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J Biol Chem, Vol. 274, Issue 38, 26743-26750, September 17, 1999
From Wyeth Research, Cambridge, Massachusetts 02140
Recently the genes encoding the human and
Escherichia coli GDP-mannose dehydratase and GDP-fucose
synthetase (GFS) protein have been cloned and it has been shown that
these two proteins alone are sufficient to convert GDP mannose to GDP
fucose in vitro. GDP-fucose synthetase from E. coli is a novel dual function enzyme in that it catalyzes
epimerizations and a reduction reaction at the same active site. This
aspect separates fucose biosynthesis from that of other deoxy and
dideoxy sugars in which the epimerase and reductase activities are
present on separate enzymes encoded by separate genes. By NMR
spectroscopy we have shown that GFS catalyzes the stereospecific
hydride transfer of the ProS hydrogen from NADPH to carbon 4 of the
mannose sugar. This is consistent with the stereospecificity observed
for other members of the short chain dehydrogenase reductase family of
enzymes of which GFS is a member. Additionally the enzyme is able to
catalyze the epimerization reaction in the absence of NADP or NADPH.
The kinetic mechanism of GFS as determined by product inhibition and
fluorescence binding studies is consistent with a random mechanism. The
dissociation constants determined from fluorescence studies indicate
that the enzyme displays a 40-fold stronger affinity for the substrate NADPH as compared with the product NADP and utilizes NADPH
preferentially as compared with NADH. This study on GFS, a unique
member of the short chain dehydrogenase reductase family, coupled with
that of its recently published crystal structure should aid in the development of antimicrobial or anti-inflammatory compounds that act by
blocking selectin-mediated cell adhesion.
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