13 Protein L-isoaspartyl, D-aspartyl O-methyltransferases: Catalysts for protein repair

Abstract

Protein L-isoaspartyl, D-aspartyl O-methyltransferases (PIMTs) are ancient enzymes distributed through all phylogenetic domains. PIMTs catalyze the methylation of L-isoaspartyl, 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. PIMT-catalyzed 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 PEVITs 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 has 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 fatalepilepsy, suggesting that PIMT function is particularly important to neurons in mammals.