (A, D, E& K).

Digestion of lipids:

1) Digestion of triacylglycerols (TAG):

* In the mouth: lingual lipase is not significant as food passes rapidly to the stomach.

* In the stomach: gastric lipase acts shortly as it is destroyed by the high acidity (it acts only in infants due to low acidity).

* In the intestine:

a) Pancreatic lipase: it is the main enzyme responsible for digestion of TAG, it converts most of TAG into 2-MAG and free fatty acids.

b) Intestinal lipase: it acts intracellular converting 1-MAG into glycerol and free fatty acid.

2) Digestion of cholesterol esters (CE):

By cholesteryl esterase, which hydrolyses cholesterol esters to cholesterol and free fatty acids.

H2O FFA Cholesterol ester cholesteryl esterase

cholesterol 3) Digestion of phospholipids:

Phospholipids can be partially absorbed without digestion, also they are hydrolyzed by pancreatic phospholipase A2 which removes fatty acids in position 2 producing lysophospholipids.

So, the end products of digested lipids are:

 2-MAG,

 1-MAG, glycerol,

 cholesterol,

 phospholipids,

 lysophospholipids

 free fatty acids.

TAG 2-MAG

(47)

Absorption of lipids:

1) Glycerol and short and medium chain fatty acids are water soluble, so they pass directly from the intestinal lumen into the intestinal cells then to the liver through the portal circulation.

2) The other products form with bile salts fine emulsified particles called micelles, which will be transported into the intestinal cells.

3) Inside the intestinal cells:

-The long chain fatty acids with MAG are reassembled into TAG.

-Lysophospholipids are converted to phospholipids, and cholesterol is esterified to cholesterol esters.

-TAG, cholesterol esters and phospholipids all are conjugated with protein to form chylomicrons which are then passed to lymph system to the blood .

Nonesterified cholesterol

(48)

Fate of absorbed lipids:

Absorbed lipids are used by tissues as follows:

1) Oxidation for energy production: mainly through FA oxidation.

2) Gluconeogenesis (conversion to glucose): by conversion of glycerol to glucose.

3) Synthesis of biologically active compounds: as different steroids and eicosanoids.

4) Formation of tissue fat: which enters in the structure of cells.

5) Formation of depot fat (storage): through lipogenesis.

6) Secretion: by lactating mammary gland in milk and by sebaceous gland in sebum.

(49)

METABOLISM OF DEPOT FAT

It is the fat present in adipose tissue.

It is formed mainly of TAGs which are rich in saturated FAs.

Depot fat has many functions:

1.It is the main source of energy during fasting and starvation through lipolysis and FA oxidation.

2.Acts as heat insulator around the body.

3.Helps in fixation of some organs.

4.Protects many organs from trauma.

The amount of TAG in depot fat is controlled by two processes lipolysis and lipogenesis.

Lipolysis:

It is hydrolysis of TAG of adipose tissues into glycerol and fatty acids.

This occurs by specific enzyme termed hormone sensitive lipase (HSL) HSL FA HSL FA

Triacylglycerols diacylglycerols monoacylglycerols

Then by the action of monoacylglycerol lipase (MAG lipase), monoacylglycerols are converted to glycerols and fatty acids.

Monoacylglyccerol MAG lipase glycerol + fatty acid Regulation:

Lipolysis is inhibited by insulin hormone, i.e. after carbohydrate feeding, and stimulated by anti-insulin hormones, i.e. fasting, starvation, low carbohydrate diet or stress.

Lipogenesis:

-It is synthesis of TAG by esterification of fatty acids with glycerol.

-The active form of glycerol is glycerol-3-phosphate, while the active form of fatty acids is acyl-CoA.

-Glycerol-3-P is esterified with 2 FAs to form phosphatidic acid, which will be converted to TAG by removal of phosphate group then addition of the third FA.

(50)

METABOLISM OF FATTY ACIDS

The metabolism of fatty acids is formed of two processes:

1) Fatty acid oxidation.

2) Fatty acid synthesis.

(51)

1- β-Oxidation of Fatty Acids

It is the pathway by which activated fatty acids (acyl-CoA) are converted to active acetate.

-Site: occurs in the mitochondria of many cells.

-Function: It is the main source of energy during fasting and starvation.

-Energy production:

-Oxidation of one molecule of palmitic acid (C16) produces 129 ATP molecules.

-By 7 cycles of β-oxidation, palmitic acid is converted to 8 molecules of active acetate, each cycle produces one FADH2 and one NADH,H+.

7 FADH2 + 7 NADH,H+ + 8 active acetate =14 ATP + 21 ATP + 96 ATP

=131ATP – 2 ATP used for FA activation = 129 ATP molecules

Fatty acid (Cn)

2 ATP Activation

Acyl-CoA (Cn)

R.C.

FADH2 2 ATP

R.C.

NADH,H+ 3 ATP

TCA

Acetyl CoA 12 ATP Repeat the cycle (C2)

Acyl-CoA (Cn-2)

(52)

2- Fatty Acid Synthesis

Fatty acid synthesis is nearly the reversal of fatty acid oxidation.

-Site: synthesis occurs in the cytoplasm, whereas, oxidation occurs in the mitochondria.

Oxidation involves the reduction of FAD+ and NAD+ to FADH2 and NADH+H+, whereas, synthesis involves the oxidation of NADPH+H+ to NADP.

-Enzyme responsible for fatty acid synthesis

:

Fatty acid synthase complex.

-Building units

:

Acetyl-CoA which is carboxylated to malonyl-CoA by the enzyme acetyl-CoA carboxylase (rate limiting reaction)

acetyl-CoA carboxylase

Acetyl CoA + CO2 Malonyl CoA Biotin , Mn2+

ATP ADP+Pi

-Regulation:

-Acetyl-CoA carboxylase is the key enzyme of fatty acid synthesis:

-It is activated by insulin and citrate.

-It is inhibited by glucagon and long chain fatty acyl-CoAs.

References

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