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ProteinMetbolism part1

The document outlines protein and amino acid metabolism, covering essential processes such as the breakdown of proteins, amino acid catabolism phases, and the urea cycle which detoxifies ammonia. It highlights the biological importance of amino acids in protein synthesis and their metabolic pathways, including transamination and deamination. Clinical implications of amino acid metabolism disorders, including hyperammonemia and genetic defects, are also discussed.

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Protein & Amino acid Metabolism Dr.Ganesh
Protein and Amino acid Metabolism The syllabus for this chapter includes the following topics. PART I
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
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
Protein and Amino acid Metabolism PART II Metabolism of Amino acids sulfur containing amino acids, aromatic amino acids, histidine & arginine
Introduction Proteins 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.
Biological importance: 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. 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.)
Medical importance: 1.Genetic defects in the pathways of amino acid metabolism can cause serious disease. Eg: Albinism, Phenlyketonuria, Alkaptonuria etc. 2. Dietary deficiancy of proteins can result in disease such as P.E.M (protein energy malnutrition)
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.
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 Converted to UREA acid. Enters 2nd phase and excreted. (most important route for disposing of nitrogen from the body.)
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
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.
BODY PROTEIN DIATARY PROTEIN Digestion and absorption Synthesis of new amino acids catabolism synthesis AMINO ACID POOL SYNTHESIS OF BIOLOGICALLY IMP. COMPOUNDS CATABOLISM
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 Reutilization for new protein synthesis degradation Amino acids Catabolism
Metabolism of Amino Nitrogen Overview Transamination Deamination Reactions (Ammonia Formation) •Oxidative deamination •Non-oxidative deamination Ammonia Transport Disposal of Ammonia – Urea cycle.
Overview of Metabolism of Amino Nitrogen -Ketoglutarate Amino acids Transmination Glutamate Keto acids -NH2 Oxidative deamination Aspartate -NH2 CO2 Other Reactions NH3 Urea Cycle Urea H2N-CO-NH2
TRANSAMINATION Definition: 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).
General Reaction: AMINO ACID 1 KETO ACID 1 PLP TRANSAMINASE KETO ACID 2 AMINO ACID2
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.
Examples: 1) Alanine Ketoglutarate 2) Aspartate ALT PLP AST Pyruvate Glutamate Oxaloacetate PLP Ketoglutarate Glutamate ALT Alanine Transaminase; AST Aspartate transaminase
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.
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
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)
Describe transamination. Mention the clinical significance of serum transaminases. (4) Clinical importance of transamination (3) Questions?? Write the reaction, with cofactors if any, catalyzed by Alanine transaminase. (3) Name the coenzyme forms of vitamin B6; write the mechanism of transamination
Ammonia Formation – Deamination Reactions Ammonia is Produced in the Body by: 1) Cellular Metabolism and 2) In the Intestinal Lumen.
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
Deamination Reactions(Ammonia formation) Deamination is removal of amino group from compounds, mostly amino acids, as ammonia (NH3). NH3 +carbon skeleton of amino acid (KETOACID) CONVERTED TO UREA
Deamination….2types 1.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
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 deamination Site: 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+
Oxidative deamination of glutamate… + NAD / NADP + Glutamate + H2O NADH/ NADPH + H + -Ketoglutarate + NH3 Glutamate dehydrogenase (GDH)
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.
What Is Transdeamination ?? Transamination and deamination often occur simultaneously involving glutamate as the central molecule. this process is called transdeamination.
What Is Transdeamination ?? All amino acids TISSUES transamination -KG Keto acids GLUTAMATE Deamination in liver NH3+ -KG UREA Carried by blood Reaches liver
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 – NH group of urea.
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.
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
Non-Oxidative Deamination Enzymes Involved are: Dehydratases Lyases and Amide Hydrolases
Dehydratase Amino Acid Dehydratases (PLP-dependent) Serine/Threonine Dehydratase PLP NH3 Pyruvate/ -Ketobutyrate
Amino Acid Lyase Histidine Aspartate Histidase Aspartase NH3 NH3 Urocanate Fumarate
Amino Acid Amide Hydrolases Glutamine Aspargine H2O H2O Glutaminase Asparginase NH3 NH3 Glutamate Aspartate
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.
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.
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.
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 NH3 Glutamine synthetase Glutamate ATP glutamine .Mg2+ ADP+Pi Transported to liver via blood
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 .
In the liver.. Glutaminase Glutamine H2O glutamate NH3 UREA
UREA CYCLE (Detoxification of Ammonia) Contents: • Synonyms • Site • Sources of Atoms of Urea • Reactions • Functions • Ammonia Toxicity – Hyperammonemia
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.
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
Sources of Atoms of Urea NH2 O || C NH2 NH3 CO2 Aspartate
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
Reactions of Urea Cycle CO2 + NH3 + 2 ATP Carbamoyl Phosphate Synthetase–I (CPS-I) Carbamoyl Phosphate + 2 ADP + Pi Urea Ornithine Arginase TCA cycle Arginine Ornithine Transcarbamoylase Fumarate Arginosuccinase Citruline Arginosuccinate Aspartate Arginosuccinate Synthetase ATP AMP + PPi
Functions of Urea Cycle 1.Detoxification of NH3 2.Biosynthesis of Arginine.
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.
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.
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
Inherited Causes of Hyperammonemia Disease Hyperammonemia Type-I Enzyme involved CPS-I Hyperammonemia Type –II Ornithine Transcarbamoylase Citrullinemia Argininosuccinate Synthetase Argininosuccinic Aciduria Argininosuccinase Hyperarginemia Arginase
Ammonia Toxicity – Hyperammonemia • Biochemical Alterations: – Hyperammonemia, – In Blood of Intermediates Prior to Metabolic Block – Urinary NH3 • Clinical Manifestations Nausea, Vomiting, Protein Intolerance. Slurring of Speech, Blurring of Vision Tremor (Flapping Tremors), Ataxia, Lethargy Mental Retardation (in the Inherited Hyperammonemia in Children) Dizziness, Coma, Death
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)
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
Metabolism of Glycine H H2N–C–COOH H R Group GLYCINE is the simplest, optically inactive, glucogenic and non-essential amino acid.
Metabolism of Glycinecontents Synthesis Catabolism Synthesis of biologically imp. Compounds from glycine Inborn errors of glycine metabolism
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.
• 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
1. Synthesis of Glycine from Serine: Serine hydroxy methyl transferase COOH COOH PLP HC-NH2 CH2OH Serine CH2 FH4 N5, N10-methylene FH4 NH2 Glycine One carbon unit (methylene group, –CH2–) from serine is transfered to tetrahydro folic acid (FH4).
2. Synthesis of Glycine from CO2, NH3 and N5, N10 methylene THFA: • This reaction is catalyzed by glycine synthase. COOH NADH + H+ NAD+ CH2-NH2 GLYCINE CO2 + NH3 N5, N10-methylene FH4 FH4
3. Synthesis of Glycine from Glyoxalate: Glutamate COOH CHO Glyoxylate -Ketoglutarate PLP Transaminase Glycine
4. Synthesis of Glycine from Threonine: COOH Threonine Aldolase COOH HC - NH2 H –C- OH CH3 Threonine CHO + CH2-NH2 Glycine CH3 Acetaldehyde
Catabolism: • There are several paths for catabolism of glycine. • All, except one, are reversals of biosynthetic pathways.
1. By the Action of Serine Hydroxy Methyl Transferase: -This is also utilized for the synthesis of serine. 5 10 FH4 N , N methylene FH4 PLP Glycine Serine Serine hydroxy methyl transferase Pyruvate
2. By the Action of Glycine synthase ( also called Glycine Cleavage System): 5 10 N , N methylene FH4 FH4 Glycine CO2 + NH3 Glycine synthase NAD + + NADH+H
3. Transamination: - Ketoglutarate Glutamate PLP Glycine Glyoxylate Oxalate (excreted in urine) Transaminase
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
Functions of Glycine…..detoxification Benzoic acid, a food preservative, is found in small amounts in foods. Glycine Benzoic acid CoA SH Benzoyl CoA It is detoxified in the liver by conjugation with Glycine to form water soluble, Non-toxic Hippuric acid. Hippuric acid CoA SH Excreted in urine
Functions of Glycine…. Synthesis of biologically imp. compounds 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…. 3.SYNTHESIS OF SERINE Serine hydroxy methyl transferase Glycine Serine
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
Functions of Glycine…. 5. SYNTHESIS OF CONJUGATED BILE ACIDS: Cholic acid Glycine Glycocholic acid Conjugated Bile Acids Chenodeoxy cholic acid Glycine Glycochenodeoxy cholic acid.
Functions of Glycine…. 5.CREATINE SYNTHESIS Creatine phosphate is formed from glycine, arginine and S-adenosyl methionine (SAM), in kidneys and liver.
Functions of Glycine….creatine synthesis Glycine Arginine In Kidney Ornithine Guanidoacetate 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)
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
In muscles…… During resting phase(*ATP stores are full) ATP Muscle creatine phosphokinase ADP (CPK) CREATINE CREATINE PHOSPHATE During prolonged contraction (*when ATP stores are depleted)
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.
GLUTATHIONE….. – Glu – Cys – Gly – Glu – Cys – Gly SH S Reduced Glutathione (GSH) S – Glu – Cys – Gly Oxidized Glutathione (GS–SG)
GLUTATHIONE SYNTHESIS: Glutamic acid + Cysteine ATP ADP+Pi - Glutamyl cysteine Glycine Glutathione
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.
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. •
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.
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).
progressive bilateral calcium renal stones nephrocalcinosis and frequent urinary tract infection hypertension and renal failure.
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
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.
Metabolism of Serine H2N – CH – COOH CH2 OH Serine is an aliphatic hydroxy, nonessential and glucogenic amino acid.
Metabolism of Serine H2N – CH – COOH CH2 OH Serine is an aliphatic hydroxy, nonessential and glucogenic amino acid.
Metabolism of serine: Synthesis: Catabolism: Functions:
Synthesis: 3-Phosphoglycerate(Glycolytic intermediate) (major source) SERINE serine hydroxy methyl transferase Glycine
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)
Functions of Serine…. 3.It forms many biologically important compounds a)glucose, b)non-essential amino acids • Serine is glucogenic • cysteine, alanine and glycine • required for synthesis of c) choline, phospholipids and ethanolamine acetylcholine d)sphingosine • for synthesis of sphingolipids.
SERINE-Clinical Aspects Serine analogues inhibit nucleotide synthesis So, they are used as drugs e.g. azaserine (anticancer drug) cycloserine (antitubercular drug)

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ProteinMetbolism part1

  • 2.
    Protein & Aminoacid Metabolism Dr.Ganesh
  • 3.
    Protein and Aminoacid Metabolism The syllabus for this chapter includes the following topics. PART I
  • 4.
    Protein and Aminoacid 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
  • 5.
    Introduction Overview of AminoAcid Metabolism Nitrogen Balance and amino acid pool Protein Turnover Metabolism of Amino Nitrogen Metabolism of Individual Amino Acids – Glycine and serine
  • 6.
    Protein and Aminoacid Metabolism PART II Metabolism of Amino acids sulfur containing amino acids, aromatic amino acids, histidine & arginine
  • 7.
    Introduction Proteins are linearhetero 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.
  • 8.
    Biological importance: 1.Proteins containnitrogen and they are main source of nitrogen for the body. Dietary Proteins are the sources of essential amino acids for the body. 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.)
  • 9.
    Medical importance: 1.Genetic defectsin the pathways of amino acid metabolism can cause serious disease. Eg: Albinism, Phenlyketonuria, Alkaptonuria etc. 2. Dietary deficiancy of proteins can result in disease such as P.E.M (protein energy malnutrition)
  • 10.
    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.
  • 11.
    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 Converted to UREA acid. Enters 2nd phase and excreted. (most important route for disposing of nitrogen from the body.)
  • 12.
    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
  • 13.
    Amino acid pool Aminoacids 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.
  • 14.
    BODY PROTEIN DIATARY PROTEIN Digestionand absorption Synthesis of new amino acids catabolism synthesis AMINO ACID POOL SYNTHESIS OF BIOLOGICALLY IMP. COMPOUNDS CATABOLISM
  • 15.
    PROTEIN TURNOVER: the continuousdegradation and resynthesis of all cellular proteins Each day about 1–2% of the total body proteins, principally muscle protein, undergoes turnover. Body proteins Reutilization for new protein synthesis degradation Amino acids Catabolism
  • 16.
    Metabolism of AminoNitrogen Overview Transamination Deamination Reactions (Ammonia Formation) •Oxidative deamination •Non-oxidative deamination Ammonia Transport Disposal of Ammonia – Urea cycle.
  • 17.
    Overview of Metabolismof Amino Nitrogen -Ketoglutarate Amino acids Transmination Glutamate Keto acids -NH2 Oxidative deamination Aspartate -NH2 CO2 Other Reactions NH3 Urea Cycle Urea H2N-CO-NH2
  • 18.
    TRANSAMINATION Definition: Transamination isthe 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).
  • 19.
    General Reaction: AMINO ACID1 KETO ACID 1 PLP TRANSAMINASE KETO ACID 2 AMINO ACID2
  • 20.
    Mechanism:  Pyridoxal phosphateis 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.
  • 21.
  • 22.
    Salient features: All aminoacids 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.
  • 23.
    Metabolic Functions: 1.Diverting excessof 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
  • 24.
    Clinical Aspects: Blood levelsof 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)
  • 25.
    Describe transamination. Mention theclinical significance of serum transaminases. (4) Clinical importance of transamination (3) Questions?? Write the reaction, with cofactors if any, catalyzed by Alanine transaminase. (3) Name the coenzyme forms of vitamin B6; write the mechanism of transamination
  • 26.
    Ammonia Formation – DeaminationReactions Ammonia is Produced in the Body by: 1) Cellular Metabolism and 2) In the Intestinal Lumen.
  • 27.
    1.Ammonia formation bycellular metabolism Cells produce ammonia mostly from amino acids by deamination, which may be either 1. oxidative or 2. non-oxidative
  • 28.
    Deamination Reactions(Ammonia formation) Deamination isremoval of amino group from compounds, mostly amino acids, as ammonia (NH3). NH3 +carbon skeleton of amino acid (KETOACID) CONVERTED TO UREA
  • 29.
    Deamination….2types 1.Oxidative deamination a)deamination ofglutamate 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
  • 30.
    Oxidative Deamination by GlutamateDehydrogenase (GDH): The removal of the amino group from glutamate to release NH3 and -ketoglutarate coupled with oxidation is known as oxidative deamination Site: 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+
  • 31.
    Oxidative deamination ofglutamate… + NAD / NADP + Glutamate + H2O NADH/ NADPH + H + -Ketoglutarate + NH3 Glutamate dehydrogenase (GDH)
  • 32.
    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.
  • 33.
    What Is Transdeamination?? Transamination and deamination often occur simultaneously involving glutamate as the central molecule. this process is called transdeamination.
  • 34.
    What Is Transdeamination?? All amino acids TISSUES transamination -KG Keto acids GLUTAMATE Deamination in liver NH3+ -KG UREA Carried by blood Reaches liver
  • 35.
    Glutamate occupies acentral 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 – NH group of urea.
  • 36.
    What are thesources 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.
  • 37.
    Oxidative Deamination by AminoAcid Oxidases • Amino Acid Oxidases are: -- Flavoproteins -- Possessing either FMN or FAD Amino Acid FAD/FMN Amino Acid Oxidase FADH2/FMNH2 -Keto Acid + NH3
  • 38.
    Non-Oxidative Deamination Enzymes Involvedare: Dehydratases Lyases and Amide Hydrolases
  • 39.
    Dehydratase Amino Acid Dehydratases(PLP-dependent) Serine/Threonine Dehydratase PLP NH3 Pyruvate/ -Ketobutyrate
  • 40.
  • 41.
    Amino Acid AmideHydrolases Glutamine Aspargine H2O H2O Glutaminase Asparginase NH3 NH3 Glutamate Aspartate
  • 42.
    2)NH3 production inintestine 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.
  • 43.
    Transport of Ammonia Ammoniais 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.
  • 44.
    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.
  • 45.
    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 NH3 Glutamine synthetase Glutamate ATP glutamine .Mg2+ ADP+Pi Transported to liver via blood
  • 46.
    This reaction maybe 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 .
  • 47.
  • 48.
    UREA CYCLE (Detoxification ofAmmonia) Contents: • Synonyms • Site • Sources of Atoms of Urea • Reactions • Functions • Ammonia Toxicity – Hyperammonemia
  • 49.
    UREA CYCLE . (Detoxificationof 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.
  • 50.
    UREA CYCLE (Detoxification ofAmmonia) • Synonyms: Urea Cycle Ornithine Cycle Krebs-Henseleit Cycle • Site: Urea Synthesized in Liver Carried by Blood And Excreted by Kidneys
  • 51.
    Sources of Atomsof Urea NH2 O || C NH2 NH3 CO2 Aspartate
  • 52.
    UREA CYCLE (Detoxification ofAmmonia) • Urea Synthesis: -- A 5-step Cyclic Process • Enzymes of the First 2 Steps: -- Present in Mitochondria • While the Rest: -- Located in the Cytosol
  • 53.
    Reactions of UreaCycle CO2 + NH3 + 2 ATP Carbamoyl Phosphate Synthetase–I (CPS-I) Carbamoyl Phosphate + 2 ADP + Pi Urea Ornithine Arginase TCA cycle Arginine Ornithine Transcarbamoylase Fumarate Arginosuccinase Citruline Arginosuccinate Aspartate Arginosuccinate Synthetase ATP AMP + PPi
  • 54.
    Functions of UreaCycle 1.Detoxification of NH3 2.Biosynthesis of Arginine.
  • 55.
    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.
  • 56.
    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.
  • 57.
    2.Inherited Causes -- DefectsAssociated 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
  • 58.
    Inherited Causes ofHyperammonemia Disease Hyperammonemia Type-I Enzyme involved CPS-I Hyperammonemia Type –II Ornithine Transcarbamoylase Citrullinemia Argininosuccinate Synthetase Argininosuccinic Aciduria Argininosuccinase Hyperarginemia Arginase
  • 59.
    Ammonia Toxicity – Hyperammonemia •Biochemical Alterations: – Hyperammonemia, – In Blood of Intermediates Prior to Metabolic Block – Urinary NH3 • Clinical Manifestations Nausea, Vomiting, Protein Intolerance. Slurring of Speech, Blurring of Vision Tremor (Flapping Tremors), Ataxia, Lethargy Mental Retardation (in the Inherited Hyperammonemia in Children) Dizziness, Coma, Death
  • 60.
    Blood Urea In HealthyPeople, 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)
  • 61.
    1. How ammoniais 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
  • 62.
    Metabolism of Glycine H H2N–C–COOH H RGroup GLYCINE is the simplest, optically inactive, glucogenic and non-essential amino acid.
  • 63.
    Metabolism of Glycinecontents Synthesis Catabolism Synthesisof biologically imp. Compounds from glycine Inborn errors of glycine metabolism
  • 64.
    Synthesis Glycine is anon-essential amino acid as it can be synthesized in the body. It can be synthesized from many substances by separate reactions.
  • 65.
    • The majorreactions 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
  • 66.
    1. Synthesis ofGlycine from Serine: Serine hydroxy methyl transferase COOH COOH PLP HC-NH2 CH2OH Serine CH2 FH4 N5, N10-methylene FH4 NH2 Glycine One carbon unit (methylene group, –CH2–) from serine is transfered to tetrahydro folic acid (FH4).
  • 67.
    2. Synthesis ofGlycine from CO2, NH3 and N5, N10 methylene THFA: • This reaction is catalyzed by glycine synthase. COOH NADH + H+ NAD+ CH2-NH2 GLYCINE CO2 + NH3 N5, N10-methylene FH4 FH4
  • 68.
    3. Synthesis ofGlycine from Glyoxalate: Glutamate COOH CHO Glyoxylate -Ketoglutarate PLP Transaminase Glycine
  • 69.
    4. Synthesis ofGlycine from Threonine: COOH Threonine Aldolase COOH HC - NH2 H –C- OH CH3 Threonine CHO + CH2-NH2 Glycine CH3 Acetaldehyde
  • 70.
    Catabolism: • There areseveral paths for catabolism of glycine. • All, except one, are reversals of biosynthetic pathways.
  • 71.
    1. By theAction of Serine Hydroxy Methyl Transferase: -This is also utilized for the synthesis of serine. 5 10 FH4 N , N methylene FH4 PLP Glycine Serine Serine hydroxy methyl transferase Pyruvate
  • 72.
    2. By theAction of Glycine synthase ( also called Glycine Cleavage System): 5 10 N , N methylene FH4 FH4 Glycine CO2 + NH3 Glycine synthase NAD + + NADH+H
  • 73.
  • 74.
    Functions of Glycine: 1.Requiredfor 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
  • 75.
    Functions of Glycine…..detoxification Benzoic acid,a food preservative, is found in small amounts in foods. Glycine Benzoic acid CoA SH Benzoyl CoA It is detoxified in the liver by conjugation with Glycine to form water soluble, Non-toxic Hippuric acid. Hippuric acid CoA SH Excreted in urine
  • 76.
    Functions of Glycine…. Synthesisof biologically imp. compounds 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
  • 77.
    Functions of Glycine…. 3.SYNTHESISOF SERINE Serine hydroxy methyl transferase Glycine Serine
  • 78.
    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
  • 79.
    Functions of Glycine…. 5.SYNTHESIS OF CONJUGATED BILE ACIDS: Cholic acid Glycine Glycocholic acid Conjugated Bile Acids Chenodeoxy cholic acid Glycine Glycochenodeoxy cholic acid.
  • 80.
    Functions of Glycine…. 5.CREATINESYNTHESIS Creatine phosphate is formed from glycine, arginine and S-adenosyl methionine (SAM), in kidneys and liver.
  • 81.
    Functions of Glycine….creatinesynthesis Glycine Arginine In Kidney Ornithine Guanidoacetate 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)
  • 82.
    Function of Creatine Phosphate: Creatinephosphate 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
  • 83.
    In muscles…… During restingphase(*ATP stores are full) ATP Muscle creatine phosphokinase ADP (CPK) CREATINE CREATINE PHOSPHATE During prolonged contraction (*when ATP stores are depleted)
  • 84.
    Functions of Glycine…. 6. SYNTHESISOF 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.
  • 85.
    GLUTATHIONE….. – Glu –Cys – Gly – Glu – Cys – Gly SH S Reduced Glutathione (GSH) S – Glu – Cys – Gly Oxidized Glutathione (GS–SG)
  • 86.
    GLUTATHIONE SYNTHESIS: Glutamic acid+ Cysteine ATP ADP+Pi - Glutamyl cysteine Glycine Glutathione
  • 87.
    FUNCTIONS OF GLUTATHIONE: 1.Itserves 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.
  • 88.
    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. •
  • 89.
    Inborn Errors ofGlycine 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.
  • 90.
    2.Primary Hyperoxaluria: Genetic/metabolic defect: failureto catabolize glyoxalate. glyoxalate is oxidized to oxalate. overproduction of oxalate excessive excretion of oxalate in urine (hyperoxaluria).
  • 91.
    progressive bilateral calciumrenal stones nephrocalcinosis and frequent urinary tract infection hypertension and renal failure.
  • 92.
    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
  • 93.
    1.Explain the metabolismof 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.
  • 94.
    Metabolism of Serine H2N– CH – COOH CH2 OH Serine is an aliphatic hydroxy, nonessential and glucogenic amino acid.
  • 95.
    Metabolism of Serine H2N– CH – COOH CH2 OH Serine is an aliphatic hydroxy, nonessential and glucogenic amino acid.
  • 96.
  • 97.
  • 98.
    Functions of Serine: 1.Requiredfor 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)
  • 99.
    Functions of Serine…. 3.Itforms many biologically important compounds a)glucose, b)non-essential amino acids • Serine is glucogenic • cysteine, alanine and glycine • required for synthesis of c) choline, phospholipids and ethanolamine acetylcholine d)sphingosine • for synthesis of sphingolipids.
  • 100.
    SERINE-Clinical Aspects Serine analogues inhibit nucleotide synthesis So, theyare used as drugs e.g. azaserine (anticancer drug) cycloserine (antitubercular drug)