Pemberton Travis A, Christianson David W
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, USA.
Radcliffe Institute for Advanced Study, and Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
J Antibiot (Tokyo). 2016 Jul;69(7):486-93. doi: 10.1038/ja.2016.39. Epub 2016 Apr 13.
Terpenoid cyclases catalyze the most complex reactions in biology, in that more than half of the substrate carbon atoms often undergo changes in bonding during the course of a multistep cyclization cascade that proceeds through multiple carbocation intermediates. Many cyclization mechanisms require stereospecific deprotonation and reprotonation steps, and most cyclization cascades are terminated by deprotonation to yield an olefin product. The first bacterial terpenoid cyclase to yield a crystal structure was pentalenene synthase from Streptomyces exfoliatus UC5319. This cyclase generates the hydrocarbon precursor of the pentalenolactone family of antibiotics. The structures of pentalenene synthase and other terpenoid cyclases reveal predominantly nonpolar active sites typically lacking amino acid side chains capable of serving general base-general acid functions. What chemical species, then, enables the Brønsted acid-base chemistry required in the catalytic mechanisms of these enzymes? The most likely candidate for such general base-general acid chemistry is the co-product inorganic pyrophosphate. Here, we briefly review biological and nonbiological systems in which phosphate and its derivatives serve general base and general acid functions in catalysis. These examples highlight the fact that the Brønsted acid-base activities of phosphate derivatives are comparable to the Brønsted acid-base activities of amino acid side chains.
萜类环化酶催化生物学中最复杂的反应，因为在通过多个碳正离子中间体进行的多步环化级联反应过程中，通常超过一半的底物碳原子的键会发生变化。许多环化机制需要立体特异性的去质子化和再质子化步骤，并且大多数环化级联反应通过去质子化终止以产生烯烃产物。第一个获得晶体结构的细菌萜类环化酶是来自脱落链霉菌UC5319的戊塔烯合成酶。这种环化酶产生戊内酯类抗生素的烃前体。戊塔烯合成酶和其他萜类环化酶的结构显示，其活性位点主要是非极性的，通常缺乏能够发挥广义酸碱功能的氨基酸侧链。那么，是什么化学物质促成了这些酶催化机制中所需的布朗斯特酸碱化学呢？这种广义酸碱化学最有可能的候选者是副产物无机焦磷酸。在这里，我们简要回顾一下磷酸盐及其衍生物在催化中发挥广义酸碱功能的生物和非生物系统。这些例子突出了一个事实，即磷酸盐衍生物的布朗斯特酸碱活性与氨基酸侧链的布朗斯特酸碱活性相当。
