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Amino

Dr. Shyamal Desai October 1, 2010 METABOLISM AND

Source of Energy

Citric acid cycle Amino Acid metabolism/catabolism

Amino

α-amino group skeletons

seven intermediate products

1 α-ketaglutarate 2 oxaloacetate 3 pyruvate 4 fumarate Metabolic Pathways 5 succinyl 6 acetyl coenzyme A 7 acetoacetate Classification of Amino Acid

Pyruvate and other Acetoacetate ( Bodies) TCA cycle intermediates or Acetyl CoA precurssors Acetoacetyl CoA of acetoacetate Succinyl coenzyme A cycle (TCA)

Alternate energy source Role of “one-carbon pool” in Amino Acid Metabolism/catabolism

The “one-carbon pool” refers to single carbon units attached to the group of carrier compounds such as Tetrahydrofolate, S-adenosylmethione, etc.

These single carbon units can be transferred from carrier compounds to specific that are being synthesized or modified. Tetrahydrofolate

Tetrahydrofolate is an active form of Folic acid ( B9 or folacin).

Nucleotide and synthesis, THF of many biological compounds etc

Dihydrofolate Anti-Cancer reductase Methotrexate

Dihydrofolate reductase

Glycine

One-carbon-unit Tetrahydrofolate

The One-Carbon Units include different groups linked to THF:

THF acts as a carrier of reactive single carbon units, N5-Formimino which are bonded to N-5 and N-10. 5 Tetrahydrofolate N -Methyl THF THF (THF) The oxidation level can be changed to methyl or methenyl by reduction or oxidation; methenylTHF can be hydrolyzed to formylTHF.

These derivatives can be used in synthetic reactions as donors of single C at the appropriate oxidation level.

N5, N10- N10-Formyl 5 10 N , N -Methylene Methenyl THF THF THF S-adenosylmethionine SAM

Methionine adenosyltransferase (MAT), which catalyzes the of S- adenosylmethionine (SAM) , the principal methyl donor.

Methylation targets are: DNA RNA Proteins and Synthesis of SAM

S-adenosylmethionine SAM

SAM serves as a precursor for numerous methyl transfer reactions Conversion of to Epinephrine requires SAM Classification of Amino Acid

Pyruvate and other Acetoacetate or Acetyl CoA TCA cycle intermediates Acetoacetyl CoA Succinyl coenzyme A

Citric acid cycle (TCA) Alternate energy source

Gluconeogenesis and Aspartate enter metabolism as oxaloacetate

Asparginase Anti-cancer drug Gln, Pro, Arg, and His enter metabolism as α- ketoglutarate Amino acids that forms α-ketoglutarate

Glutamine

Glutamate + NH3

Oxidative Amino acids that forms α-ketoglutarate

Proline

Oxidized Glutamate

Oxidative Deamination Amino acids that forms α-ketoglutarate

Arginine

Arginase cycle

Ornithine

α-ketoglutarate Amino acids that forms α-ketoglutarate

Histidine

Oxidatively deaminated

Oxidative Deamination Amino Acid that forms pyruvate

Alanine

Transamination of to form pyruvate Amino Acid that forms pyruvate

Glycine

This reaction provides the largest part of the one-carbon units available to the . Amino Acid that forms pyruvate

Serine

This reaction provides the largest part of the one-carbon units available to the cell. Amino Acid that forms pyruvate

Cystine is a dimeric amino acid formed by the oxidation of two residues Reduced using NADH + H+ as which covalently link to make a disulphide a reductant bond. Cysteine desulfuration pyruvate

Cystine Cysteine Amino Acid that forms pyruvate Glucogenic & Ketogenic

Threonine dehydrated Succinyl Propionyl CoA CoA

Threonine dehydrogenase α-amino-β-ketobutyrate lyase

Pyruvate dehydrogenase Amino acids that form fumarate

Phenylalanine and

Glucogenic Ketogenic Amino acids that form succinyl CoA

Methionine

Methionine is special because:

* Converted to S-adenosylmethionine (SAM), the major methyl-group donor in one-carbon metabolism * Source of ----a metabolite associated with atherosclerotic vascular disease Amino Acid that forms Succinyl CoA

Hydrolysis of SAM: Homocysteine

S-Adenosylmethionine synthatase

SAM Methionine cysteine Methyltransferase

S-adenosylhomocysteine Methionine Synthatase

L-Homocysteine Cystathione Methionine β-synthase

Cystathionine γ-cystathionase Oxidatively Propionyl Succinyl α-ketbutyrate L-Cysteine decarboxylated CoA CoA

Homocysteine and vascular diseases

Promotes oxidative damage Homocysteine Risk factors for Inflammation occlusive vascular Endothelial dysfunction diseases

Plasma levels of homocystein is inversely related to folate, , and B6.

Homocysteine levels are also increased in Homocystinurea; disease caused due to the defective cystathione β-synthatase is defective Catabolism of the branched-Chain amino acids

Essential aa

TRANSAMINATION (Branched-chain α-amino acid

α-Ketoisocaproic acid α-Ketoisovaleric acid α-Keto-β-methylvaleric acid OXIDATIVE Urine disease Branched-chain α- dehydrogenase complex (TPP, NAD, CoA Lipolic acid, FAD)

Isovaleryl CoA Isobutyryl CoA a-Methyl butyryl CoA

FAD-linked DEHYDROGENATION

Acetoacetate + Acetyl CoA Propionyl CoA Acetyl CoA

Succinyl CoA Amino acids that form acetyl CoA and acetoacetyl CoA

Leucine * Trptophan

Acetoacetate Acetyl CoA Acetoacetyl CoA Alanine Acetyl CoA Propionyl CoA * Unusal---never and acetoacetyl undergoes CoA transamination

Ketogenic Ketogenic Ketogenic Ketogenic And And Glucogenic Gucogenic Biosynthesis of non-essential amino acids Biosynthesis of non-essential amino acids

Synthesis from α-keto acids: Alanine, Aspartate, Glutamate

Alanine, aspartate, and glutamate are synthesized by transfer of an amino group to the α- keto acids pyruvate, oxaloacetate, and α-ketoglutarate, respectively. Biosynthesis of Glutamine and Aspargine

Synthesis by amidation: Glutamine, Aspargine

Aspargine Glutamine Biosynthesis of Proline, Serine and Cysteine

Cyclization and reduction Proline Glutamate Proline

Cysteine Serine Serine and Glycine 3-phosphoglycerate Oxidized 3-phosphopyruvate transaminated 3-phosphoserine of phosphate Serine Biosynthesis of Tyrosine

Tyrosine