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Chembiochem. 2016 Jan;17(2):164-73. doi: 10.1002/cbic.201500467. Epub 2015 Dec 23.

The Phormidolide Biosynthetic Gene Cluster: A trans-AT PKS Pathway Encoding a Toxic Macrocyclic Polyketide.

Author information

1
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, 9500 Gilman Drive, MC 0212, La Jolla, CA, 92093, USA.
2
Department of Biochemistry and Biophysics, Oregon State University, 2011 Agricultural and Life Sciences, 2750 SW Campus Way, Corvallis, OR, 97331, USA.
3
Department of Biology, William Paterson University, 300 Pompton Road, Wayne, NJ, 07470, USA.
4
The Center for Algorithmic Biotechnology, Department of Statistical Modeling, St. Petersburg State University, Universitetskiy 28, Stary Peterhof, St. Petersburg, 198504, Russia.
5
Life Sciences Institute, Department of Medicinal Chemistry, Department of Chemistry, Department of Microbiology and Immunology, University of Michigan, 4008 Life Sciences Institute, 210 Washtenaw Avenue, Ann Arbor, MI, 48109, USA.
6
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, MC 0212, La Jolla, CA, 92093, USA) address. wgerwick@ucsd.edu.

Abstract

Phormidolide is a polyketide produced by a cultured filamentous marine cyanobacterium and incorporates a 16-membered macrolactone. Its complex structure is recognizably derived from a polyketide synthase pathway, but possesses unique and intriguing structural features that prompted interest in investigating its biosynthetic origin. Stable isotope incorporation experiments confirmed the polyketide nature of this compound. We further characterized the phormidolide gene cluster (phm) through genome sequencing followed by bioinformatic analysis. Two discrete trans-type acyltransferase (trans-AT) ORFs along with KS-AT adaptor regions (ATd) within the polyketide synthase (PKS) megasynthases, suggest that the phormidolide gene cluster is a trans-AT PKS. Insights gained from analysis of the mode of acetate incorporation and ensuing keto reduction prompted our reevaluation of the stereochemistry of phormidolide hydroxy groups located along the linear polyketide chain.

KEYWORDS:

biosynthesis; macrolactones; phormidolide; polyketide synthase; trans-AT

PMID:
26769357
PMCID:
PMC4878910
DOI:
10.1002/cbic.201500467
[Indexed for MEDLINE]
Free PMC Article

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