Organization of the biosynthetic gene cluster in Streptomyces sp. DSM 4137 for the novel neuroprotectant polyketide meridamycin.
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.
Sun
Yuhui
Y
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Hong
Hui
H
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Samborskyy
Markiyan
M
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Mironenko
Tatiana
T
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Leadlay
Peter F
PF
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Haydock
Stephen F
SF
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
D001426:Bacterial Proteins / Q000235:genetics* / Q000502:physiology; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004269:DNA, Bacterial / Q000737:chemistry / Q000235:genetics; D004798:Enzymes / Q000235:genetics / Q000502:physiology; D017353:Gene Deletion; D005798:Genes, Bacterial; D018942:Macrolides / Q000378:metabolism* / Q000494:pharmacology; D008969:Molecular Sequence Data; D005810:Multigene Family; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D048630:Polyketide Synthases / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D013302:Streptomyces / Q000235:genetics* / Q000378:metabolism
D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004798:Enzymes; D018942:Macrolides; D018696:Neuroprotective Agents; D048630:Polyketide Synthases; D003577:Cytochrome P-450 Enzyme System