Biosynthetic Multitasking Facilitates Thalassospiramide Structural Diversity in Marine Bacteria

TitleBiosynthetic Multitasking Facilitates Thalassospiramide Structural Diversity in Marine Bacteria
Publication TypeJournal Article
Year of Publication2013
AuthorsRoss AC, Xu Y, Lu L, Kersten RD, Shao ZZ, Al-Suwailem AM, Dorrestein PC, Qian PY, Moore BS
JournalJournal of the American Chemical Society
Volume135
Pagination1155-1162
Date Published2013/01
Type of ArticleArticle
ISBN Number0002-7863
Accession NumberWOS:000314141200032
Keywordsabsolute-configuration; adenylation; amino-acids; assembly-line enzymology; carrier domains; constituent; domain; mass-spectrometry; natural-product; nonribosomal peptide synthetases; polyketide synthase; synthetase; yersiniabactin
Abstract

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.

DOI10.1021/ja3119674
Short TitleJ. Am. Chem. Soc.
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