Amino Acid Metabolism - School of Medicine - LSU Health ...€¦ · Role of “one -carbon pool”...
Transcript of Amino Acid Metabolism - School of Medicine - LSU Health ...€¦ · Role of “one -carbon pool”...
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Amino Acid Metabolism
Dr. Shyamal DesaiOctober 1, 2010
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AMINO ACID METABOLISM AND CATABOLISM
Source of Energy
Citric acid cycle
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Proteins
Amino Acids
α-amino group carbon skeletons
seven intermediate products
oxaloacetateα-ketaglutarate
pyruvatefumaratesuccinyl coenzyme Aacetyl coenzyme Aacetoacetate
Metabolic Pathways
Amino Acid metabolism/catabolism Metabolic pathway
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Classification of Amino Acid
Pyruvate and other TCA cycle intermediates
Citric acid cycle (TCA)
Gluconeogenesis
Acetoacetate (Ketone Bodies) or Acetyl CoAAcetoacetyl CoA
Alternate energy source
Succinyl coenzyme A
precurssorsof acetoacetate
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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, Biotin etc.
These single carbon units can be transferred from carrier compounds to specific structures that are being synthesized or modified.
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Tetrahydrofolate is an active form of Folic acid (vitamin B9 or folacin).
Folate THFDihydrofolate reductase
Nucleotide and protein synthesis, Methylation of many biological compounds etc
Tetrahydrofolate
Dihydrofolatereductase
Glycine Serine
One-carbon-unit
Dihydrofolatereductase Methotrexate
Anti-Cancer drug
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Tetrahydrofolate
The One-Carbon Units include different groups linked to THF:
THF acts as a carrier of reactive single carbon units, which are bonded to N-5 and N-10.
The oxidation level can be changed to methyl or methenyl by reduction or oxidation; methenylTHFcan be hydrolyzed to formylTHF.
These derivatives can be used in synthetic reactions as donors of single C at the appropriate oxidation level.
Tetrahydrofolate(THF)
N5-Methyl THFN5-Formimino THF
N10-Formyl THF
N5, N10-MethyleneTHF
N5, N10-
MethenylTHF
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S-adenosylmethionine SAM
Methionine adenosyltransferase (MAT), which catalyzes the biosynthesis of S-adenosylmethionine (SAM) , the principal methyl donor.
Methylation targets are:DNA RNA Proteins Lipids Hormones and neurotransmitters
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S-adenosylmethionine SAM
SAM serves as a precursor for numerous methyl transfer reactions
Synthesis of SAM
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Conversion of Norepinephrine to Epinephrine requires SAM
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Classification of Amino Acid
Pyruvate and other TCA cycle intermediates
Citric acid cycle (TCA)
Gluconeogenesis
Acetoacetate or Acetyl CoAAcetoacetyl CoA
Alternate energy source
Succinyl coenzyme A
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Asparagine and Aspartate enter metabolism as oxaloacetate
AsparginaseAnti-cancer drug
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Gln, Pro, Arg, and His enter metabolism as α-ketoglutarate
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Glutamine Glutamine
Glutamate + NH3
OxidativeDeamination
Amino acids that forms α-ketoglutarate
Glutaminase
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Amino acids that forms α-ketoglutarate
Proline
Proline GlutamateOxidized
OxidativeDeamination
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Amino acids that forms α-ketoglutarate
ArginineArginine
Arginase
Ornithine
α-ketoglutarate
Urea cycle
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Histidine
Amino acids that forms α-ketoglutarate
Oxidativelydeaminated
OxidativeDeamination
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Amino Acid that forms pyruvate
AlanineTransamination of alanine to form pyruvate
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Amino Acid that forms pyruvate
Glycine
This reaction provides the largest part of the one-carbon units available to the cell.
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Amino Acid that forms pyruvate
Serine
This reaction provides the largest part of the one-carbon units available to the cell.
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Cystine
Cysteine
desulfuration
pyruvate
Reduced using NADH + H+ as a reductant
Cystine is a dimeric amino acid formed by the oxidation of two Cysteine residues which covalently link to make a disulphidebond.
Amino Acid that forms pyruvate
CystineCysteine
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Amino Acid that forms pyruvate
SuccinylCoA
Glucogenic & Ketogenic
Propionyl CoAdehydrated
Threonine dehydrogenaseα-amino-β-ketobutyrate lyase
Pyruvate dehydrogenase
Threonine
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Amino acids that form fumarate
Phenylalanine and Tyrosine
Glucogenic Ketogenic
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Amino acids that form succinyl CoA
Methionine
Methionine is special because:
* Converted to S-adenosylmethionine (SAM), the major methyl-group donor inone-carbon metabolism
* Source of homocysteine ----a metabolite associated with atherosclerotic vascular disease
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Amino Acid that forms Succinyl CoA
S-Adenosylmethioninesynthatase
SAMMethyltransferase
S-adenosylhomocysteine
L-Homocysteine
MethionineSynthatase
MethionineCystathioneβ-synthase
Cystathionine
γ-cystathionaseL-Cysteine
Hydrolysis of SAM: Homocysteine
Methionine cysteine
α-ketbutyrate Oxidativelydecarboxylated
PropionylCoA
SuccinylCoA
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Homocysteine and vascular diseases
HomocysteinePromotes oxidative damageInflammationEndothelial dysfunction
Risk factors for occlusive vascular diseases
Plasma levels of homocystein is inversely related to folate, Vitamin B12 , and B6.
Homocysteine levels are also increased in Homocystinurea; disease caused due to the defectivecystathione β-synthatase is defective
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Catabolism of the branched-Chain amino acids
Essential aa
TRANSAMINATION(Branched-chain α-amino acid transferase
α-Ketoisocaproic acid α-Ketoisovaleric acid α-Keto-β-methylvaleric acid
OXIDATIVE DECARBOXYLATIONBranched-chain α-keto acid dehydrogenase complex (TPP, NAD, CoA
Lipolic acid, FAD)
Isovaleryl CoA Isobutyryl CoA a-Methyl butyryl CoA
FAD-linked DEHYDROGENATION
Acetoacetate +Acetyl CoA Propionyl CoA
Succinyl CoA
Acetyl CoA
Maple SyrupUrine disease
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Amino acids that form acetyl CoA and acetoacetyl CoA
Leucine Isoleucine *Lysine Trptophan
AcetoacetateAcetyl CoA
Acetyl CoAPropionyl CoA
Acetoacetyl CoA
* Unusal---never undergoestransamination
Alanineand acetoacetylCoA
Ketogenic KetogenicAndGucogenic
KetogenicKetogenicAnd Glucogenic
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Biosynthesis of non-essential amino acids
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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.
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Biosynthesis of Glutamine and Aspargine
Synthesis by amidation: Glutamine, Aspargine
GlutamineAspargine
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Biosynthesis of Proline, Serine and Cysteine
Proline Glutamate ProlineCyclization and reduction
Serine and Glycine
Cysteine
3-phosphoglycerate
Oxidized
3-phosphopyruvate
transaminated
3-phosphoserineHydrolysis ofphosphate
Serine
Serine
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Biosynthesis of Tyrosine
Tyrosine