Protein-L-isoaspartate(D-aspartate) O-methyltransferase (EC 2.1.1.77) (PIMT) (L-isoaspartyl protein carboxyl methyltransferase) (Protein L-isoaspartyl/D-aspartyl methyltransferase) (Protein-beta-aspartate methyltransferase)

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Polymorphic forms of the protein L-isoaspartate (D-aspartate) O-methyltransferase involved in the repair of age-damaged proteins.

The protein L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) can initiate the repair of age-damaged aspartyl and asparaginyl residues of intracellular proteins. The human gene PCMT1 encoding this enzyme has at least four polymorphic sites, one of which results in two major isoforms with either an Ile residue or a Val residue at amino acid position 119. The frequencies of the alleles encoding the Ile119 and Val119 variants are similar in Caucasian populations, but a predominance of the Ile119 allele exists in Asian and African populations. Analyses of the enzymatic activities of the Ile119 and Val119 variants in red blood cell lysates show that the higher specific activity and thermostability of the Ile119 isoform is balanced by the potentially compensating higher substrate affinity of the Val119 isoform. In a preliminary attempt to find an association between genotype frequency at the PCMT1 locus and healthy aging, we compared the distribution of genotypes in a healthy older population of Ashkenazi Jewish individuals with that in a younger ethnically matched control group. We found that 65% of the healthy older population had the heterozygous genotype, greater than the 50% expected by Hardy-Weinberg equilibrium, suggesting a possible selection for having both alleles of the repair methyltransferase in successful aging. Three additional polymorphisms in noncoding regions of the methyltransferase gene were found to be biallelic and demonstrated nonrandom association in a specific haplotype with the codon 119 polymorphism. Finally, we also detected a heterozygous mutation in the splicing branch site of intron 2 that did not appear to affect activity. This study will help define the normal physiological range of activity for this repair methyltransferase and give us a better understanding of its role in the processes of aging and disease.

MeSH Terms

  • African Continental Ancestry Group
  • Aging
  • Amino Acid Sequence
  • Asian Continental Ancestry Group
  • Base Sequence
  • Consensus Sequence
  • European Continental Ancestry Group
  • Female
  • Genetic Variation
  • Humans
  • Isoenzymes
  • Isoleucine
  • Jews
  • Kinetics
  • Korea
  • Los Angeles
  • Male
  • Molecular Sequence Data
  • Norway
  • Pedigree
  • Polymorphism, Genetic
  • Protein D-Aspartate-L-Isoaspartate Methyltransferase
  • Protein Methyltransferases
  • Substrate Specificity
  • Valine