Studies of lincosamide formation complete the biosynthetic pathway for lincomycin A

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 117; no. 40; pp. 24794 - 24801
Main Authors Wang, Shao-An, Lin, Chia-I, Zhang, Jiawei, Ushimaru, Richiro, Sasaki, Eita, Liu, Hung-wen
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 06.10.2020
Subjects
Bacterial Proteins - genetics
Bacterial Proteins - metabolism
Biological Sciences
Biosynthesis
Biosynthetic Pathways
Carbohydrates
Chemical reactions
Dehydration
Enzymes
Intermediates
Lincomycin
Lincomycin - biosynthesis
Lincomycin - chemistry
Lincosamides - chemistry
Lincosamides - metabolism
Natural products
Physical Sciences
Streptomyces - chemistry
Streptomyces - enzymology
Streptomyces - genetics
Streptomyces - metabolism
celesticetin
lincosamide
thiosugar
lincomycin
biosynthesis
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Summary: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-gluco-octose 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.
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Author contributions: S.-A.W., C.-I.L., and H.-w.L. designed research; S.-A.W., C.-I.L., J.Z., R.U., and E.S. performed research; S.-A.W., C.-I.L., J.Z., R.U., E.S., and H.-w.L. analyzed data; and S.-A.W., C.-I.L., and H.-w.L. wrote the paper.
2Present address: Laboratory of Natural Products Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 113-0033 Tokyo, Japan.
Edited by Chi-Huey Wong, Academia Sinica, Taipei, Taiwan, and approved August 20, 2020 (received for review May 10, 2020)
1S.-A.W. and C.-I.L. contributed equally to this work.
3Present address: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 113-8657 Tokyo, Japan.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2009306117