Protein carboxylmethylation and nervous system function

Enzymatic protein-O-carboxylmethylation transfers methyl groups from S-adenosylmethionine to aspartyl and/or glutamyl residues of various methyl acceptor proteins. The function of this post-translational modification of protein, originally detected as "methanol-forming" activity in pituitary gland, has remained enigmatic in nervous tissue. Theories concerning the function of protein methylation have focused on possible roles in neurotransmitter release, neurophysin carboxylmethylation, regulation of calmodulin and calmodulin-binding proteins, chemotaxis, processing of precursor peptides, and repair/recognition of racemized D-amino acids. However, difficulties in establishing quantitative and temporal relationships between methylation and the biochemical event described have led to controversies. Similarly, the alkaline lability of the carboxylmethyl ester bond has led to difficulties in using the high resolution gel electrophoresis systems so successfully used in characterization of other post-translational events. Recent studies localizing protein-O-carboxylmethyltransferase to neurons in the rat brain suggest that this enzyme may be involved in signal transduction in the CNS. Alternative theories concerning protein methylation will be discussed and future directions for research in this area will be outlined.