Malate dehydrogenase: a model for structure, evolution, and catalysis

Protein Sci. 1994 Oct;3(10):1883-8. doi: 10.1002/pro.5560031027.


Malate dehydrogenases are widely distributed and alignment of the amino acid sequences show that the enzyme has diverged into 2 main phylogenetic groups. Multiple amino acid sequence alignments of malate dehydrogenases also show that there is a low degree of primary structural similarity, apart from in several positions crucial for nucleotide binding, catalysis, and the subunit interface. The 3-dimensional structures of several malate dehydrogenases are similar, despite their low amino acid sequence identity. The coenzyme specificity of malate dehydrogenase may be modulated by substitution of a single residue, as can the substrate specificity. The mechanism of catalysis of malate dehydrogenase is similar to that of lactate dehydrogenase, an enzyme with which it shares a similar 3-dimensional structure. Substitution of a single amino acid residue of a lactate dehydrogenase changes the enzyme specificity to that of a malate dehydrogenase, but a similar substitution in a malate dehydrogenase resulted in relaxation of the high degree of specificity for oxaloacetate. Knowledge of the 3-dimensional structures of malate and lactate dehydrogenases allows the redesign of enzymes by rational rather than random mutation and may have important commercial implications.

Publication types

  • Comparative Study
  • Review

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Biological Evolution*
  • Catalysis
  • Coenzymes
  • Malate Dehydrogenase / chemistry*
  • Malate Dehydrogenase / genetics
  • Malate Dehydrogenase / metabolism
  • Molecular Sequence Data
  • Sequence Alignment
  • Substrate Specificity


  • Coenzymes
  • Malate Dehydrogenase