Mechanistic Studies of 1-Deoxy-D-Xylulose-5-Phosphate Synthase from Deinococcus radiodurans
2018
The non-mevalonate dependent (NMVA) pathway for the biosynthesis of
isopentenyl pyrophosphate and dimethylallyl pyrophosphate is the sole source
of these terpenoids for the production of isoprenoids in the apicomplexan
parasites, in many eubacteria, and in plants. The absence of this pathway in
higher organisms has opened a new platform for the development of novel
antibiotics and anti-malarials. The enzyme catalyzing the first step of the NMVA
pathway is 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). DXPS catalyzes the
thiamine pyrophosphate- and Mg (II)-dependent conjugation of pyruvate and
D-glyceraldehyde-3-phosphate to form 1-deoxy-D-xylulose-5-phosphate and CO2.
The kinetic mechanism of DXPS from Deinococcus radiodurans most consistent
with our data is random sequential as shown using a combination of kinetic
analysis and product and dead-end inhibition studies. The role of active site amino
acids, identified by sequence alignment to other DXPS proteins, was probed by
constructing and analyzing the catalytic efficacy of a set of targeted site-directed
mutants.
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