Journal
CHEMISTRY & BIOLOGY
Volume 15, Issue 11, Pages 1231-1240Publisher
CELL PRESS
DOI: 10.1016/j.chembiol.2008.09.012
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Funding
- Biotechnology and Biological Sciences Research Council (UK)
- Cambridge Commonwealth Trust
- Natural Sciences and Engineering Research Council of Canada
- Universities UK-Overseas Research Scholarship
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When an enoylreductase enzyme of a modular poly-ketide synthase reduces a propionate extender unit that has been newly added to the growing polyketide chain, the resulting methyl branch may have either S or R configuration. We have uncovered a correlation between the presence or absence of a unique tyrosine residue in the ER active site and the chirality of the methyl branch that is introduced. When this position in the active site is occupied by a tyrosine residue, the methyl branch has S configuration, otherwise it has R configuration. In a model PKS in vivo, a mutation (Tyr to Val) in an erythromycin PKS-derived ER caused a switch in the methyl branch configuration in the product from S to R. In contrast, alteration (Val to Tyr) at this position in a rapamycin-derived PKS ER was insufficient to achieve a switch from R to S, showing that additional residues also participate in stereocontrol of enoylreduction.
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