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The activity of wild type and mutant phenylalanine hydroxylase with respect to the C-oxidation of phenylalanine and the S-oxidation of S-carboxymethyl-L-cysteine. 2009

Glyn B Steventon, and Stephen C Mitchell, and Belen Pérez, and Lourdes R Desviat, and Magdalena Ugarte
King's College London, Pharmaceutical Science Division, Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. glyn.steventon@kcl.ac.uk

The involvement of the enzyme, phenylalanine hydroxylase (PAH), in the S-oxidation of S-carboxymethyl-L-cysteine (SCMC) is now firmly established in man and rat. However, the underlying role of the molecular genetics of PAH in dictating and influencing the S-oxidation polymorphism of SCMC metabolism is as yet unknown. In this work we report that the S-oxidation of SCMC was dramatically reduced in the tetrahydrobiopterin (BH(4)) responsive mutant PAH proteins (I65T, R68S, R261Q, V388M and Y414C) with these enzymes possessing between 1.2% and 2.0% of the wild type PAH activity when SCMC was used as substrate. These same mutant proteins express between 23% and 76% of the wild type PAH activity when phenylalanine was used as the substrate. The PAH mutant proteins (R158Q, I174T and R408W) that result in the classical phenylketonuria (PKU) phenotype expressing 0.2-1.8% of the wild type PAH activity when using phenylalanine as substrate were found to have <0.1% of the wild type PAH activity when SCMC was used as the substrate. Mutations that result in PAH proteins retaining some residual PAH activity with phenylalanine as substrate have <2.0% residual activity when SCMC was used as a substrate. This investigation has led to the hypothesis that the S-oxidation polymorphism in man is a consequence of an individual carrying one mutant PAH allele which has resulted in the loss of the ability of the residual PAH protein to undertake the S-oxidation of SCMC in vivo.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D010084 Oxidation-Reduction A chemical reaction in which an electron is transferred from one molecule to another. The electron-donating molecule is the reducing agent or reductant; the electron-accepting molecule is the oxidizing agent or oxidant. Reducing and oxidizing agents function as conjugate reductant-oxidant pairs or redox pairs (Lehninger, Principles of Biochemistry, 1982, p471). Redox,Oxidation Reduction
D010649 Phenylalanine An essential aromatic amino acid that is a precursor of MELANIN; DOPAMINE; noradrenalin (NOREPINEPHRINE), and THYROXINE. Endorphenyl,L-Phenylalanine,Phenylalanine, L-Isomer,L-Isomer Phenylalanine,Phenylalanine, L Isomer
D010651 Phenylalanine Hydroxylase An enzyme of the oxidoreductase class that catalyzes the formation of L-TYROSINE, dihydrobiopterin, and water from L-PHENYLALANINE, tetrahydrobiopterin, and oxygen. Deficiency of this enzyme may cause PHENYLKETONURIAS and PHENYLKETONURIA, MATERNAL. EC 1.14.16.1. Phenylalanine 4-Hydroxylase,Phenylalanine 4-Monooxygenase,4-Hydroxylase, Phenylalanine,4-Monooxygenase, Phenylalanine,Hydroxylase, Phenylalanine,Phenylalanine 4 Hydroxylase,Phenylalanine 4 Monooxygenase
D010661 Phenylketonurias A group of autosomal recessive disorders marked by a deficiency of the hepatic enzyme PHENYLALANINE HYDROXYLASE or less frequently by reduced activity of DIHYDROPTERIDINE REDUCTASE (i.e., atypical phenylketonuria). Classical phenylketonuria is caused by a severe deficiency of phenylalanine hydroxylase and presents in infancy with developmental delay; SEIZURES; skin HYPOPIGMENTATION; ECZEMA; and demyelination in the central nervous system. (From Adams et al., Principles of Neurology, 6th ed, p952). Biopterin Deficiency,Dihydropteridine Reductase Deficiency Disease,Hyperphenylalaninemia, Non-Phenylketonuric,Phenylalanine Hydroxylase Deficiency Disease,BH4 Deficiency,DHPR Deficiency,Deficiency Disease, Dihydropteridine Reductase,Deficiency Disease, Phenylalanine Hydroxylase,Deficiency Disease, Phenylalanine Hydroxylase, Severe,Dihydropteridine Reductase Deficiency,Folling Disease,Folling's Disease,HPABH4C,Hyperphenylalaninaemia,Hyperphenylalaninemia Caused by a Defect in Biopterin Metabolism,Hyperphenylalaninemia, BH4-Deficient, C,Hyperphenylalaninemia, Tetrahydrobiopterin-Deficient, Due To DHPR Deficiency,Non-Phenylketonuric Hyperphenylalaninemia,Oligophrenia Phenylpyruvica,PAH Deficiency,PKU, Atypical,Phenylalanine Hydroxylase Deficiency,Phenylalanine Hydroxylase Deficiency Disease, Severe,Phenylketonuria,Phenylketonuria I,Phenylketonuria II,Phenylketonuria Type 2,Phenylketonuria, Atypical,Phenylketonuria, Classical,QDPR Deficiency,Quinoid Dihydropteridine Reductase Deficiency,Tetrahydrobiopterin Deficiency,Atypical PKU,Atypical Phenylketonuria,Biopterin Deficiencies,Classical Phenylketonuria,Deficiency, BH4,Deficiency, Biopterin,Deficiency, DHPR,Deficiency, Dihydropteridine Reductase,Deficiency, PAH,Deficiency, Phenylalanine Hydroxylase,Deficiency, QDPR,Deficiency, Tetrahydrobiopterin,Disease, Folling,Disease, Folling's,Hyperphenylalaninemia, Non Phenylketonuric,Non Phenylketonuric Hyperphenylalaninemia,Non-Phenylketonuric Hyperphenylalaninemias
D002233 Carbocysteine A compound formed when iodoacetic acid reacts with sulfhydryl groups in proteins. It has been used as an anti-infective nasal spray with mucolytic and expectorant action. 3-(Carboxymethylthio)alanine,Carbocysteine, L-Isomer,Mucodine,Mucodyne,Mukodin,Rhinathiol,S-(Carboxymethyl)-L-cysteine,S-Carboxymethylcysteine,Thiodril,Carbocysteine, L Isomer,L-Isomer Carbocysteine,S Carboxymethylcysteine
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D013379 Substrate Specificity A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts. Specificities, Substrate,Specificity, Substrate,Substrate Specificities
D020125 Mutation, Missense A mutation in which a codon is mutated to one directing the incorporation of a different amino acid. This substitution may result in an inactive or unstable product. (From A Dictionary of Genetics, King & Stansfield, 5th ed) Missense Mutation,Missense Mutations,Mutations, Missense

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