Construction of the octose 8-phosphate intermediate in lincomycin A biosynthesis: characterization of the reactions catalyzed by LmbR and LmbN

  • J Am Chem Soc. 2012 Oct 24;134(42):17432-5. doi: 10.1021/ja308221z.
Eita Sasaki  1 ,  Chia-I Lin ,  Ke-Yi Lin ,  Hung-Wen Liu
Affiliations
  • 1. Division of Medicinal Chemistry, College of Pharmacy, and Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712, USA.
PMID: 22989310 DOI: 10.1021/ja308221z
Abstract

Lincomycin A is a potent antimicrobial agent noted for its unusual C1 methylmercapto-substituted 8-carbon sugar. Despite its long clinical history for the treatment of Gram-positive infections, the biosynthesis of the C(8)-sugar, methylthiolincosamide (MTL), is poorly understood. Here, we report our studies of the two initial enzymatic steps in the MTL biosynthetic pathway leading to the identification of D-erythro-D-gluco-octose 8-phosphate as a key intermediate. Our experiments demonstrate that this intermediate is formed via a transaldol reaction catalyzed by LmbR using D-fructose 6-phosphate or D-sedoheptulose 7-phosphate as the C(3) donor and D-ribose 5-phosphate as the C(5) acceptor. Subsequent 1,2-isomerization catalyzed by LmbN converts the resulting 2-keto C(8)-sugar (octulose 8-phosphate) to octose 8-phosphate. These results provide, for the first time, in vitro evidence for the biosynthetic origin of the C(8) backbone of MTL.

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