Biosynthesis of the beta-amino acid moiety of the enediyne antitumor antibiotic C-1027 featuring beta-amino acyl-S-carrier protein intermediates.
The enediyne antitumor antibiotic C-1027 chromoprotein is produced by Streptomyces globisporus. The biosynthesis of the (S)-3-chloro-4,5-dihydroxy-beta-phenylalanine moiety (boxed) of the C-1027 chromophore (1) from l-tyrosine (3) and its incorporation into 1 are catalyzed by six enzymes: SgcC, SgcC1, SgcC2, SgcC3, SgcC4, ShcC5. In vivo and in vitro characterization of these enzymes delineated this pathway, unveiling a novel strategy for beta-amino acid modification featuring beta-amino acyl-S-carrier protein intermediates. These findings shed new light into beta-amino acid biosynthesis and present a new opportunity to engineer the C-1027 biosynthetic machinery for the production of novel analogues as exemplified by 20-deschloro-C-1027 (4), 20-deschro-22-deshydroxy-C-1027 (5), and 22-deshydroxy-C-1027 (6).
Van Lanen
Steven G
SG
Division of Pharmaceutical Sciences and Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
Dorrestein
Pieter C
PC
Christenson
Steve D
SD
Liu
Wen
W
Ju
Jianhua
J
Kelleher
Neil L
NL
Shen
Ben
B
D000213:Acyl Carrier Protein / Q000737:chemistry / Q000378:metabolism*; D000596:Amino Acids / Q000096:biosynthesis*; D000617:Aminoglycosides / Q000096:biosynthesis* / Q000737:chemistry; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000378:metabolism; D053281:Enediynes; D004798:Enzymes / Q000737:chemistry / Q000378:metabolism; D008968:Molecular Conformation; D013237:Stereoisomerism
D000213:Acyl Carrier Protein; D000596:Amino Acids; D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D004798:Enzymes; C058024:C 1027