Studies of lincosamide formation complete the biosynthetic pathway for lincomycin A

Shao An Wang, Chia I. Lin, Jiawei Zhang, Richiro Ushimaru, Eita Sasaki, Hung Wen Liu

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

The structure of lincomycin A consists of the unusual eight-carbon thiosugar core methyllincosamide (MTL) decorated with a pendent N-methylprolinyl moiety. Previous studies on MTL biosynthesis have suggested GDP-D-erythro-α-D-gluco-octose and GDP-D-α-D-lincosamide as key intermediates in the pathway. However, the enzyme-catalyzed reactions resulting in the conversion of GDP-D-erythro-α-D-glucooctose to GDP-D-α-D-lincosamide have not yet been elucidated. Herein, a biosynthetic subpathway involving the activities of four enzymes-LmbM, LmbL, CcbZ, and CcbS (the LmbZ and LmbS equivalents in the closely related celesticetin pathway)-is reported. These enzymes catalyze the previously unknown biosynthetic steps including 6-epimerization, 6,8-dehydration, 4-epimerization, and 6-transamination that convert GDP-D-erythro- α-D-gluco-octose to GDP-D-α-D-lincosamide. Identification of these reactions completes the description of the entire lincomycin biosynthetic pathway. This work is significant since it not only resolves the missing link in octose core assembly of a thiosugar-containing natural product but also showcases the sophistication in catalytic logic of enzymes involved in carbohydrate transformations.

Original languageEnglish
Pages (from-to)24794-24801
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number40
DOIs
Publication statusPublished - 2020 Oct 6
Externally publishedYes

Keywords

  • Biosynthesis
  • Celesticetin
  • Lincomycin
  • Lincosamide
  • Thiosugar

ASJC Scopus subject areas

  • General

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