ProteinMetbolism part1

100

description

metabolism of proteins and amino acids, ammonia metabolism, urea cycle,transamination and deamination.

Transcript of ProteinMetbolism part1

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Protein & Amino acid Metabolism

Dr.Ganesh

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Protein and Amino acid Metabolism

The syllabus for this chapter includes the following topics.

PART I

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Protein and Amino acid Metabolism

Breakdown of tissue proteins and amino acid pool, General Reactions of Amino acids.

Disposal of Ammonia: urea cycle, glutamate and glutamine formation.

Metabolism of Amino acids,- Glycine, serine

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Introduction

Overview of Amino Acid Metabolism

Nitrogen Balance and amino acid pool

Protein Turnover

Metabolism of Amino Nitrogen

Metabolism of Individual Amino Acids – Glycine and serine

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Protein and Amino acid Metabolism

PART II

Metabolism of Amino acids sulfur containing amino acids, aromatic amino acids, histidine & arginine

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IntroductionProteins are linear hetero polymers

of α – L – Amino acids, which are linked by peptide bonds. Nitrogen (N) is characteristic of proteins.

Amino acids are not stored by the body. Hence, they must be obtained from the diet, synthesized de novo,

or produced from normal protein degradation.

Any amino acids in excess of the biosynthetic needs of the cell

are rapidly degraded.

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Biological importance:

2.All amino acids are required for the synthesis of proteins and many amino acids serve as precursors for the synthesis of biologically important compounds (Eg: Melanin, serotonin, creatine etc.)

1.Proteins contain nitrogen and they are main source of nitrogen for the body. Dietary Proteins are the sources of essential amino acids for the body.

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Medical importance:

2. Dietary deficiancy of proteins can result in disease such as P.E.M (protein energy malnutrition)

1.Genetic defects in the pathways of amino acid metabolism can cause serious disease. Eg: Albinism, Phenlyketonuria, Alkaptonuria etc.  

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NITROGEN BALANCE Nitrogen balance = Difference between

total nitrogen intake and total nitrogen loss

from the body.

The normal adult is in nitrogen equilibrium,

nitrogen intake = nitrogen output.

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Amino acid catabolism- phases

1.The first phase of catabolism involves the removal of the α – amino groups (usually by transamination and subsequent deamination)

ammonia + corresponding α – Keto acid.

Converted to UREA Enters 2nd phase

and excreted.

(most important route for disposing of nitrogen from the body.)

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Amino acid catabolism- phases

2. 2nd phase of amino acid catabolism

the carbon skeleton of the α – Ketoacids via intermediates of energy

producing, metabolic pathways

CO2 + H2O, glucose, fatty acids, or ketone bodies

Non essential amino acids are synthesized from the intermediates of metabolism or from essential amino acids

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Amino acid pool

Amino acids released by

hydrolysis of dietary or tissue protein or

synthesized de novo, and are

distributed throughout the body.

Collectively, they constitute the amino acid

pool.

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DIATARY PROTEIN BODY PROTEIN

AMINO ACID POOL

SYNTHESIS OF BIOLOGICALLY IMP.

COMPOUNDSCATABOLISM

catabolism synthesisDigestion and absorption

Synthesis of new amino

acids

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PROTEIN TURNOVER:the continuous degradation and resynthesis of all cellular

proteins

Each day about 1–2% of the total body proteins, principally muscle protein, undergoes turnover.

Body proteins

Amino acids

Catabolism

degradationReutilization for

new protein synthesis

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Metabolism of Amino Nitrogen

Overview

Transamination

Deamination Reactions (Ammonia Formation)

•Oxidative deamination •Non-oxidative deamination

Ammonia Transport

Disposal of Ammonia – Urea cycle.

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Overview of Metabolism of Amino Nitrogen  

Amino acids a-Ketoglutarate Transmination

Keto acids Glutamate

Oxidative deamination Other

Reactions

CO2 NH3 Urea Urea Cycle

-NH2

-NH2

Aspartate

H2N-CO-NH2

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TRANSAMINATIONDefinition: Transamination is the transfer of the amino group of an amino acid to a keto acid, changing the latter into a new amino acid and the original amino acid into a new keto acid.

Transamination reaction is freely reversible and hence involved both in biosynthesis and catabolism of amino acids.

Enzyme Involved:“Transaminases” (aminotransferases) – liver, skeletal muscles and heart are particularly rich in transaminases.

Cofactor Required: Pyridoxal phosphate (PLP) derived from Vit B6 (pyridoxine).

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General Reaction:

AMINO ACID 1

AMINO ACID2

KETO ACID 1

KETO ACID 2

TRANSAMINASE

PLP

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Mechanism:Pyridoxal phosphate is bound to the transaminase

at the catalytic site and during transamination the bound coenzyme serves as a carrier of amino groups.

Transamination occurs in 2 stages –

1.Transfer of the amino group of an amino acid to the coenzyme PLP (bound to the enzyme) to form pyridoxamine phosphate and the corresponding -ketoacid.

2.The amino group of pyridoxamine phosphate is then transferred to an -ketoacid to produce a new amino acid and the enzyme with PLP is regenerated.

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Examples:

ALT Alanine Transaminase; AST Aspartate transaminase

1) Alanine ALT Pyruvate

-a Ketoglutarate Glutamate 2) Aspartate

AST Oxaloacetate

-a -Ketoglutarate PLP

Glutamate

PLP

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Salient features:All amino acids except lysine, threonine,

proline and hydroxyproline undergo transamination.

It is a reversible reaction and can serve in both formation of an amino acid and its catabolism.

For all transaminases, glutamate and

-Ketoglutarate are one pair of substrate ( an amino acid and its corresponding keto acid) and differ in the other pair.

The amino acids undergo transamination to finally concentrate nitrogen in glutamate.

 

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Metabolic Functions:

1.Diverting excess of amino acids towards catabolism and energy production with simultaneous urea synthesis.

2.Biosynthesis of non-essential amino acids.

3.Producing -keto acids (e.g. oxaloacetate, Pyruvate, -ketoglutarate) for subsequent gluconeogenesis

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Clinical Aspects:

Blood levels of ALT and AST are elevated in liver diseases and AST levels in myocardial infarction. Their estimation is

useful in the diagnosis of these conditions. (refer Enzymes)

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Describe transamination.

Mention the clinical significance of serum transaminases. (4)

Clinical importance of transamination

(3)Write the reaction, with

cofactors if any, catalyzed by Alanine transaminase. (3)

Name the coenzyme forms of vitamin B6; write the mechanism of transamination

Questions??

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Ammonia Formation – Deamination Reactions

Ammonia is Produced in the Body by:

1) Cellular Metabolism and

2) In the Intestinal Lumen.

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1.Ammonia formation by cellular metabolism

Cells produce ammonia mostly from amino acids by deamination, which may be either

1. oxidative or

2. non-oxidative

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Deamination Reactions(Ammonia formation)

Deamination is removal of amino group from compounds, mostly amino acids, as ammonia (NH3).

NH3 +carbon skeleton of amino acid

CONVERTED TO

UREA

(KETOACID)

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Deamination….2types1.Oxidative deamination

a)deamination of glutamate catalyzed by glutamate dehydrogenase.

-Most important b)Other Oxidative Deamination Reactions are Mainly Those: -- Catalyzed by Amino Acid Oxidases 2.Non-Oxidative Deamination(less important)

Enzymes Involved are: Dehydratases Lyases and Amide Hydrolases

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Oxidative Deamination by Glutamate Dehydrogenase (GDH):

The removal of the amino group from glutamate to release NH3 and -ketoglutarate coupled with oxidation is known as oxidative deaminationSite: Most active in mitochondria of liver

cells, though present in all cells.Enzyme: Glutamate dehydrogenase (GDH) – a

Zn containing mitochondrial enzyme.Coenzymes: NAD+ or NADP+

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Oxidative deamination of glutamate…

NAD+/ NADP+ NADH/ NADPH + H+

Glutamate + H2O -Ketoglutarate + NH3 Glutamate dehydrogenase (GDH)

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Role of GDH:-

1. Produces NH3, thus channeling the amino groups of most amino acids for urea synthesis.

2. Regenerates -ketoglutarate for further collection of amino groups of amino acids by transamination and producing their carbon skeletons.

3. NADH produced generates ATP in the ETC.

4. The reverse reaction is required for the biosynthesis of glutamate and in the tissues for fixing ammonia, which is toxic.

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What Is Transdeamination ??

Transamination and deamination often occur simultaneously involving glutamate as the central molecule. this process is called transdeamination.

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What Is Transdeamination ??TISSUES

transamination

Reaches liver

Deamination in liver

NH3+-KG

UREA

Carried by blood

All amino acids Keto acids

-KGGLUTAMATE

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Glutamate occupies a central position in the metabolism of -amino nitrogen of -amino acids. The -amino groups of most of the amino acids ultimately are channeled/transferred to -ketoglutarate by transamination, forming glutamate

Glutamate channels the amino groups to form urea (H2N–CO–NH2) in the liver.

By oxidative deamination the amino group in glutamate may form ammonia, which forms one of the –NH2 groups of urea.

By transamination glutamate can also pass its amino group to oxaloacetate forming aspartate, which donates its amino group to form the other – NH2 group of urea.

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What are the sources of ammonia in the body?

Explain the biochemical basis: glutamate plays a central role in the catabolism of amino nitrogen of amino acids.

Give 2 examples for each of the following. a)Transaminases b) Reactions forming ammonia

Write the reaction, with cofactors if any, catalyzed by Glutamate dehydrogenase.

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Oxidative Deamination by Amino Acid Oxidases

• Amino Acid Oxidases are: -- Flavoproteins

-- Possessing either FMN or FAD Amino Acid

FAD/FMN Amino Acid Oxidase

FADH2/FMNH2

-Keto Acid + NH3

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Non-Oxidative Deamination

Enzymes Involved are:

Dehydratases

Lyases

and

Amide Hydrolases

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Dehydratase

Amino Acid Dehydratases (PLP-dependent)

Serine/Threonine

Dehydratase

PLP

NH3

Pyruvate/-Ketobutyrate

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Amino Acid Lyase

Histidine Aspartate

Histidase Aspartase

NH3

NH3

Urocanate

Fumarate

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Amino Acid Amide Hydrolases

Glutamine Aspargine

H2O

H2O Glutaminase

Asparginase

NH3 NH3

Glutamate Aspartate

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2)NH3 production in intestine

Intestinal Lumen -- Another Major Source of Ammonia

by the Action of Bacteria on: -- Urea Present in the

Intestinal Juice And Dietary Amino Acids. • This Ammonia is Absorbed into Hepatic

Vein and Enters Liver Directly.

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Transport of Ammonia

Ammonia is toxic to tissues, especially to brain (see Ammonia

Toxicity).

Ammonia that is constantly produced in the tissues is

transported to liver for detoxification by urea synthesis.

Ammonia is transported in blood as 1) free NH3, as 2) glutamate or

as 3) glutamine.

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Transport of Ammonia…

• NH3is transported in 3 forms.

1) As free NH3 Ammonia, whose blood level is 10 to 80 gm/dl, is rapidly removed from the circulation by the liver and converted to urea.

2) as glutamate Inside the cells of almost all tissues ammonia combines with -Ketoglutarate to form glutamate by GDH and is transported to the liver.

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Transport of Ammonia…

3) as glutamine. Ammonia is also trapped by glutamate in the tissues, especially in the brain, to form glutamine, which is catalyzed by glutamine synthetase

Glutamate

ATP ADP+Pi

glutamine.Mg2+

Glutamine synthetase

Transported to liver via blood

NH3

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This reaction may be considered as the first line of detoxification of

NH3 in the brain.

Glutamine is then transported through

circulation (highest blood level among all amino

acids) to liver

In liver, this reaction is reversed to release NH3 .

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In the liver..

Glutamine

H2O NH3

glutamateGlutaminase

UREA

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UREA CYCLE (Detoxification of Ammonia)

Contents:• Synonyms• Site• Sources of Atoms of Urea• Reactions • Functions • Ammonia Toxicity – Hyperammonemia

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UREA CYCLE .(Detoxification of Ammonia)

• Ammonia is Toxic to the Body. • Hence it is Necessary that the NH3

Produced During Metabolism of Amino Acids be Removed Immediately.

• This is Done by Conversion of Toxic NH3 into Harmless Water-soluble Urea in the Liver by Urea Cycle.

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UREA CYCLE (Detoxification of Ammonia)

• Synonyms:

Urea Cycle

Ornithine Cycle

Krebs-Henseleit Cycle• Site:

Urea Synthesized in Liver

Carried by Blood

And

Excreted by Kidneys

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Sources of Atoms of Urea

O ||

NH2 C NH2

NH3

CO2

Aspartate

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UREA CYCLE (Detoxification of Ammonia)

• Urea Synthesis:

-- A 5-step Cyclic Process • Enzymes of the First 2 Steps:

-- Present in Mitochondria• While the Rest:

-- Located in the Cytosol

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Reactions of Urea Cycle CO2 + NH3 + 2 ATP

Carbamoyl Phosphate Synthetase–I (CPS-I) Carbamoyl Phosphate + 2 ADP + Pi

Urea Ornithine

Arginase

Arginine Ornithine Transcarbamoylase Fumarate

Arginosuccinase Citruline

ArginosuccinateAspartate Arginosuccinate Synthetase ATP

AMP + PPi

TCA cycle

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Functions of Urea Cycle

1.Detoxification of NH3

2.Biosynthesis of Arginine.

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Ammonia Toxicity – Hyperammonemia

• Ammonia Concentration Rises in the Blood (Hyperammonemia) and in other Tissues in:

-- Liver Failure

and

-- Inborn Errors of Urea Synthesis

(that is, due to Genetic Defect) • This Produces Ammonia Toxicity in Many

Ways.

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Causes Of Hyperammonemia

• Causes may be

1.Acquired or 2. Inherited

1.Acquired Causes – Liver Diseases (e.g. Cirrhosis and Severe

Hepatitis)

-- Liver is Unable to Convert Ammonia into Urea

– -- Blood Ammonia Level Rises.

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2.Inherited Causes -- Defects Associated with each of the

Enzymes of Urea Cycle Exist.-- The Levels Substrate of the

Defective Enzyme Rises in the Cells.-- This Causes Product Inhibition of

the Enzyme Catalyzing the Earlier Step.

-- Leading to Accumulation Ultimately of the Starting Substrate,

Namely, NH3

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Inherited Causes of Hyperammonemia

Disease Enzyme involvedHyperammonemia Type-I CPS-I

Hyperammonemia Type –II Ornithine Transcarbamoylase

Citrullinemia Argininosuccinate

Synthetase

Argininosuccinic Aciduria Argininosuccinase

Hyperarginemia Arginase

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Ammonia Toxicity – Hyperammonemia

• Biochemical Alterations: – Hyperammonemia, – In Blood of Intermediates Prior to Metabolic Block

– Urinary NH3

• Clinical ManifestationsNausea, Vomiting, Protein Intolerance.

Slurring of Speech, Blurring of VisionTremor (Flapping Tremors), Ataxia, Lethargy Mental Retardation (in the Inherited Hyperammonemia in Children)Dizziness, Coma, Death

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Blood Urea

In Healthy People, Normal Blood Urea Concentration is 12-36 mg/dL

Higher Protein Intake Marginally Increases Blood Urea Level; however, this will be within Normal Range.

(See Practical Manual for Clinical Significance of Blood Urea)

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1. How ammonia is formed in the body? Explain the reaction leading to the detoxification of ammonia.

2. Describe the urea cycle. What is the normal blood urea level? Name two conditions in which blood urea level increases.

3. Explain the steps of Urea cycle & Mention the names of its disorders.

4.Carbamoyl phosphate synthetase deficiency. 5.Give 2 examples for each of the following.

a) Causes for inherited disorders of urea cycle b)Conditions in which blood urea level

increases

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Metabolism of Glycine H

H2N–C–COOH H

R Group GLYCINE is the simplest, optically inactive, glucogenic and non-essential amino acid. 

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Metabolism of Glycine-contents

Synthesis

Catabolism

Synthesis of biologically imp. Compounds from glycine

Inborn errors of glycine metabolism

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Synthesis

Glycine is a non-essential amino acid as it can be synthesized in the body.  

It can be synthesized from many substances by separate reactions.

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• The major reactions are from:

1.Serine

2.CO2, NH3 and N5, N10 methylene tetrahydrofolate (N5, N10 methylene FH4)

3. And Glyoxylate • These are reversible reactions and thus

also play a role in the catabolism of glycine.

• Minor pathways for synthesis of glycine are from:

Threonine and Choline

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1. Synthesis of Glycine from Serine:

Serine hydroxy methyl transferase COOH COOH PLP HC-NH2 CH2 CH2OH FH4 N

5, N10-methylene FH4 NH2 Serine Glycine

One carbon unit (methylene group, –CH2–) from serine is transfered to tetrahydro folic

acid (FH4).

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2. Synthesis of Glycine from CO2, NH3 and N5, N10 methylene THFA:

• This reaction is catalyzed by glycine synthase.

COOH

CO2 + NH3

NADH + H+

FH4

COOH

NAD+

CH2-NH2

GLYCINE

N5, N10-methylene FH4

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3. Synthesis of Glycine from Glyoxalate:

Glutamate -Ketoglutarate COOH PLP Glycine Transaminase CHO Glyoxylate

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4. Synthesis of Glycine from Threonine:

COOH Threonine Aldolase COOH CHO HC - NH2 + CH2-NH2 CH3 H –C- OH CH3 Threonine Glycine Acetaldehyde

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Catabolism:  

• There are several paths for catabolism of glycine.

• All, except one, are reversals of biosynthetic pathways.

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1. By the Action of Serine Hydroxy Methyl Transferase:

-This is also utilized for the synthesis of serine.

FH4 N5, N10 methylene FH4 PLP Glycine Serine Pyruvate Serine hydroxy methyl transferase

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2. By the Action of Glycine synthase ( also called Glycine

Cleavage System):

N5, N10 methylene FH4 FH4 Glycine CO2 + NH3 Glycine synthase NAD+ NADH+H+

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3. Transamination:

- Ketoglutarate Glutamate PLP Glycine Glyoxylate Oxalate (excreted in urine) Transaminase

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Functions of Glycine:  1.Required for protein

synthesis.

2.It forms many biologically important compounds – glucose,

serine (a non-essential amino acid), heme, conjugated bile acids,

creatine, glutathione and purines

3.It provides its carbon atom for one carbon pool.

4.It is required for certain detoxification reactions.

4.It acts as a neurotransmitter

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Functions of Glycine…..detoxification

Benzoic acid, a food preservative, is found in small

amounts in foods.

It is detoxified in the liver by

conjugation with Glycine to form water soluble,

Non-toxic Hippuric acid.

Glycine Benzoic acid Benzoyl CoA Hippuric acid CoA SH CoA SH

Excreted in urine

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1. CONSTITUENT OF PROTEINS: Glycine is mainly present at the bending points

because of its small size.

Collagen is the protein rich in Glycine; about 33% of the amino acids is Glycine.

2. GLUCOGENIC ROLE

Glycine Serine Pyruvate

Glucose

Functions of Glycine….Synthesis of biologically imp.

compounds

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Functions of Glycine….

3.SYNTHESIS OF SERINE

Serine hydroxy methyl transferase Glycine Serine

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Functions of Glycine….

4. HEME BIOSYNTHESIS

Glycine is one of the starting materials along with succinyl CoA for heme biosynthesis.

Glycine + succinyl CoA -Amino levulinic acid (ALA) Heme ALA synthase

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Functions of Glycine….

5. SYNTHESIS OF CONJUGATED BILE ACIDS:

Cholic acid Glycocholic acid Glycine

Conjugated Bile Acids Chenodeoxy cholic acid Glycochenodeoxy cholic acid. Glycine

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Functions of Glycine….

5.CREATINE SYNTHESIS

Creatine phosphate is formed from glycine, arginine and S-adenosyl methionine (SAM), in kidneys and liver.

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Functions of Glycine….creatine synthesis Glycine In Kidney Guanidoacetate Arginine Ornithine S-adenosyl methionine (SAM) In Liver

S-adenosyl homocysteine (SAH) Creatine ATP

Creatine Phosphokinase (CPK) ADP Pi + H2O Creatinine Creatine phosphate (NPN substance excreted Non-enzymatic (spontaneous) In urine)

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Function of Creatine Phosphate:

Creatine phosphate occurs mainly in muscles.

It is a high-energy compound (Go'= 10.5) and storage form of energy in muscle.

During the resting phase in muscle (relaxed) creatine is stored as creatine phosphate, which is produced by phosphorylation of creatine by ATP.

Muscle needs ATP for contraction. During prolonged muscle contraction depletion of ATP. During this period creatine phosphate rephosphorylates ADP to ATP

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In muscles……

ATP ADP

CREATINE CREATINE PHOSPHATE

Muscle creatine phosphokinase (CPK)

During resting phase(*ATP stores are full)

During prolonged contraction(*when ATP stores are depleted)

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Functions of Glycine….

6. SYNTHESIS OF GLUTATHIONE:

Glutathione (-glutamyl-cysteinyl-glycine) is a tripeptide formed from glycine, glutamate and cysteine. The reduced form is monomeric and carries hydrogen atom in the sulfhydryl group(-SH) of cysteinyl residue.

The oxidized form is dimeric.

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GLUTATHIONE…..

– Glu – Cys – Gly – Glu – Cys – Gly SH S

Reduced Glutathione (GSH) S

– Glu – Cys – Gly Oxidized Glutathione (GS–SG)

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GLUTATHIONE SYNTHESIS: Glutamic acid + Cysteine

- Glutamyl cysteine

Glutathione

ATP

ADP+Pi

Glycine

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FUNCTIONS OF GLUTATHIONE:

1.It serves as an Anti- oxidant in the body.

2.It serves as a cofactor for certain enzymes, such as glutathione peroxidase, which uses reduced glutathione to detoxify hydrogen peroxide.

Eg : RBC membrane integrity is maintained due to this action.

3.It is conjugated to drugs to make them more water-soluble, so that, they can be easily excreted ..

4.It also plays a role in the transport of amino acids across the plasma membrane in certain cells.

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Functions of Glycine….

7. SYNTHESIS OF PURINE RING:• C4, C5 and N7 of the purine ring are

provided by glycine.• Thus the whole molecule of glycine is

involved in the synthesis of purine.•  

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Inborn Errors of Glycine Metabolism:

1.Glycinuria:

This is a rare genetic disorder, probably resulting from a defect in the renal tubular reabsorption of glycine.

It is characterized by excessive excretion of glycine in urine (0.6 – 1 g per day) and a tendency to form oxalate renal stones.

However, plasma glycine levels are normal. 

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2.Primary Hyperoxaluria:Genetic/metabolic defect:

failure to catabolize glyoxalate.

glyoxalate is oxidized to oxalate.

overproduction of oxalate

excessive excretion of oxalate in urine (hyperoxaluria).

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progressive bilateral calcium renal stones

nephrocalcinosis and frequent urinary tract infection

hypertension and renal failure.

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Proteins Serine GLYCINE CO2 + NH3

Transamination Urea

Threonine Oxidation Glyoxylate

Creatine C4, C5, N7 of Purine ring Heme Glutathione Bile salts Conjugation E.g. Hippuric acid

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1.Explain the metabolism of glycine. Mention two disorders of glycine metabolism and their defects. 2.Enumerate the compounds formed from glycine, giving their biochemical importance. 3.Why glycine is nutritionally non-essential?4.Metabolic role of glycine. 5.Mention the compounds formed from Glycine.6.How is Creatinine synthesized? Discuss about creatinine clearance and its significance.

7.How creatine phosphate is synthesized. Mention the significance of estimation of urinary creatinine.

8.Glutathione and its functions.

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Metabolism of Serine 

H2N – CH – COOH

CH2 OH

Serine is an aliphatic hydroxy, non-essential and glucogenic amino acid.

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Metabolism of Serine 

H2N – CH – COOH

CH2 OH

Serine is an aliphatic hydroxy, non-essential and glucogenic amino acid.

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Metabolism of serine:

Synthesis:

Catabolism:

Functions:

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Synthesis:

3-Phosphoglycerate(Glycolytic intermediate)

(major source)

SERINE

Glycine

serine hydroxy methyl transferase

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Functions of Serine: 1.Required for protein synthesis. -As a constituent of protein it serves an important role in esterifying the phosphate groups as prosthetic group of proteins. Eg: casein

-Enzyme regulation by phosphorylation and dephosphorylation

-Forms active site of a group of enzymes called as serine proteases. Eg: trypsin

2.It provides its carbon atom for one carbon pool (by serine hydroxy methyl transferase reaction)

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Functions of Serine….3.It forms many biologically important

compounds

• Serine is glucogenica)glucose,

• cysteine, alanine and glycine

b)non-essential amino acids

• required for synthesis of phospholipids and acetylcholine

c) choline, ethanolamine

• for synthesis of sphingolipids.

d)sphingosine

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SERINE-Clinical Aspects

So, they are used as drugs e.g. azaserine

(anticancer drug) cycloserine

(antitubercular drug)

Serine analogues

inhibit nucleotide synthesis