Biosynthesis of 2-hydroxyethylphosphonate, an unexpected intermediate common to multiple phosphonate biosynthetic pathways
Biosynthesis of 2-hydroxyethylphosphonate, an unexpected intermediate common to multiple phosphonate biosynthetic pathways
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DOI：
10.1074/jbc.m801788200
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发表时间：
2008-08-22
影响因子：
4.8
通讯作者：
Zhao, Huimin
中科院分区：
文献类型：
--
作者：
Shao, Zengyi;Blodgett, Joshua A. V.;Zhao, Huimin
磷酸包括一类共同的但化学上不同的天然产品，这些产品往往具有强大的生物活性。在这里，我们报道，尽管这些化合物之间存在显著的结构差异，但它们的生物合成路线包含一种意想不到的共同中间体-2-羟乙基膦酸酯，它是由膦乙醛通过一系列不同的金属依赖的乙醇脱氢酶(ADHS)合成的。虽然ADH家族成员的序列同源性相对较低(34-37%)，但参与抗生素磷霉素、草甘膦三肽和脱氢酶(以前的A53868)生物合成的同系物的体外生化特征明确地证实了它们的酶活性。这些独特的ADHS具有精致的衬底特性、独特的金属要求和前所未有的单体四元结构。此外，序列分析表明，这些ADH与推测的磷酸盐类生物合成基因簇编码的其他家族成员一起形成了一个单系群。因此，将膦乙醛还原为羟乙基膦酸酯可能代表了许多膦酸类天然产物生物合成的共同步骤，这一发现有助于深入了解膦酸类生物合成途径的演变和新的含C-P的次生代谢物的化学结构。
Phosphonic acids encompass a common yet chemically diverse class of natural products that often possess potent biological activities. Here we report that, despite the significant structural differences among many of these compounds, their biosynthetic routes contain an unexpected common intermediate, 2-hydroxyethyl-phosphonate, which is synthesized from phosphonoacetaldehyde by a distinct family of metal-dependent alcohol dehydrogenases (ADHs). Although the sequence identity of the ADH family members is relatively low (34-37%), in vitro biochemical characterization of the homologs involved in biosynthesis of the antibiotics fosfomycin, phosphinothricin tripeptide, and dehydrophos (formerly A53868) unequivocally confirms their enzymatic activities. These unique ADHs have exquisite substrate specificity, unusual metal requirements, and an unprecedented monomeric quaternary structure. Further, sequence analysis shows that these ADHs form a monophyletic group along with additional family members encoded by putative phosphonate biosynthetic gene clusters. Thus, the reduction of phosphonoacetaldehyde to hydroxyethyl-phosphonate may represent a common step in the biosynthesis of many phosphonate natural products, a finding that lends insight into the evolution of phosphonate biosynthetic pathways and the chemical structures of new C-P containing secondary metabolites.