Department of Chemistry, Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, University of Texas at Austin, Austin, TX, 78712, USA.
Angew Chem Int Ed Engl. 2021 Jul 26;60(31):17148-17154. doi: 10.1002/anie.202105667. Epub 2021 Jun 24.
Showdomycin is a C-nucleoside bearing an electrophilic maleimide base. Herein, the biosynthetic pathway of showdomycin is presented. The initial stages of the pathway involve non-ribosomal peptide synthetase (NRPS) mediated assembly of a 2-amino-1H-pyrrole-5-carboxylic acid intermediate. This intermediate is prone to air oxidation whereupon it undergoes oxidative decarboxylation to yield an imine of maleimide, which in turn yields the maleimide upon acidification. It is also shown that this pyrrole intermediate serves as the substrate for the C-glycosidase SdmA in the pathway. After coupling with ribose 5-phosphate, the resulting C-nucleoside undergoes a similar sequence of oxidation, decarboxylation and deamination to afford showdomcyin after exposure to air. These results suggest that showdomycin could be an artifact due to aerobic isolation; however, the autoxidation may also serve to convert an otherwise inert product of the biosynthetic pathway to an electrophilic C-nucleotide thereby endowing showdomycin with its observed bioactivities.
展示霉素是一种带有亲电马来酰亚胺基的 C-核苷。本文介绍了展示霉素的生物合成途径。该途径的初始阶段涉及非核糖体肽合成酶 (NRPS) 介导的 2-氨基-1H-吡咯-5-羧酸中间体的组装。该中间体容易被空气氧化，随后发生氧化脱羧反应生成马来酰亚胺亚胺，酸化后生成马来酰亚胺。还表明，该吡咯中间体是途径中 C-糖苷酶 SdmA 的底物。与 5-磷酸核糖偶联后，所得的 C-核苷经历类似的氧化、脱羧和脱氨序列，在暴露于空气后得到展示霉素。这些结果表明，展示霉素可能是由于需氧分离而产生的人工产物；然而，自动氧化也可能将生物合成途径中原本惰性的产物转化为亲电 C-核苷酸，从而使展示霉素具有观察到的生物活性。
