The V388M Mutation Results in a Kinetic Variant Form of Phenylalanine Hydroxylase

Leandro, Paula; Rivera, Isabel; Lechner, Maria Celeste; Almeida, Isabel Tavares de; Konecki, David

doi:10.1006/mgme.2000.2970

Cited by 38 publications

(25 citation statements)

References 28 publications

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“…The two missense mutations, V388M and Q375R, were each detected in one allele. Kinetic studies of the mutant protein with the V388M mutation showed reduced affinity of the enzyme for L-Phe and tetrahydrobiopterin (Leandro et al, 2000). This mutation is relatively common in Brazil, Portugal, and Spain (Santos et al, 2006).…”

Section: Discussionmentioning

confidence: 95%

A preliminary mutation analysis of phenylketonuria in southwest Iran

Ajami¹,

Nezhad²,

Foroughmand³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Phenylketonuria (PKU) is a heterogeneous and autosomal recessive metabolic disorder that is mainly caused by mutations in the hepatic phenylalanine hydroxylase (PAH) gene. This study was designed to identify PAH mutations within exons 6, 7, and 10-12 in PKU patients from southwest Iran. Forty Iranian patients with clinical and biochemically confirmed PKU were enrolled. The exons were sequenced directly and 13 different mutations were identified including I224T, S231P, R176X, c.592_613del22, R243X, R252W, R261Q, Y356X, V388M, IVS10-11G>A, IVS11+1G>C, IVS11-2A>G, and Q375R, which were associated with 23 genotypes. A novel sequence variant, Q375R (c.1124A>G), was detected in exon 11. In one patient, a typical genotype with more than two mutations (R243X/S231P/ S231P) was found. Seven different polymorphisms and three new variants were also detected in intron regions of PAH. A high mutation spectrum was predicted in the southwestern region of Iran due to its ethnic heterogeneity, especially the Khuzestan Province. The detection PAH mutations in southwest Iran of 13 different mutations, corresponding to a mutation detection rate of 53.75%, confirmed this phenomenon.

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Section: Discussionmentioning

confidence: 95%

A preliminary mutation analysis of phenylketonuria in southwest Iran

Ajami¹,

Nezhad²,

Foroughmand³

et al. 2013

Genet. Mol. Res.

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“…Recent structural and mutational studies of hinge-bending regions (41,42,44) have revealed further evidence that global activating conformational changes caused by L-Phe binding have the epicenter at the active site and are transmitted throughout the enzyme through hinge-bending motions. A reduction or loss of the cooperative substratedependent activation has been seen for most of the kinetically characterized PKU mutations to date (20,45,46), severe as well as mild forms, suggesting that the enzyme is quite susceptible to mutations that destroy the cooperative activation mechanism probably by hindering the transmission of the conformational change. The kinetic Hill coefficient (h) shows that some of the mutants tested in our study displayed a complete loss of cooperativity, in particular the I65T, E178G, R261Q, A300S, and V388M mutants (h ϭ 1.1 or 1.0) ( Table 2).…”

Section: Discussionmentioning

confidence: 99%

Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations

Erlandsen

Pey

Gámez

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

152

162

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Phenylketonuria patients harboring a subset of phenylalanine hydroxylase (PAH) mutations have recently shown normalization of blood phenylalanine levels upon oral administration of the PAH cofactor tetrahydrobiopterin [(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4)]. Several hypotheses have been put forward to explain BH 4 responsiveness, but the molecular basis for the corrective effect(s) of BH4 has not been understood. We have investigated the biochemical, kinetic, and structural changes associated with BH4-responsive mutations (F39L, I65T, R68S, H170D, E178G, V190A, R261Q, A300S, L308F, A313T, A373T, V388M, E390G, P407S, and Y414C). The biochemical and kinetic characterization of the 15 mutants studied points toward a multifactorial basis for the BH4 responsiveness; the mutants show residual activity (>30% of WT) and display various kinetic defects, including increased Km (BH4) and reduced cooperativity of substrate binding, but no decoupling of cofactor (BH4) oxidation. For some, BH4 seems to function through stabilization and protection of the enzyme from inactivation and proteolytic degradation. In the crystal structures of a phenylketonuria mutant, A313T, minor changes were seen when compared with the WT PAH structures, consistent with the mild effects the mutant has upon activity of the enzyme both in vitro and in vivo. Truncations made in the A313T mutant PAH form revealed that the N and C termini of the enzyme influence active site binding. Of fundamental importance is the observation that BH4 appears to increase Phe catabolism if at least one of the two heterozygous mutations has any residual activity remaining.

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“…Only a minority of the disease-causing mutations directly affect the kinetic properties of the enzyme (e.g., D143G ). Some mutations appear to have combined effects on both sutrate or cofactor binding [Leandro et al, 2000;Gjetting et al, 2001b] and on protein folding Gamez et al, 2000].…”

Section: In Vitro Expression Analysismentioning

confidence: 99%

PAHdb 2003: What a locus-specific knowledgebase can do

et al. 2003

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For the PKU Special IssuePAHdb, a legacy of and resource in genetics, is a relational locus-specific database (http:// www.pahdb.mcgill.ca). It records and annotates both pathogenic alleles (n = 439, putative diseasecausing) and benign alleles (n = 41, putative untranslated polymorphisms) at the human phenylalanine hydroxylase locus (symbol PAH). Human alleles named by nucleotide number (systematic names) and their trivial names receive unique identifier numbers. The annotated gDNA sequence for PAH is typical for mammalian genes. An annotated gDNA sequence is numbered so that cDNA and gDNA sites are interconvertable. A site map for PAHdb leads to a large array of secondary data (attributes): source of the allele (submitter, publication, or population); polymorphic haplotype background; and effect of the allele as predicted by molecular modeling on the phenylalanine hydroxylase enzyme (EC 1.14.

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The V388M Mutation Results in a Kinetic Variant Form of Phenylalanine Hydroxylase

Cited by 38 publications

References 28 publications

A preliminary mutation analysis of phenylketonuria in southwest Iran

A preliminary mutation analysis of phenylketonuria in southwest Iran

Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations

PAHdb 2003: What a locus-specific knowledgebase can do

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