Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis
Structural genomics of enzymes involved in sterol/isoprenoid biosynthesis
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DOI：
10.1073/pnas.181466998
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发表时间：
2001-11-06
影响因子：
11.1
通讯作者：
Burley, SK
中科院分区：
文献类型：
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作者：
Bonanno, JB;Edo, C;Burley, SK
在一项结构基因组学的初步研究中，已经确定了甾醇/类异戊二烯生物合成途径中两种酶的X射线结构。甲羟戊酸-5-二磷酸羧化酶（MDD）是一种单结构域α/β蛋白，其催化将甲羟戊酸转化为异戊烯基二磷酸的三个连续ATP依赖性反应中的最后一个。异戊烯基二磷酸异构酶（IDI）是催化异戊烯基二磷酸和二甲基烯丙基二磷酸的相互转化的α/β金属酶，所述异戊烯基二磷酸和二甲基烯丙基二磷酸在下一步中缩合以合成甾醇和许多天然产物。相关蛋白质的同源性建模和MIDD和IDI结构与其他两个实验确定的结构的比较表明，MDD是小分子激酶的GHMP超家族的成员，IDI类似于nutrient水解酶，其作用于含核苷酸二磷酸的底物。产生了379种蛋白质的结构模型，包括两个蛋白质超家族的很大一部分。负责从甲羟戊酸合成异戊烯基二磷酸的所有三种酶（甲羟戊酸激酶、磷酸甲羟戊酸激酶和MDD）共享相同的折叠，催化化学相似底物的磷酸化（MDD脱羧涉及甲羟戊酸二磷酸的磷酸化），并且似乎从共同的祖先进化而来。这些结构和衍生自它们的结构模型为解释生物化学功能和进化关系提供了一个框架。
X-ray structures of two enzymes in the sterol/isoprenoid blosynthesis pathway have been determined in a structural genomics pilot study. Mevalonate-5-diphosphate clecarboxylase (MDD) is a single-domain alpha/beta protein that catalyzes the last of three sequential ATP-depenclent reactions which convert mevalonate to isopentenyl diphosphate. Isopentenyl disphosphate isomerase (IDI) is an alpha/beta metalloenzyme that catalyzes interconversion of isopentenyl diphosphate and dimethylallyl diphosphate, which condense in the next step toward synthesis of sterols and a host of natural products. Homology modeling of related proteins and comparisons of the MIDD and IDI structures with two other experimentally determined structures have shown that MDD is a member of the GHMP superfamily of small-molecule kinases and IDI is similar to the nudix hydrolases, which act on nucleotide diphosphate-containing substrates. Structural models were produced for 379 proteins, encompassing a substantial fraction of both protein superfamilies. All three enzymes responsible for synthesis of isopentenyl diphosphate from mevalonate (mevalonate kinase, phosphomevalonate kinase, and MDD) share the same fold, catalyze phosphorylation of chemically similar substrates (MDD decarboxylation involves phosphorylation of mevalonate diphosphate), and seem to have evolved from a common ancestor. These structures and the structural models derived from them provide a framework for interpreting biochemical function and evolutionary relationships.