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Titolo:
In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: Correlation with metabolic phenotypes and susceptibility toward protein aggregation
Autore:
Gjetting, T; Petersen, M; Guldberg, P; Guttler, F;
Indirizzi:
John F Kennedy Inst, DK-2600 Glostrup, Denmark John F Kennedy Inst Glostrup Denmark DK-2600 , DK-2600 Glostrup, Denmark
Titolo Testata:
MOLECULAR GENETICS AND METABOLISM
fascicolo: 2, volume: 72, anno: 2001,
pagine: 132 - 143
SICI:
1096-7192(200102)72:2<132:IVEO3N>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
MISSENSE MUTATIONS; STRUCTURAL BASIS; GENE PAH; PHENYLKETONURIA; ENZYME; DEGRADATION; HYPERPHENYLALANINEMIA; GENOTYPE; HETEROGENEITY; DEHYDRATASE;
Keywords:
phenylalanine hydroxylase; phenylketonuria; in vitro expression; protein aggregation; genotype-phenotype correlations;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Guttler, F John F Kennedy Inst, Gl Landevej 7, DK-2600 Glostrup, Denmark John F Kennedy Inst Gl Landevej 7 Glostrup Denmark DK-2600 ark
Citazione:
T. Gjetting et al., "In vitro expression of 34 naturally occurring mutant variants of phenylalanine hydroxylase: Correlation with metabolic phenotypes and susceptibility toward protein aggregation", MOL GEN MET, 72(2), 2001, pp. 132-143

Abstract

Phenylalanine hydroxylase (PAH) is a homotetrameric enzyme that catalyzes the conversion of phenylalanine to tyrosine, the rate-limiting step of phenylalanine disposal in humans. Primary dysfunction of PAH caused by mutations in the PAH gene results in hyperphenylalaninemia, which may impair cognitive development unless corrected by dietary restriction of phenylalanine. The mechanism(s) by which PAH missense mutations cause enzyme impairment hasbeen studied in detail only in a small number of cases, but existing evidence points to a major role of enhanced proteolytic degradation due to aberrant folding of mutant polypeptides. We have used two heterologous in vitro expression systems (a mammalian cell-free transcription-translation system and the pET system of Escherichia coli) to examine 34 mutations that have been associated with PAH deficiency in the Danish population. These mutations represent a broad range of amino acid substitutions, functional enzyme domains, and metabolic phenotypes. In both systems, residual in vitro activities correlated broadly with metabolic phenotypes, however, with significantdiscrepancies. Analysis of E. coli extracts by nondenaturing polyacrylamide gel electrophoresis and storage experiments showed that (i) in general, mutations in the N-terminal regulatory domain are associated with relativelystable proteins compared to most mutations in the central catalytic domain, and (ii) for mutations in the catalytic domain, high levels of protein aggregation do not always correspond with a severe phenotype. Our data support and extend previous evidence that PAH mutations exert their pathogenic effects by several distinct mechanisms that may operate individually or in concert. (C) 2001 Academic Press.

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Documento generato il 11/07/20 alle ore 04:34:10