title: On the biosynthetic origin of methoxymalonyl-acyl carrier protein, the substrate for incorporation of "glycolate" units into ansamitocin and soraphen A.
abstract: Feeding experiments with isotope-labeled precursors rule out hydroxypyruvate and TCA cycle intermediates as the metabolic source of methoxymalonyl-ACP, the substrate for incorporation of "glycolate" units into ansamitocin P-3, soraphen A, and other antibiotics. They point to 1,3-bisphosphoglycerate as the source of the methoxymalonyl moiety and show that its C-1 gives rise to the thioester carbonyl group (and hence C-1 of the "glycolate" unit), and its C-3 becomes the free carboxyl group of methoxymalonyl-ACP, which is lost in the subsequent Claisen condensation on the type I modular polyketide synthases (PKS). d-[1,2-(13)C(2)]Glycerate is also incorporated specifically into the "glycolate" units of soraphen A, but not of ansamitocin P-3, suggesting differences in the ability of the producing organisms to activate glycerate. A biosynthetic pathway from 1,3-bisphosphoglycerate to methoxymalonyl-ACP is proposed. Two new syntheses of R- and S-[1,2-(13)C(2)]glycerol were developed as part of this work.
authors.affiliation: Institute of Pharmaceutical Biotechnology, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany.
authors.forename: Silke C
authors.initials: SC
authors.lastname: Wenzel
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Williamson
authors.forename: Christian
authors.initials: C
authors.lastname: Grünanger
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Klaus
authors.initials: K
authors.lastname: Gerth
authors.forename: Rodolfo A
authors.initials: RA
authors.lastname: Martinez
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Moss
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Carroll
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grond
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Unkefer
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.forename: Heinz G
authors.initials: HG
authors.lastname: Floss
mesh_terms: D000213:Acyl Carrier Protein / Q000096:biosynthesis* / Q000737:chemistry; D000595:Amino Acid Sequence; D002247:Carbon Isotopes; D002952:Citric Acid Cycle / Q000502:physiology; D004163:Diphosphoglyceric Acids / Q000737:chemistry / Q000378:metabolism; D006016:Glycolates / Q000737:chemistry*; D007553:Isotope Labeling; D018942:Macrolides / Q000737:chemistry / Q000378:metabolism*; D008314:Malonates / Q000737:chemistry*; D008453:Maytansine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D048630:Polyketide Synthases / Q000737:chemistry / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism
chemical_list: D000213:Acyl Carrier Protein; D002247:Carbon Isotopes; D004163:Diphosphoglyceric Acids; D006016:Glycolates; D018942:Macrolides; D008314:Malonates; D011773:Pyruvates; C031149:glycolic acid; C086151:soraphen A; D008453:Maytansine; C015891:glycerate 1,3-biphosphate; C015682:ansamitocins; D048630:Polyketide Synthases; C012375:hydroxypyruvic acid; C030290:malonic acid