Individual amino acids metabolism of clinical importance ط Overview of synthesis of some important products of amino acids : Phenylalanine, Tyrosine, Tryptophane, … ط Inborn error of protein metabolism : site of metabolic defect : Alkaptenuria, Albinism, Tyrosinosis, parkinson’s disease…. ط Branched chain amino acids degradation ط Maple syrup syndrome D

Phenylketouria (PKU) cc11.5 · fig11.46, Most common cause by enzymes deficiency of AA metabolism - Autosomal recessive deficiency of phenylalanine hydroxylase - fig11.48, Deficiency of biopterin synthesis or reduction (dihydrobiopterin reductase) · fig11.47, High excretion of phenyllactate, phenylpyruvate & phenylacetate leading to mousy odour urine · Phenylalanine toxicity lead to reduced transport and metabolism of other aromatic AAs in brain - Causing mental retardation, sever neurological symptoms and low IQ · Tyrosine deficiency lead to underpigmentation of skin and eyes · fig11.50, Biopterin deficiency lowers serotonin and catecholamine (neurotransmitters) synthesis - Leading to defect in CNS function · If after birth routine screening is positive, treat for 4-5 years - deficiency of hydroxylase, treat by low phenylalanine diet and including tyrosine - deficiency of biopterin, treat by addition of biopterin to diet and precursors of serotonin & catecholamines

Disorders of Tyrosine Metabolism cc11.6 Deficiency of Enzymes of tyrosine metabolism lead to accumulation and excretion of tyrosine and its metabolites 1. Tyrosinemia fig11.49 a) Type I, rare - autosomal recessive deficiency of fumarylacetoacetate (FLA) hydroxylase - accumulation of FLA lead to * liver failure, renal tubular dysfunction, rickets, poly neuropathy * DNA alkylation and tumorigenesis b) Type II, - deficiency of tyrosine aminotransferase - lead to eye and skin lesions, metal retardation 2. Alcaptonuria fig11.53 Autosomal recessive deficiency of homogentisate oxidase lead to Excretion of tyrosine in urine (colourless urine) Pigments deposit in bone and connective tissue (oxidize accumulation) - pigmentations could cause arthritis 3. Albinism fig11.52 · Deficiency of tyrosine (tyrosinase) lead to skin and eyes having little or no pigment - sensitivity to light leading to burns and carcinoma of skin - photophobia

Parkinson’s Disease cc11.7 · Usually occur to over 60 years old but can occur to drug addicts (pyridine derivatives) · Tremors may develop and interfere with muscle fuction · Caused by degeneration of brain cells (nigra and locus caeruleus), but aetiology still unknown - fig11.50, these cells produce dopamine (neurotransmitters) · DOPA (dopamine precursor) can be used for treatment - cause side effects: nausea, vomiting, hypotension, cardiac arrhythmia and various CNS symptoms · DOPA analogue (can not cross blood brain barrier) are effective in reducing side effects · Attempts still been made to transplant fetal adrenal medullary tissue in brain

· Deficiency of BC-AA catabolic enzymes (aminotransferases) is not common · Deficiency produce acidosis in newborn and children - rarely produce hypervalinemia, -leucinemia, -isoleucinemia · most common deficiency is of branched-chain keto acid dehydrogenase complex - accumulation of BC-keto acids cause mental retardation, keto acidosis, short-life span - excretion of BC-keto acids lead to maple syrup urine disease · Can be treated by high doses of thiamine in diet · fig11.68, Other enzymes deficiency in later BC-AA catabolic reactions - Isovaleryl CoA Dehydrogenase - β-Methylcromonyl CoA Carboxylase - β-Hydroxy β-Methylglutaryl CoA Lyase - β-Ketothiolase Diseases of Metabolism of Branch-Chain Amino Acids (val, leu, ile) cc11.10