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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations
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Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations

机译：四氢生物蝶呤对具有某些苯丙氨酸羟化酶突变的苯丙酮尿​​症患者的动力学和稳定性缺陷的校正

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摘要

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 tetra hydrobiopterin [(6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4. Several hypotheses have been put forward to explain BH4 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, 165T, 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 K-m (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 IN 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.
机译：携带部分苯丙氨酸羟化酶（PAH）突变的苯丙酮尿​​症患者最近显示口服PAH辅因子四氢生物蝶呤[（6R）-L-erythro-5,6,7,8-四氢生物蝶呤（BH4）后血液中苯丙氨酸水平正常化。提出了几种假说来解释BH4反应性，但尚不清楚BH4纠正作用的分子基础。我们已经研究了与BH4反应性突变相关的生化，动力学和结构变化（F39L，165T ，R68S，H170D，E178G，V190A，R261Q，A300S，L308F，A313T，A373T，V388M，E390G，P407S和Y414C）。研究的15个突变体的生化和动力学特性为BH4响应性的多因素基础提供了依据；突变体显示残留活性（> WT的30％）并显示各种动力学缺陷，包括Km（BH4）增加和底物结合的协同作用降低，但辅因子（BH4）氧化没有解偶联。 BH4似乎通过稳定和保护酶免受失活和蛋白水解降解而起作用。在苯基酮尿症突变体A313T的晶体结构中，与WT PAH结构相比，观察到微小变化，这与该突变体在体外和体内对酶活性的轻微影响相一致。以A313T突变PAH形式截短表明，该酶的IN和C末端会影响活性位点结合。最重要的观察结果是，如果两个杂合突变中至少有一个保留任何剩余的活性，则BH4似乎会增加Phe分解代谢。

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