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Catabolism of the Carbon Skeletons
of 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 histidine
catabolism
• Impaired histidase
– Histidinemia
– Urocanic aciduria
• Folic acid deficiency
– Figlu is excreted
Interconversion of serine and glycine
Reversible cleavage of glycine by the
mitochondrial 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 cysteine
sulfinate pathway
Catabolism of L-cysteine via the 3mercaptopyruvate 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 phenylalanine
catabolism in phenylketonuria
Catabolism of L-lysine.
• Periodic hyperlysinemia
– Lysine competitively inhibits liver arginase
• Hyperammonemia
Catabolism of L-tryptophan
Formation of xanthurenate in vitamin
B6 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 BRANCHEDCHAIN
AMINO 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-methylcrotonylCoA formed from L-leucine
Subsequent catabolism of the tiglylCoA formed from L-isoleucine.
Subsequent catabolism of the
methacrylyl-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