Biosynthetic multitasking facilitates thalassospiramide structural diversity in marine bacteria

Avena C. Ross, Ying Xü, Liang Lu, Roland D. Kersten, Zongze Shao, Abdulaziz M. Al-Suwailem, Pieter C. Dorrestein, Pei-Yuan Qian, Bradley S. Moore

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Thalassospiramides A and B are immunosuppressant cyclic lipopeptides first reported from the marine α-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. © 2012 American Chemical Society.
Original languageEnglish (US)
Pages (from-to)1155-1162
Number of pages8
JournalJournal of the American Chemical Society
Volume135
Issue number3
DOIs
StatePublished - Dec 27 2012

ASJC Scopus subject areas

  • Biochemistry
  • Colloid and Surface Chemistry
  • Chemistry(all)
  • Catalysis

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