Insights into the biosynthesis of isoprenoid precursors and their potential in semisynthetic strategies

类异戊二烯（萜）是已知的天然产物中最大的一类（至少有35000种）。虽然动物通过甲羟戊酸途径生物合成类异戊二烯，但现在已经确定许多致病菌和致病性原生动物的顶复合体亚群使用最近发现的非甲羟戊酸途径来实现这一目的。非甲羟戊酸途径的酶在这些病原体中是必不可少的。它们是开发新型抗感染药物的有希望的靶标，由于在人类宿主中缺乏这一途径，这些药物应该免于与靶标相关的毒性。非甲羟戊酸途径的最后一步提供通用的类异戊二烯前体IPP和DMAPP，由ispG和ispH基因指定的两个铁硫蛋白催化。最近，我们确定了IspG和IspH蛋白的晶体结构。这项工作将为利用x射线晶体学、酶动力学、核磁共振以及定点诱变进一步阐明这些蛋白质的反应机制奠定基础。这些方法也将应用于研究IspG和IspH抑制剂的作用方式。

Isoprenoids (terpenes) are the largest group of known natural products (at least 35,000) [1]. Whereas animals biosynthesize isoprenoids via the mevalonate pathway, it is now established that many pathogenic bacteria and the apicomplexan subgroup of pathogenic protozoa use the more recently discovered nonmevalonate pathway for that purpose. The enzymes of the non-mevalonate pathway are essential in these pathogens. They are promising targets for the development of novel antiinfective drugs which should be exempt from target-related toxicity, due to the absence of the pathway in the human host. The final steps of the non-mevalonate pathway affording the universal isoprenoid precursors IPP and DMAPP are catalyzed by two iron-sulfur proteins specified by the ispG and ispH genes. Recently, we have determined the crystal structures of IspG and IspH protein. This work will serve as basis for the further elucidation of the reaction mechanisms of these proteins, using X-ray crystallography, enzyme kinetics, NMR and as well as sitedirected mutagenesis. These methods will also be applied to study the mode of action of IspG and IspH inhibitors.