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Homo sapiens Enzyme: protein-L-isoaspartate(D-aspartate) O-methyltransferase

Gene: PCMT1 Accession Number: HS04385 (HumanCyc)

Synonyms: L-isoaspartyl protein carboxyl methyltransferase, PIMT, protein L-isoaspartyl/D-aspartyl methyltransferase, protein-beta-aspartate methyltransferase

Summary:
Isoaspartyl residues arise spontaneously in proteins from deamidation of asparagines and isomerization of aspartates [Smith02]. This disrupts the structure and function of many normal proteins. Cytosolic protein-L-isoaspartate(D-aspartate) O-methyltransferase catalyzes the methyl esterification of isoAsp residues and converts them back to normal L-aspartate residues. This process plays a role in the repair and/or degradation of damaged proteins.

The formation of isoAsp residues may play a role in certain autoimmune diseases and Alzheimer's disease, suggesting an important role for protein-L-isoaspartate(D-aspartate) O-methyltransferase in the protection against such diseases [Shimizu00][Mamula99]. The enzyme requires the presence of S-adenosyl-L-methionine as a cofactor [Ryttersgaard02]. Two isozymes of protein-L-isoaspartate(D-aspartate) O-methyltransferase arising from alternate splicing have been detected in human erythrocytes [Ota88][MacLaren92].

Gene Citations: [DeVry99, MacLaren92a]

Locations: cytosol

Map Position: [150,006,352 -> 150,027,820] (87.89 centisomes) on Chromosome 6
Length: 21469 bp

Unification Links: Ensembl:ENSG00000120265 , Entrez-gene:5110 , Entrez-Nucleotide:AK098739 , Entrez-Nucleotide:BC007501 , Entrez-Nucleotide:BC008748 , Entrez-Nucleotide:D13892 , Entrez-Nucleotide:D25545 , Entrez-Nucleotide:D25546 , Entrez-Nucleotide:D25547 , Entrez-Nucleotide:M93008 , Entrez:AAA90933 , Entrez:AAA90934 , Entrez:AAB38386 , Entrez:AAH07501 , Entrez:AAH08748 , Entrez:BAA02991 , Entrez:BAA05028 , Entrez:BAA05029 , Entrez:BAA05030 , GeneCards:PCMT1 , MOPED:P22061 , OMIM:176851 , RefSeq:NM_005389 , RefSeq:NP_005380 , UCSC Human Genome:NM_005389 , UniGene:79137 , UniProt:P22061

Gene-Reaction Schematic: ?

Gene-Reaction Schematic

GO Terms:

Biological Process: GO:0006464 - cellular protein modification process
GO:0006479 - protein methylation
Molecular Function: GO:0004719 - protein-L-isoaspartate (D-aspartate) O-methyltransferase activity
GO:0016740 - transferase activity
Cellular Component: GO:0005829 - cytosol


Enzymatic reaction of: Protein-L-isoaspartate(D-aspartate) O-methyltransferase (protein-L-isoaspartate(D-aspartate) O-methyltransferase)

EC Number: 2.1.1.77

S-adenosyl-L-methionine + a [protein]-L-β-isoaspartate <=> S-adenosyl-L-homocysteine + a protein L-β-isoaspartate α-methyl ester

The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the direction in which it was curated.

The reaction is physiologically favored in the direction shown.


Gene Local Context (not to scale): ?

Gene local context diagram

Exons/Introns:

Schematic showing introns, exons and/or isoforms of PCMT1


References

DeVry99: DeVry CG, Clarke S (1999). "Assignment of the protein L-isoaspartate (D-aspartate) O-methyltransferase gene (PCMT1) to human chromosome bands 6q24-->q25 with radiation hybrid mapping." Cytogenet Cell Genet 84(1-2);130-1. PMID: 10343128

MacLaren92: MacLaren DC, Kagan RM, Clarke S (1992). "Alternative splicing of the human isoaspartyl protein carboxyl methyltransferase RNA leads to the generation of a C-terminal -RDEL sequence in isozyme II." Biochem Biophys Res Commun 185(1);277-83. PMID: 1339271

MacLaren92a: MacLaren DC, O'Connor CM, Xia YR, Mehrabian M, Klisak I, Sparkes RS, Clarke S, Lusis AJ (1992). "The L-isoaspartyl/D-aspartyl protein methyltransferase gene (PCMT1) maps to human chromosome 6q22.3-6q24 and the syntenic region of mouse chromosome 10." Genomics 14(4);852-6. PMID: 1478665

Mamula99: Mamula MJ, Gee RJ, Elliott JI, Sette A, Southwood S, Jones PJ, Blier PR (1999). "Isoaspartyl post-translational modification triggers autoimmune responses to self-proteins." J Biol Chem 274(32);22321-7. PMID: 10428801

Ota88: Ota IM, Gilbert JM, Clarke S (1988). "Two major isozymes of the protein D-aspartyl/L-isoaspartyl methyltransferase from human erythrocytes." Biochem Biophys Res Commun 151(3);1136-43. PMID: 3355545

Ryttersgaard02: Ryttersgaard C, Griffith SC, Sawaya MR, MacLaren DC, Clarke S, Yeates TO (2002). "Crystal structure of human L-isoaspartyl methyltransferase." J Biol Chem 277(12);10642-6. PMID: 11792715

Shimizu00: Shimizu T, Watanabe A, Ogawara M, Mori H, Shirasawa T (2000). "Isoaspartate formation and neurodegeneration in Alzheimer's disease." Arch Biochem Biophys 381(2);225-34. PMID: 11032409

Smith02: Smith CD, Carson M, Friedman AM, Skinner MM, Delucas L, Chantalat L, Weise L, Shirasawa T, Chattopadhyay D (2002). "Crystal structure of human L-isoaspartyl-O-methyl-transferase with S-adenosyl homocysteine at 1.6-A resolution and modeling of an isoaspartyl-containing peptide at the active site." Protein Sci 11(3);625-35. PMID: 11847284


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Please cite the following article in publications resulting from the use of HumanCyc: Genome Biology 6(1):1-17 2004
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