Armt1: a phoenix rises from the ashes

In the mid 1960s scientists discovered an enzyme activity in pituitary extracts that hydrolyzed s-adenosyl methionine (AdoMet) leading to the generation of methanol. Initially, the sole purpose for this enzyme was thought to be cleavage of AdoMet into methanol; but, it was later identified as protein carboxyl methyltransferase or protein methylase II [1]. Similar to the already described protein methylase I, protein methylase II required the co-factor AdoMet to donate its methyl group. But unlike protein methylase I, protein methylase II did not N-methylate amine groups of lysyl and arginyl side chains. Instead, it appeared to O-methylate free carboxyl groups in aspartyl and glutamyl residues and/or the carboxyl-termini of proteins. The exact target(s) of protein methylase II and the significance O-methylation had on protein function was unclear. Some years later an important role for this type of enzyme was described in chemotactic bacteria. In 1977, Springer and Koshland, Jr. uncovered that a necessary component of the bacterial chemical sensing system and product of the CheR gene was a protein O-methyltransferase [2]. It is now known that methylation of four specific glutamyl residues in chemoreceptors by CheR is required for adaption in chemotaxis for some bacterial species. It was logical that a system similar to CheR-regulated bacterial chemotaxis would be present in higher organisms. Despite studies identifying protein O-methyltransferase activities in cytoplasmic membranes of mouse neutrophils and mammalian targets of protein methylase II being erythrocyte membrane proteins and the pituitary hormone ACTH, a direct link between protein methylase II and eukaryotic cell signal transduction would not be made. In the early 1980s, O'Connor and Clarke challenged the idea that protein methylase II was involved in signaling events in eukaryotic cells when they discovered that the mammalian enzyme catalyzed the transfer of methyl groups from AdoMet not to glutamyl or aspartyl residues, but to damaged L-isoapartyl or D-aspartyl residues that occur spontaneously in aging proteins [3]. Aswad subsequently demonstrated that methylation of ACTH by protein methylase II required deamination of an asparginyl residue in the hormone [4]. Protein methylase II hence would come to be known as the protein repair enzyme protein L-isoaspartate (D-aspartate) O-methyltransferase 1 (PCMT1). Two additional protein carboxyl methyltransferases would be identified in the 1990s: isoprenylcysteine carboxyl methyltransferase (ICMT) and leucine carboxyl methyltransferase (LCMT1), but neither of these enzymes would target glutamyl or undamaged aspartyl residues. It seemed that a eukaryotic equivalent of the prokaryotic glutamyl methyltransferase CheR was …