Publication: DFT Investigation on the Mechanism of the Deacteylation Reaction Catalyzed by LpxC
All || By Area || By Year| Title | DFT Investigation on the Mechanism of the Deacteylation Reaction Catalyzed by LpxC | Authors/Editors* | J. J. Robinet, J. W. Gauld |
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| Where published* | J. Phys. Chem. B |
| How published* | Journal |
| Year* | 2008 |
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| Abstract |
LpxC is a key enzyme in the biochemical synthesis of Lipid A, an important outer cell-membrane component found in a number of pathogenic bacteria. Using DFT we have investigated the binding of the substrate within its active site as well as the deacetylation mechanism it catalyzes. The substrate is found to preferentially coordinate to the active site Zn(2+) via its carbonyl oxygen between a Zn(2+)-bound H2O and an adjacent threonine (Thr191). Furthermore, upon substrate binding a nearby Glu78 residue is found to readily deprotonate the remaining Zn(2+)-bound H2O. Unlike several related metallopeptidases the mechanism of LpxC is found to proceed via four steps; (i) initial hydroxylation of the substrates' carbonyl carbon to give a gemâdiolate intermediate, (ii) protonation of the amide nitrogen by the histidine His265âH+, (iii) a barrier-less change in the active site-intermediate hydrogen bond network and finally, (iv) CâN bond cleavage. Notably, the rate-determining step of the mechanism of LpxC is found to be the initial hydroxylation while the final CâN bond cleavage occurs with an overall barrier of 23.6 kJ/mol. Furthermore, LpxC uses a general acid/base pair mechanism as indicated by the fact that both His265âH+ and Glu78 are accordingly involved. |
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