Pérez Belén, Desviat Lourdes R, Gómez-Puertas Paulino, Martínez Aurora, Stevens Rymond C, Ugarte Magdalena
Centro de Biología Molecular Severo Ochoa, CSIC-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Mol Genet Metab. 2005 Dec;86 Suppl 1:S11-6. doi: 10.1016/j.ymgme.2005.06.009. Epub 2005 Aug 8.
From all the different molecular mechanisms put forward to explain the basis of BH4 responsiveness in PKU patients, a clear picture is now emerging based on the results from expression studies performed with a number of missense mutations identified in patients with a positive response in BH4 loading tests. Two of the proposed mechanisms, namely decreased binding affinity of the mutant proteins for the natural cofactor and stabilization effect of BH4, have been confirmed for several PKU mutations and the results are reviewed here. The actual view supports a multifactorial basis of the response, highlighting the necessity of detailed in vitro characterization of each mutant PAH protein. Several of the confirmed molecular mechanisms may be operating simultaneously, as exemplified in the data presented, and this may result in different degrees of BH4 responsiveness.
从所有为解释苯丙酮尿症（PKU）患者对四氢生物蝶呤（BH4）反应性的基础而提出的不同分子机制来看，基于对在BH4负荷试验中有阳性反应的患者中鉴定出的一些错义突变进行表达研究的结果，一幅清晰的图景正在浮现。所提出的两种机制，即突变蛋白对天然辅因子的结合亲和力降低以及BH4的稳定作用，已在几种PKU突变中得到证实，此处对结果进行综述。实际观点支持反应的多因素基础，强调了对每个突变型苯丙氨酸羟化酶（PAH）蛋白进行详细体外表征的必要性。正如所呈现的数据示例那样，一些已证实的分子机制可能同时起作用，这可能导致不同程度的BH4反应性。
