American Society for Biochemistry and Molecular Biology, Inc.
Abstract
Triose-phosphate isomerase, a key enzyme of the glycolytic
pathway, catalyzes the isomerization of dihydroxy
acetone phosphate and glyceraldehyde 3-phosphate.
In this communication we report the crystal
structure of Plasmodium falciparum triose-phosphate
isomerase complexed to the inhibitor 2-phosphoglycerate
at 1.1-Å resolution. The crystallographic asymmetric
unit contains a dimeric molecule. The inhibitor bound to
one of the subunits in which the flexible catalytic loop 6
is in the open conformation has been cleaved into two
fragments presumably due to radiation damage. The
cleavage products have been tentatively identified as
2-oxoglycerate and meta-phosphate. The intact 2-phosphoglycerate
bound to the active site of the other subunit
has been observed in two different orientations.
The active site loop in this subunit is in both open and
"closed" conformations, although the open form is predominant.
Concomitant with the loop closure, Phe-96,
Leu-167, and residues 208–211 (YGGS) are also observed
in dual conformations in the B-subunit. Detailed comparison
of the active-site geometry in the present case
to the Saccharomyces cerevisiae triose-phosphate isomerase-
dihydroxy acetone phosphate and Leishmania
mexicana triose-phosphate isomerase-phosphoglycolate
complexes, which have also been determined at atomic
resolution, shows that certain interactions are common
to the three structures, although 2-phosphoglycerate is
neither a substrate nor a transition state analogue