title: Effects of amino acid and trace element supplementation on pneumocandin production by Glarea lozoyensis: impact on titer, analogue levels, and the identification of new analogues of pneumocandin B(0).
abstract: Addition of the amino acids threonine, serine, proline, and arginine to fermentations of the fungus Glarea lozoyensis influenced both the pneumocandin titer and the spectrum of analogues produced. Addition of threonine or serine altered the levels of the "serine analogues" of pneumocandins B(0) and B(5) and allowed for their isolation and identification. Proline supplementation resulted in a dose-dependent increase in the levels of pneumocandins B(0) and E(0), whereas pneumocandins C(0) and D(0) decreased as a function of proline level. Moreover, proline supplementation resulted in an overall increase in the synthesis of both trans-3- and trans-4-hydroxyproline while maintaining a low trans-4-hydroxyproline to trans-3-hydroxyproline ratio compared to the unsupplemented culture. Pneumocandin production and the synthesis of hydroxyprolines was also affected by addition of the proline-related amino acid arginine but not by the addition of glutamine or ornithine. Zinc, cobalt, copper, and nickel, trace elements that are known to inhibit alpha-ketoglutarate-dependent dioxygenases, affected the pneumocandin B(0) titer and altered the levels of pneumocandins B(1), B(2), B(5), B(6), and E(0), analogues that possess altered proline, ornithine, and tyrosine hydroxylation patterns.
authors.affiliation: Biocatalysis and Fermentation Development, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Petersen
authors.forename: D L
authors.initials: DL
authors.lastname: Hughes
authors.forename: R
authors.initials: R
authors.lastname: Hughes
authors.forename: L
authors.initials: L
authors.lastname: DiMichele
authors.forename: P
authors.initials: P
authors.lastname: Salmon
authors.forename: N
authors.initials: N
authors.lastname: Connors
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D001203:Ascomycota / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D002413:Cations, Divalent / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D054714:Echinocandins; D005285:Fermentation; D006909:Hydroxyproline / Q000096:biosynthesis; D010455:Peptides; D010456:Peptides, Cyclic / Q000096:biosynthesis* / Q000737:chemistry; D011392:Proline / Q000494:pharmacology; D012694:Serine / Q000494:pharmacology; D013912:Threonine / Q000494:pharmacology; D014131:Trace Elements / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D000900:Anti-Bacterial Agents; D002413:Cations, Divalent; D054714:Echinocandins; D010455:Peptides; D010456:Peptides, Cyclic; D014131:Trace Elements; C079465:pneumocandin B(0); C079464:pneumocandin C(0); D013912:Threonine; D012694:Serine; D001120:Arginine; D011392:Proline; D006909:Hydroxyproline