title: Biosynthetic multitasking facilitates thalassospiramide structural diversity in marine bacteria.
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.
authors.affiliation: Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California 92037, USA.
authors.forename: Avena C
authors.initials: AC
authors.lastname: Ross
authors.forename: Ying
authors.initials: Y
authors.lastname: Xu
authors.forename: Liang
authors.initials: L
authors.lastname: Lu
authors.forename: Roland D
authors.initials: RD
authors.lastname: Kersten
authors.forename: Zongze
authors.initials: Z
authors.lastname: Shao
authors.forename: Abdulaziz M
authors.initials: AM
authors.lastname: Al-Suwailem
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Dorrestein
authors.forename: Pei-Yuan
authors.initials: PY
authors.lastname: Qian
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Moore
mesh_terms: D059001:Aquatic Organisms / Q000737:chemistry* / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors; D019295:Computational Biology; D006023:Glycoproteins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008968:Molecular Conformation; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012244:Rhodospirillaceae / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D006023:Glycoproteins; D010456:Peptides, Cyclic; C039304:calpain inhibitors; D002154:Calpain