PKU AND OTHER DISEASES CAUSED BY DEFECTS IN BIOPTERIN DEPENDENT ENZYMES

我们以前已经证明， 蝶呤甲醇胺脱氢酶（PCD），一种功能 作为催化苯丙氨酸转化的系统的一部分 酪氨酸，可引起高苯丙氨酸血症（HPA）。因为PCD 仅在相对难以接近的组织如肾脏中富集， 肝脏，PCD缺陷的检测是困难的。我们已经证明， 然而，这种酶mRNA在人体中很容易检测到 毛囊和白色血细胞。mRNA的检测 毛囊和白色血细胞中的PCD将大大促进 由于缺乏PCD，HPA的诊断应该作为一个有用的 开始治疗这种疾病的指南。我们一直 研究两种不同的人类突变体的特性 苯丙氨酸羟化酶与苯丙酮尿症相关 (PKU)在体内，I65T，其中位置65处的异亮氨酸残基被 被苏氨酸残基和T92I取代，其中， 位置92被异亮氨酸替代。这两种突变蛋白都具有 沿着， 用野生型酶。虽然在这方面存在显著差异， 苯丙氨酸和四氢生物蝶呤的Km值已被 在突变蛋白中检测到，这些变化似乎并不 足以引起患者的PKU。最有可能的解释是， 因此，对于这些突变如何导致PKU表型， 在体内它们比野生型降解得更快 酵素我们计划调查这种解释是否有效。

We have previously shown that a deficiency of pterin carbinolamine dehydratase (PCD), an enzyme that functions as part of the system that catalyzes the conversion of phenylalanine to tyrosine, can cause hyperphenylalaninemia (HPA). Because PCD is only enriched in relatively inaccessible tissues such as kidney and liver, detection of PCD deficiency is difficult. We have shown, however, that mRNA for this enzyme is easily detectable in human hair follicles and in white blood cells. The detection of mRNA for PCD in hair follicles and white blood cells will greatly facilitate diagnosis of HPA due to a lack of PCD and should serve as a useful guideline for initiation of treatment of this disease. We have been studying the properties of two different mutant forms of human phenylalanine hydroxylase that are associated with phenylketonuria (PKU) in vivo, I65T, in which an isoleucine residue at position 65 is replaced by a threonine residue and T92I, in which a threonine at position 92 is replaced by an isoleucine. Both mutant proteins have been purified and their catalytic characteristics determined, along with the wild- type enzyme. Although significant differences in the Km values for phenylalanine and tetrahydrobiopterin have been detected in the mutant proteins, these changes do not appear to be sufficient to cause PKU in the patients. The most likely explanation, therefore, for how these mutations lead to the PKU phenotype is that in vivo they are degraded more rapidly than the wild-type enzyme. We plan to investigate whether this explanation is valid.