On the biosynthetic origin of methoxymalonyl-acyl carrier protein, the substrate for incorporation of "glycolate" units into ansamitocin and soraphen A.
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.
Wenzel
Silke C
SC
Institute of Pharmaceutical Biotechnology, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany.
Williamson
Rachel M
RM
Grünanger
Christian
C
Xu
Jun
J
Gerth
Klaus
K
Martinez
Rodolfo A
RA
Moss
Steven J
SJ
Carroll
Brian J
BJ
Grond
Stephanie
S
Unkefer
Clifford J
CJ
Müller
Rolf
R
Floss
Heinz G
HG
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
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