Catabolism of the Carbon Skeletonsof Amino Acids
• Excess amino acids are catabolized to amphibolic intermediates used as sources of energy or for carbohydrate and lipid biosynthesis.
• Initial reaction • Transamination• Remove any additional nitrogen
– Hydrocarbon skeleton
Amphibolic intermediates formed from the carbon skeletons of amino acids.
• Transamination typically initiates amino acid catabolism– Except • Proline, hydroxyproline, threonine, and lysine.
Catabolism of L-asparagine and of L-glutamine to amphibolic intermediates.
Ornithine
• Ornithine-aminotransferase – Elevate plasma and urinary ornithine• Gyrate atrophy of the retina
• Hyperornithinemia- hyperammonemia syndrome– Defective mitochondrial ornithine-citrulline
antiporter
Catabolism of arginine
Catabolism of proline.
• Type I hyperprolinemia– Proline dehydrogenase
• Type II hyperprolinemia– Glutamate-semialdehyde dehydrogenase – Δ1-pyrroline-3-hydroxy-5-carboxylate is excreted.
Catabolism of histidine.
Disorders of histidinecatabolism
• Impaired histidase– Histidinemia – Urocanic aciduria
• Folic acid deficiency – Figlu is excreted
Interconversion of serine and glycine
Reversible cleavage of glycine by themitochondrial glycine synthase complex.
• Glycinuria– Defect in renal tubular reabsorption
• Primary hyperoxaluria– Failure to catabolize glyoxylate formed by
deamination of glycine.• Oxalate
– Urolithiasis, nephrocalcinosis » Renal failure, hypertension
The cystine reductase reaction.
Catabolism of L-cysteine via the cysteinesulfinate pathway
Catabolism of L-cysteine via the 3-mercaptopyruvate pathway
abnormalities of cysteine metabolism
• Cystine-lysinuria (cystinuria)– Defect in renal reabsorption
• Cystinosis – Deposition of cystine crystals in tissues
• Homocystinuria– Cardiovascular disease
Mixed disulfide of cysteine and homocysteine.
Conversion of threonine to glycine and acetyl-CoA.
Intermediates in L-hydroxyproline catabolism
• Hyperhydroxyprolinemia – 4-hydroxyproline dehydrogenase
• Type II hyperprolinemia – Second dehydrogenase
Intermediates in tyrosine catabolism.
Tyrosine metabolic disorders
• Type I tyrosinemia (tyrosinosis) – fumarylacetoacetate hydrolase
• Type II tyrosinemia (Richner-Hanhart syndrome) – Tyrosine aminotransferase
• Neonatal tyrosinemia– Lowered p-hydroxyphenylpyruvate hydroxylase
activity
• Alkaptonuria – Homogentisate oxidase• The urine darkens on exposure to air • arthritis and connective tissue pigmentation
(ochronosis)
Phenylalanine metabolic disorders
• Hyperphenylalaninemias– Type I, classic phenylketonuria or PKU)• Defects in phenylalanine hydroxylase
– Types II and III• defects in dihydrobiopterin reductase
– Types IV and V• Defects in dihydrobiopterin biosynthesis
• DNA probes facilitate prenatal diagnosis– Mental retardation
Alternative pathways of phenylalaninecatabolism in phenylketonuria
Catabolism of L-lysine.
• Periodic hyperlysinemia– Lysine competitively inhibits liver arginase• Hyperammonemia
Catabolism of L-tryptophan
Formation of xanthurenate in vitaminB6 deficiency
• Hartnup disease – Impaired intestinal and renal transport of
tryptophan and other neutral amino acids
Formation of S-adenosylmethionine
Conversion of methionine to propionyl- CoA
• The initial reactions are common to all three branched-chain amino acids
• branched-chain –keto acid dehydrogenase– Multimeric enzyme complex• A decarboxylase,• a transacylase• a dihydrolipoyl dehydrogenase
– Being inactivated by phosphorylation
The analogous first three reactions in the catabolism of leucine, valine, and isoleucine.
METABOLIC DISORDERS OF BRANCHEDCHAINAMINO ACID CATABOLISM
• Maple syrup urine disease (branched-chain ketonuria)– α-keto acid decarboxylase complex – Plasma and urinary levels of leucine, isoleucine,
valine, α-keto acids, and α-hydroxy acids (reduced α-keto acids) are elevated
• Isovaleric acidemia– Isovaleryl-CoA dehydrogenase
Catabolism of the β-methylcrotonyl-CoA formed from L-leucine
Subsequent catabolism of the tiglyl-CoA formed from L-isoleucine.
Subsequent catabolism of themethacrylyl-CoA formed from L-valine
Summary
• Excess amino acids are catabolized to amphibolic intermediates used as sources of energy or for carbohydrate and lipid biosynthesis.
• Initial reaction • Transamination• Remove any additional nitrogen
• Hydrocarbon skeleton– To amphibolic intermediates
• Metabolic diseases associated with glycine catabolism– Glycinuria – Primary hyperoxaluria
• Metabolic disorders of cysteine catabolism– Cystine-lysinuria,– Cystine storage disease, – Homocystinurias
• Metabolic diseases of tyrosine catabolism– Tyrosinosis,– Richner-Hanhart syndrome,– Neonatal tyrosinemia,– Alkaptonuria
• Metabolic disorders of phenylalanine catabolism– Phenylketonuria (PKU) – Several hyperphenylalaninemias.
• Metabolic diseases of lysine catabolism– Hyperlysinemiaammonemia • Forms
– Periodic – Persistent
• Metabolic disorders of branched-chain amino acid catabolism – Hypervalinemia – Maple syrup urine disease– Intermittent branched-chain ketonuria– Isovaleric acidemia– Methylmalonic aciduria