Protein L-isoaspartyl, D-aspartyl O-methyltransferases

Abstract

Protein L-isoaspartyl, D-aspartyl O-methyltransferases (PIMTs) are ancient enzymes that are distributed through all phylogenetic domains. PIMTs catalyze the methylation of Lisoaspartyl, and to a lesser extent D-aspartyl, residues arising from the spontaneous deamidation and isomerization of protein asparaginyl and aspartyl residues. PIMTs catalyze the methylation of isoaspartyl residues in a large number of primary sequence configurations, which accounts for the broad specificity of the enzyme for protein substrates both in vitro and in vivo. PIMTcatalyzed methylation of isoaspartyl substrates initiates the repair of the polypeptide backbone in its damaged substrates by a spontaneous mechanism that involves a succinimidyl intermediate. The repair process catalyzed by PIMTs is not completely efficient, however, leaving open the possibility that unidentified enzymatic activities cooperate with PIMT in the repair process. Structurally, PIMTs are members of the Class I family of AdoMet-dependent methyltransferases. PIMTs have a unique topological arrangement of strands in the central β-sheet that provides a signature for this class of enzymes. The regulation and physiological significance of PIMT have been studied in several model organisms. PIMTs are constitutively synthesized by cells, but they can be upregulated in response to conditions that are potentially damaging to protein structures or when proteins are stored for prolonged periods of time. Disruption of PIMT genes in bacteria and simple eukaryotes produces subtle phenotypes that are apparent only under stress. Loss of PIMT function in transgenic mice leads to fatal epilepsy, suggesting that PIMT function is particularly important to neurons in mammals.