Polyketide decarboxylative chain termination preceded by o-sulfonation in curacin a biosynthesis.
Biosynthetic innovation in natural product systems is driven by the recruitment of new genes and enzymes into these complex pathways. Here, an unprecedented decarboxylative chain termination mechanism is described for the polyketide synthase of curacin A, an anticancer lead compound isolated from the marine cyanobacterium Lyngbya majuscula. The unusual chain termination module containing adjacent sulfotransferase (ST) and thioesterase (TE) catalytic domains embedded in CurM was biochemically characterized. The TE was proved to catalyze a hydrolytic chain release of the polyketide chain elongation intermediate. Moreover, a selective ST-mediated sulfonation of the (R)-beta-hydroxyl group was found to precede TE-mediated hydrolysis, triggering a successive decarboxylative elimination and resulting in the formation of a rare terminal olefin in the final metabolite.
Gu
Liangcai
L
Life Sciences Institute, Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
Wang
Bo
B
Kulkarni
Amol
A
Gehret
Jennifer J
JJ
Lloyd
Kayla R
KR
Gerwick
Lena
L
Gerwick
William H
WH
Wipf
Peter
P
Håkansson
Kristina
K
Smith
Janet L
JL
Sherman
David H
DH
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D000458:Cyanobacteria; D003521:Cyclopropanes / Q000378:metabolism*; D003653:Decarboxylation; D018942:Macrolides / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D048630:Polyketide Synthases / Q000378:metabolism*; D013450:Sulfones; D015238:Sulfotransferases; D013844:Thiazoles / Q000378:metabolism*; D050257:Tubulin Modulators
D000970:Antineoplastic Agents; D001426:Bacterial Proteins; D003521:Cyclopropanes; D018942:Macrolides; D013450:Sulfones; D013844:Thiazoles; D050257:Tubulin Modulators; C095843:curacin A; D048630:Polyketide Synthases; D015238:Sulfotransferases