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