Department of Chemistry, The Scripps Research Institute, Jupiter, FL, 33458, USA.
Xiangya International Academy of Translational Medicine, Central South University, Changsha, Hunan, 410013, China.
Nat Commun. 2018 Jun 18;9(1):2362. doi: 10.1038/s41467-018-04747-y.
Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to β-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery.
含硫羧酸的天然产物较为罕见，其生物合成和生物学意义尚不清楚。噻咯盘菌素（thioPTM）和噻咯盘菌素（thioPTN）是抗菌天然产物盘菌素（PTM）和盘菌素（PTN）的硫代羧酸同系物，最近被发现。本文报道了 thioPTM 和 thioPTN 中硫代羧酸部分的生物合成来源。我们鉴定了一个硫代酸盒，编码两个蛋白，PtmA3 和 PtmU4，分别负责通过辅酶 A 和硫转移对羧基进行激活。噻咯盘菌素和噻咯盘菌素与β-酮酰-ACP 合酶 II（FabF）紧密结合，并保留强大的抗菌活性。结合和溶剂化自由能的密度泛函理论计算表明，thioPTM 和 thioPTN 与 FabF 的结合比 PTM 和 PTN 更有利。此外，硫代酸盒在细菌基因组中普遍存在，表明含硫羧酸的天然产物被低估了。这些结果表明，硫代羧酸作为一种替代药效团，以及含硫代羧酸的天然产物可能会被考虑用于未来的药物发现。
