期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 135, 期 3, 页码 1155-1162出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja3119674
关键词
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资金
- China Ocean Mineral Resources Research and Development Association [DY125-15-T-02]
- King Abdullah University of Science and Technology [SA-00040/UK-00016]
- NIH [GM97509]
Thalassospiramides A and B are immunosuppressant cyclic lipopeptides first reported from the marine alpha-proteobacterium Thalassospira sp. CNJ-328. We describe here the discovery and characterization of an extended family of 14 new analogues from four Tistrella and Thalassospira isolates. These potent calpain 1 protease inhibitors belong to six structure classes in which the length and composition of the acylpeptide side chain varies extensively. Genomic sequence analysis of the thalassospiramide-producing microbes revealed related, genus-specific biosynthetic loci encoding hybrid nonribosomal peptide synthetase/polyketide synthases consistent with thalassospiramide assembly. The bioinformatics analysis of the gene clusters suggests that structural diversity, which ranges from the 803.4 Da thalassospiramide C to the 1291.7 Da thalassospiramide F, results from a complex sequence of reactions involving amino acid substrate channeling and enzymatic multimodule skipping and iteration. Preliminary biochemical analysis of the N-terminal nonribosomal peptide synthetase module from the Thalassospira TtcA megasynthase supports a biosynthetic model in which in cis amino acid activation competes with in trans activation to increase the range of amino acid substrates incorporated at the N terminus.
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