MALATE-DEHYDROGENASE - A MODEL FOR STRUCTURE, EVOLUTION, AND CATALYSIS

Malate dehydrogenases are widely distributed and alignment of the amin o acid sequences show that the enzyme has diverged into 2 main phyloge netic groups. Multiple amino acid sequence alignments of malate dehydr ogenases also show that there is a low degree of primary structural si milarity, apart from in several positions crucial for nucleotide bindi ng, 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 dehydrogen ase may be modulated by substitution of a single residue, as can the s ubstrate specificity. The mechanism of catalysis of malate dehydrogena se is similar to that of lactate dehydrogenase, an enzyme with which i t shares a similar 3-dimensional structure. Substitution of a single a mino acid residue of a lactate dehydrogenase changes the enzyme specif icity to that of a malate dehydrogenase, but a similar substitution in a malate dehydrogenase resulted in relaxation of the high degree of s pecificity for oxaloacetate. Knowledge of the 3-dimensional structures of malate and lactate dehydrogenases allows the redesign of enzymes b y rational rather than random mutation and may have important commerci al implications.