Origin of starter units for erythromycin biosynthesis.
Modular polyketide synthases (PKSs), such as the 6-deoxyerythronolide B synthase (DEBS), are multifunctional proteins that govern the synthesis of a number of clinically important natural products. The modular arrangement of active sites within these enzymes suggests the possibility of a combinatorial approach to the synthesis of novel bioactive polyketides. The efficacy of combinatorial strategies toward altering the starter unit specificity of polyketide synthases critically depends on controlling the supply of competing endogenous starter acids. Using DEBS 1-TE, a bimodular derivative of DEBS, we aimed to determine whether the beta-ketosynthase (KS) domain responsible for condensation in the first module also has the ability to prime its own biosynthesis by catalyzing the decarboxylation of methylmalonyl-CoA to produce propionyl-CoA. In contrast to earlier reports with a closely similar mini-PKS DEBS 1+TE, we have found that rigorously purified DEBS 1-TE does not catalyze the decarboxylation of methylmalonyl-CoA.
Cambridge Centre for Molecular Recognition and Department of Organic Chemistry, University of Cambridge, Cambridge, UK.
K J
KJ
Weissman
M
M
Bycroft
J
J
Staunton
P F
PF
Leadlay
D000214:Acyl Coenzyme A / Q000378:metabolism; D002262:Carboxy-Lyases / Q000378:metabolism; D017666:Deuterium Oxide; D004917:Erythromycin / Q000096:biosynthesis* / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D007783:Lactones / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism*; D016930:Saccharopolyspora / Q000201:enzymology / Q000378:metabolism; D013869:Thiolester Hydrolases / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism
D000214:Acyl Coenzyme A; D007783:Lactones; D009097:Multienzyme Complexes; C024343:butyryl-coenzyme A; D004917:Erythromycin; D013869:Thiolester Hydrolases; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D017666:Deuterium Oxide