Disease relevance of PCMT1

• A known functional polymorphism (Ile120Val) of the human PCMT1 gene and risk of spina bifida [1].
• The core structure has a nucleotide binding domain motif, which is structurally homologous with the N-terminal domain of the bacterial Thermotoga maritima PIMT [2].
• Purification, gene cloning, and sequence analysis of an L-isoaspartyl protein carboxyl methyltransferase from Escherichia coli [3].
• Gene targeting has elucidated a physiological role for PIMT by showing that mice lacking PIMT died prematurely from fatal epileptic seizures [4].
• These results suggest that levels and activity of the 30-KD PCMT may be downregulated to maintain the phenotypic expression of the endometrial carcinoma [5].

High impact information on PCMT1

• To identify the proteins containing these residues, brain homogenates from Pcmt1(-/-) mice were methylated by exogenous repair enzyme and the radiolabeled methyl donor S-adenosyl-[methyl-(3)H]methionine [6].
• These results strongly suggest that L-isoaspartyl residue formation in ECM proteins such as type-I collagen could play an important role in reducing cell migration and that PIMT could be a therapeutic tool to restore normal cell migration in pathological conditions where cell motility is crucial [7].
• Here we investigated the role of PIMT in human mesial temporal lobe epilepsy [4].
• The identity of the 27 kDa protein as a PCMT was demonstrated by renaturation of PCMT activity from SDS/polyacrylamide gels [8].
• To test the possibility that the concentration of structurally abnormal cellular proteins affects PCMT activity, protein carboxyl methylation reactions were studied in HeLa cells exposed to various stresses that increase the extent of protein unfolding in cells [9].

Biological context of PCMT1

• The L-isoaspartyl/D-aspartyl protein methyltransferase gene (PCMT1) maps to human chromosome 6q22.3-6q24 and the syntenic region of mouse chromosome 10 [10].
• 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 [11].
• By analyzing the presence of an EcoRI polymorphism in DNA from backcrosses of C57BL/6J and Mus spretus strains of mice, we localized the mouse gene (Pcmt-1) to chromosome 10, at a position 8.2 +/- 3.5 cM proximal to the Myb locus [10].
• Inhibition of PIMT/Tgs1 expression by siRNA in HeLa cells resulted in an increase in the percentage of cells in G2/M phases [12].
• PIMT transcript was detected in rat embryonic brain and showed a linear up-regulation during the maturation of the brain and maintained its level in aged rat brain [13].

Anatomical context of PCMT1

• Two different sizes (approximately 1.0 and 1.6 kb) of transcripts of an isoaspartyl protein carboxyl methyltransferase (PIMT) were detected in eight cell lines derived from human hemopoietic cells on Northern blot analysis [14].
• These results indicate that both myofibrillar protein subunits undergo selective non-enzymatic degradation at neutral and alkaline pH, resulting in the formation of methyl acceptor sites for human erythrocyte and rat cardiac PCMT [15].
• The present results suggest that the expression of PIMT is associated with the amount of racemized/isomerized proteins accumulated during the developmental and aging process of the central nervous system [13].
• An immunohistochemical study showed that PIMT is strongly expressed in neurons and weakly but definitively in glial cells and oligodendrocytes [13].
• Interestingly, addition of GTPgammaS partially inhibited the methylation of two PIMT substrates, ovalbumin (24%) and bovine calmodulin (19%), when incubated with liver membranes [16].

Associations of PCMT1 with chemical compounds

• We hypothesized that a known functional polymorphism (Ile120Val) in the human PCMT1 gene is associated with an increased risk of folate-responsive human NTDs [1].
• The protein L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) can initiate the repair of age-damaged aspartyl and asparaginyl residues of intracellular proteins [11].
• Protein isoaspartyl methyltransferase (PIMT) reverts many isoAsp residues to aspartate as a protein repair process [2].
• SAH is a by-product of the reaction between protein isoaspartyl methyltransferase (PIMT), S-adenosylmethionine (SAM), and isoaspartic acid residues [17].
• PIMT increased the enzymatic activities in supernatant of ferment broth (1.6 folds) and cell lysate (1.8 folds), while it did not significantly affect the expression level of penicillin G acylase [18].

Analytical, diagnostic and therapeutic context of PCMT1

• In situ hybridization studies allowed us to confirm this identification and further localize the human gene (PCMT1) to the 6q22.3-6q24 region [10].
• Assignment of the protein L-isoaspartate (D-aspartate) O-methyltransferase gene (PCMT1) to human chromosome bands 6q24-->q25 with radiation hybrid mapping [19].
• We have cloned a cDNA encoding protein L-isoaspartyl methyltransferase (PIMT) and characterized gene expression in the development, maturation, and the aging process of the central nervous system by RNA blot analysis, western blot analysis, and immunohistochemistry [13].
• Following implantation and at quarterly outpatient clinic visits, V-A conduction and ability to initiate and sustain PCMT were systematically assessed by non-invasive techniques [20].

References