Valinophos Reveals a New Route in Microbial Phosphonate Biosynthesis That Is Broadly Conserved in Nature.
Valinophos Reveals a New Route in Microbial Phosphonate Biosynthesis That Is Broadly Conserved in Nature.
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DOI：
10.1021/jacs.2c02854
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发表时间：
2022-06-08
影响因子：
15
通讯作者：
Ju, Kou-San
中科院分区：
文献类型：
--
作者：
Zhang, Yeying;Chen, Li;Wilson, Jake A.;Cui, Jerry;Roodhouse, Hannah;Kayrouz, Chase;Pham, Tiffany M.;Ju, Kou-San
膦酸盐天然产物是细胞代谢的有效抑制剂，在医学和生物技术领域具有良好的商业化记录。尽管基因组挖掘已成为发现新膦酸盐的加速方法，但仍需要一个强大的代谢框架来确定最有可能产生具有所需活性的化合物的途径。在这里，我们通过报道缬氨磷的完整生物合成途径来扩展我们对这些天然产物的理解，缬氨磷是一种含有不寻常的 (R)-2,3-二羟丙基膦酸酯 (DHPPA) 支架的磷酸肽天然产物。该途径是由以前未知的膦酸天然产物的几种酶促转化和中间体定义的。专用脱氢酶充当新的磷酸烯醇丙酮酸变位酶偶联酶。值得注意的是，它将膦酰基丙酮酸还原为膦酸乳酸，定义了膦酸生物合成的一个新的早期分支点。功能上相互关联的激酶和还原酶催化反应，让人想起糖酵解和精氨酸生物合成，产生短暂但必需的膦酸乳醛中间体。我们证明了 L-缬氨酸在 DHPPA 上的酯化是 ATP-Grasp 连接酶的一种新生化活性。出乎意料的是，第二个氨基酸连接酶随后在缬氨酰部分连接了额外的氨基酸，产生了一套 DHPPA-二肽。 DHPPA 生物合成基因是在来自广泛栖息地的细菌基因组中发现的，这表明大量未知化合物可能源自这一核心途径。我们的研究结果为天然产物建立了新的生物合成原理，并为生物活性膦酸盐基因组挖掘的未探索途径提供了定义。
Phosphonate natural products are potent inhibitors of cellular metabolism with an established record of commercialization in medicine and biotechnology. Although genome mining has emerged as an accelerated method for the discovery of new phosphonates, a robust framework of their metabolism is needed to identify the pathways most likely to yield compounds with desired activities. Here we expand our understanding of these natural products by reporting the complete biosynthetic pathway for valinophos, a phosphonopeptide natural product containing the unusual (R)-2,3-dihydroxypropylphosphonate (DHPPA) scaffold. The pathway was defined by several enzymatic transformations and intermediates previously unknown to phosphonate natural products. A dedicated dehydrogenase served as a new phosphoenolpyruvate mutase coupling enzyme. Notably, its reduction of phosphonopyruvate to phosphonolactate defined a new early branchpoint in phosphonate biosynthesis. Functionally interconnected kinase and reductase enzymes catalyzed reactions reminiscent of glycolysis and arginine biosynthesis to produce a transient, but essential, phosphonolactaldehyde intermediate. We demonstrate esterification of l-valine onto DHPPA as a new biochemical activity for ATP-Grasp ligase enzymes. Unexpectedly, a second amino acid ligase then adjoined additional amino acids at the valinyl moiety to produce a suite of DHPPA-dipeptides. The genes for DHPPA biosynthesis were discovered among genomes of bacteria from wide-ranging habitats, suggesting a wealth of unknown compounds that may originate from this core pathway. Our findings establish new biosynthetic principles for natural products and provide definition to unexplored avenues for bioactive phosphonate genome mining.
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海洋微生物合成甲基膦酸：有氧海洋中甲烷的来源。
DOI：
10.1126/science.1219875
发表时间：
2012-08-31
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Metcalf WW;Griffin BM;Cicchillo RM;Gao J;Janga SC;Cooke HA;Circello BT;Evans BS;Martens-Habbena W;Stahl DA;van der Donk WA
通讯作者：
van der Donk WA
DOI：
10.1073/pnas.2113386119
发表时间：
2022-03-15
影响因子：
11.1
作者：
Acker M;Hogle SL;Berube PM;Hackl T;Coe A;Stepanauskas R;Chisholm SW;Repeta DJ
通讯作者：
Repeta DJ
影响因子：
--
作者：
Circello BT;Eliot AC;Lee JH;van der Donk WA;Metcalf WW
通讯作者：
Metcalf WW
影响因子：
2.9
作者：
Lee, Hyunbin;Park, Youngseon;Kim, Seokhee
通讯作者：
Kim, Seokhee
影响因子：
5.1
作者：
Cioni JP;Doroghazi JR;Ju KS;Yu X;Evans BS;Lee J;Metcalf WW
通讯作者：
Metcalf WW