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Microbiology 152 (2006), 3507-3515; DOI  10.1099/mic.0.29176-0
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Microbiology 152 (2006), 3507-3515; DOI  10.1099/mic.0.29176-0
© 2006 Society for General Microbiology

Organization of the biosynthetic gene cluster in Streptomyces sp. DSM 4137 for the novel neuroprotectant polyketide meridamycin

Yuhui Sun, Hui Hong, Markiyan Samborskyy, Tatiana Mironenko, Peter F. Leadlay and Stephen F. Haydock

Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK

Correspondence
Stephen F. Haydock
stephen.haydock{at}addenbrookes.nhs.uk

Meridamycin is a non-immunosuppressant, FKBP-binding macrocyclic polyketide, which has major potential as a neuroprotectant in a range of neurodegenerative disorders including dementia, Parkinson's disease and ischaemic stroke. A biosynthetic cluster predicted to encode biosynthesis of meridamycin was cloned from the prolific secondary-metabolite-producing strain Streptomyces sp. DSM 4137, not previously known to produce this compound, and specific gene deletion was used to confirm the role of this cluster in the biosynthesis of meridamycin. The meridamycin modular polyketide synthase consists of 14 extension modules distributed between three giant multienzyme proteins. The terminal module is flanked by a highly unusual cytochrome P450-like domain. The characterization of the meridamycin biosynthetic locus in this readily manipulated streptomycete species opens the way to the engineering of new, altered meridamycins of potential therapeutic importance.

Abbreviations: AT, acyltransferase; FKBP, FK506-binding protein; LC-MS, liquid chromatography-mass spectrometry; NRPS, non-ribosomal peptide synthetase; PKS, polyketide synthase

The GenBank/EMBL/DDBJ accession number for the sequence data reported in this paper is DQ885223.






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