Donor-acceptor distance and protein promoting vibration coupling to hydride transfer: A possible mechanism for kinetic control in isozymes of human lactate dehydrogenase

Jodi E. Basner, Steven D. Schwartz

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Theoretically based computational methods have been developed in our group to identify protein motions, symmetrically coupled to the reaction coordinate, which modulate the width and height of the barrier to reaction. Previous studies have applied the methods to horse liver alcohol dehydrogenase (HLADH), to help explain experimental kinetic isotope effects. In this paper the methods have been applied to the two isoforms of human lactate dehydrogenase (LDH) enzymes which facilitate hydride transfer during the interconversion of pyruvate and lactate. LDH isoforms have evolved to accommodate substrate demand in different parts of the body. The active sites of the isoforms are identical in amino acid content yet the kinetics are distinct. We have performed molecular dynamics simulations for each isoform with either substrate bound. The signature of the protein promoting vibration (PPV) is distinct for each isoform due to differences in the donor-acceptor distance. We hypothesize that kinetic control of hydride transfer may be exerted via a decreased donor-acceptor distance when lactate is bound to the heart isoform and when pyruvate is bound to the skeletal muscle isoform. The identity, frequency, and position of active site amino acid motions correlated to the donor-acceptor motion also vary for each isoform. These results demonstrate that even in almost identical enzymes, subtle differences in protein structure, remote from the active site, can have significant effects on reaction dynamics.

Original languageEnglish (US)
Pages (from-to)444-451
Number of pages8
JournalJournal of Physical Chemistry B
Volume108
Issue number1
DOIs
StatePublished - Jan 8 2004
Externally publishedYes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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