Structural insight into acute intermittent porphyria
Structural insight into acute intermittent porphyria
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急性间歇性卟啉症的结构洞察
DOI：
10.1096/fj.08-115469
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发表时间：
2009-02-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Zhi-Jie
中科院分区：
文献类型：
--
作者：
Song, Gaojie;Li, Yang;Liu, Zhi-Jie
急性间歇性卟啉病（AIP）是一种遗传性血红素生物合成疾病，是最常见的卟啉病类型之一。胆色素原脱氨酶（PBGD）的活性降低与AIP的症状有关，该酶催化4分子胆色素原的连续缩合以产生前尿卟啉原。我们已经在2.2 nm分辨率下确定了人PBGD的三维结构。结构分析显示，二吡咯甲烷辅因子分子共价连接到C261，坐在带正电荷的裂缝区域。除了关键的催化剂D99之外，还可以看到许多其他残基与辅因子氢键结合并在催化中发挥作用。4个吡咯分子依次进入活性位点是通过铰链周围结构域的移动来实现的。H120 P突变导致失活的酶，支持H120作为铰链残基的作用。有趣的是，在患有AIP的患者中记录的人PBGD的一些突变位于远离活性位点。该结构在分子水平上提供了对PBGD作用机制的见解，并可以帮助开发用于上调AIP中PBGD活性的潜在药物。宋，G.，李，Y.，Cheng，C，Zhao，Y.，高，A.，张，R. Joachimiak，A.，Shaw，N.，刘Z-J急性间歇性卟啉症的结构洞察。FASEB J. 23，396-404（2009）
Acute intermittent porphyria (AIP), an inherited disease of heme biosynthesis, is one of the most common types of porphyria. Reduced activity of the enzyme porphobilinogen deaminase (PBGD), which catalyzes the sequential condensation of 4 molecules of porphobilinogen to yield preuroporphyrinogen, has been linked to the symptoms of AIP. We have determined the 3‐dimensional structure of human PBGD at 2.2 Å resolution. Analysis of the structure revealed a dipyrromethane cofactor molecule covalently linked to C261, sitting in a positively charged cleft region. In addition to the critical catalytic D99, a number of other residues are seen hydrogen bonded to the cofactor and play a role in catalysis. Sequential entry of 4 pyrrole molecules into the active site is accomplished by movement of the domains around the hinges. H120P mutation resulted in an inactive enzyme, supporting the role of H120 as a hinge residue. Interestingly, some of the mutations of the human PBGD documented in patients suffering from AIP are located far away from the active site. The structure provides insights into the mechanism of action of PBGD at the molecular level and could aid the development of potential drugs for the up‐regulation of PBGD activity in AIP.— Song, G., Li, Y., Cheng, C, Zhao, Y., Gao, A., Zhang, R., Joachimiak, A., Shaw, N., Liu, Z.‐J. Structural insight into acute intermittent porphyria. FASEB J. 23, 396–404 (2009)