The three-dimensional (3D) structure of Corynebacterium
glutamicum diaminopimelate d-dehydrogenase in a
ternary complex with NADPH and l-2-amino-6-methylene-pimelate
has been solved and refined to a resolution of 2.1 Å.
l-2-Amino-6-methylene-pimelate was recently synthesized
and shown to be a potent competitive inhibitor (5 μM) vs.
meso-diaminopimelate of the Bacillus sphaericus
dehydrogenase (Sutherland et al., 1999). Diaminopimelate
dehydrogenase catalyzes the reversible NADP+-dependent
oxidation of the d-amino acid stereocenter of
meso-diaminopimelate, and is the only enzyme known to catalyze
the oxidative deamination of a d-amino acid. The enzyme is
involved in the biosynthesis of meso-diaminopimelate
and l-lysine from l-aspartate, a biosynthetic
pathway of considerable interest because it is essential
for growth of certain bacteria. The dehydrogenase is found
in a limited number of species of bacteria, as opposed
to the alternative succinylase and acetylase pathways that
are widely distributed in bacteria and plants. The structure
of the ternary complex reported here provides a structural
rationale for the nature and potency of the inhibition
exhibited by the unsaturated l-2-amino-6-methylene-pimelate
against the dehydrogenase. In particular, we compare the
present structure with other structures containing either
bound substrate, meso-diaminopimelate, or a conformationally
restricted isoxazoline inhibitor. We have identified a
significant interaction between the α-l-amino
group of the unsaturated inhibitor and the indole ring
of Trp144 that may account for the tight binding of this
inhibitor.