Thiopeptide biosynthesis featuring ribosomally synthesized precursor peptides and conserved posttranslational modifications.
Thiopeptides, with potent activity against various drug-resistant pathogens, contain a characteristic macrocyclic core consisting of multiple thiazoles, dehydroamino acids, and a 6-membered nitrogen heterocycle. Their biosynthetic pathways remain elusive, in spite of great efforts by in vivo feeding experiments. Here, cloning, sequencing, and characterization of the thiostrepton and siomycin A gene clusters unveiled a biosynthetic paradigm for the thiopeptide specific core formation, featuring ribosomally synthesized precursor peptides and conserved posttranslational modifications. The paradigm generality for thiopeptide biosynthesis was supported by genome mining and ultimate confirmation of the thiocillin I production in Bacillus cereus ATCC 14579, a strain that was previously unknown as a thiopeptide producer. These findings set the stage to accelerate the discovery of thiopeptides by prediction at the genetic level and to generate structural diversity by applying combinatorial biosynthesis methods.
Liao
Rijing
R
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Rd., Shanghai 200032, China.
Duan
Lian
L
Lei
Chun
C
Pan
Haixue
H
Ding
Ying
Y
Zhang
Qi
Q
Chen
Daijie
D
Shen
Ben
B
Yu
Yi
Y
Liu
Wen
W
D001407:Bacillus / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000096:biosynthesis* / Q000235:genetics*; D003001:Cloning, Molecular; D005798:Genes, Bacterial; D005810:Multigene Family; D010455:Peptides / Q000235:genetics* / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D012270:Ribosomes / Q000378:metabolism*; D013302:Streptomyces / Q000235:genetics / Q000378:metabolism; D013883:Thiostrepton / Q000378:metabolism
D001426:Bacterial Proteins; D010455:Peptides; C025311:siomycin; C012574:thiocillin; D013883:Thiostrepton