Journal Club: Structural Basis for Altered Activity of M- and H-Isozyme Forms of Human Lactate Dehydrogenase
Lactate dehydrogenase (LDH) interconverts
pyruvate and lactate with concomitant
interconversion of NADHand NAD1. Although crystal
structures of a variety of LDH have previously
been described, a notable absence has been any of
the three known human forms of this glycolytic
enzyme. We have nowdetermined the crystal structures
of two isoforms of human LDH—the M form,
predominantly found in muscle; and the H form,
found mainly in cardiac muscle. Both structures
have been crystallized as ternary complexes in the
presence of the NADH cofactor and oxamate, a
substrate-like inhibitor. Although each of these isoforms
has different kinetic properties, the domain
structure, subunit association, and active-site regions
are indistinguishable between the two structures.
The pKa that governs the KM for pyruvate for
the two isozymes is found to differ by about 0.94 pH
units, consistent with variation in pKa of the activesite
histidine. The close similarity of these crystal
structures suggests the distinctive activity of these
enzyme isoforms is likely to result directly from
variation of charged surface residues peripheral to
the active site, a hypothesis supported by electrostatic
calculations basedoneachstructure.