Griseorhodins D-F, neuroactive intermediates and end products of post-PKS tailoring modification in Griseorhodin biosynthesis.
The griseorhodins belong to a family of extensively modified aromatic polyketides that exhibit activities such as inhibition of HIV reverse transcriptase and human telomerase. The vast structural diversity of this group of polyketides is largely introduced by enzymatic oxidations, which can significantly influence the bioactivity profile. Four new compounds, griseorhodins D-F, were isolated from a griseorhodin producer, Streptomyces sp. CN48+, based upon their enhancement of calcium uptake in a mouse dorsal root ganglion primary cell culture assay. Two of these compounds, griseorhodins D1 and D2, were shown to be identical to the major, previously uncharacterized products of a grhM mutant in an earlier griseorhodin biosynthesis study. Their structures enabled the establishment of a more complete hypothesis for the biosynthesis of griseorhodins and related compounds. The other two compounds, griseorhodins E and F, represent new products of post-polyketide synthase tailoring in griseorhodin biosynthesis and showed significant binding activity in a human dopamine active transporter assay.
Department of Medicinal Chemistry, L.S. Skaggs Pharmacy Institute, University of Utah , Salt Lake City, Utah 84112, United States.
Zhenjian
Z
Lin
Malcolm M
MM
Zachariah
Lenny
L
Marett
Ronald W
RW
Hughen
Russell W
RW
Teichert
Gisela P
GP
Concepcion
Margo G
MG
Haygood
Baldomero M
BM
Olivera
Alan R
AR
Light
Eric W
EW
Schmidt
D000818:Animals; D018491:Dopamine Agonists / Q000737:chemistry / Q000302:isolation & purification; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000378:metabolism; D005810:Multigene Family; D009285:Naphthoquinones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010679:Philippines; D048630:Polyketide Synthases / Q000378:metabolism; D061065:Polyketides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013302:Streptomyces / Q000737:chemistry* / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors
D018491:Dopamine Agonists; D009097:Multienzyme Complexes; D009285:Naphthoquinones; D061065:Polyketides; C000591967:griseorhodin D; C000591968:griseorhodin E; C000591969:griseorhodin F; C018070:griseorhodins; D048630:Polyketide Synthases; D019098:Telomerase