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Characterization of Enzymes Catalyzing Transformations of Cysteine S ‐Conjugated Intermediates in the Lincosamide Biosynthetic Pathway
Author(s) -
Ushimaru Richiro,
Lin ChiaI,
Sasaki Eita,
Liu Hungwen
Publication year - 2016
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600223
Subject(s) - lincomycin , chemistry , biochemistry , methyltransferase , stereochemistry , o methyltransferase , cysteine , lyase , biosynthesis , transferase , enzyme , moiety , lincosamides , methylation , antibiotics , clindamycin , gene
Lincosamides such as lincomycin A, celesticetin, and Bu‐2545, constitute an important group of antibiotics. These natural products are characterized by a thiooctose linked to a l ‐proline residue, but they differ with regards to modifications of the thioacetal moiety, the pyrrolidine ring, and the octose core. Here we report that the pyridoxal 5′‐phosphate‐dependent enzyme CcbF (celesticetin biosynthetic pathway) is a decarboxylating deaminase that converts a cysteine S ‐conjugated intermediate into an aldehyde. In contrast, the homologous enzyme LmbF (lincomycin biosynthetic pathway) catalyzes C−S bond cleavage of the same intermediate to afford a thioglycoside. We show that Ccb4 and LmbG (downstream methyltransferases) convert the aldehyde and thiol intermediates into a variety of methylated lincosamide compounds including Bu‐2545. The substrates used in these studies are the β‐anomers of the natural substrates. The findings not only provide insight into how the biosynthetic pathway of lincosamide antibiotics can bifurcate to generate different lincosamides, but also reveal the promiscuity of the enzymes involved.