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22  structures 2359  species 1  interaction 3573  sequences 23  architectures

Family: PCMT (PF01135)

Summary: Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT)

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This is the Wikipedia entry entitled "L-isoaspartyl methyltransferase". More...

L-isoaspartyl methyltransferase Edit Wikipedia article

Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PIMT, PCMT)
Human L-Isoaspartyl Methyltransferase - PDB id 1KR5.jpg
Crystallographic structure of Human L-isoaspartyl methyltransferase.[1]
Identifiers
EC number 2.1.1.77
CAS number 105638-50-4
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
Protein-L-isoaspartate(D-aspartate) O-methyltransferase
Identifiers
Symbol PCMT
Pfam PF01135
InterPro IPR000682
PROSITE PDOC00985
SCOP 1dl5
SUPERFAMILY 1dl5

Protein L-isoaspartyl methyltransferase (PIMT, PCMT), also called S-adenosyl-L-methionine:protein-L-isoaspartate O-methyltransferase, is an enzyme which recognizes and catalyzes the repair of damaged L-isoaspartyl and D-aspartatyl groups in proteins. It is a highly conserved enzyme which is present in nearly all eukaryotes, archaebacteria, and Gram-negative eubacteria.[1]

Function[edit]

PIMT acts to transfer methyl groups from S-adenosyl-L-methionine to the alpha side chain carboxyl groups of damaged L-isoaspartyl and D-aspartatyl amino acids. The enzyme takes the end methyl residue from the methionine side chain and adds it to the side chain carboxyl group of L-isoaspartate or D-aspartate to create a methyl ester. Subsequent nonenzymatic reactions result in a rapid transformation to L-succinimide, which is a precursor to aspartate and isoaspartate. The L-succinimide can then undergo nonenzymatic hydrolysis, which generates some repaired L-aspartyl residues as well as some L-isoaspartyl residues, which can then enter the cycle again for eventual conversion to the normal peptide linkage.

PIMT tends to act on proteins that have been non-enzymatically damaged due to age. By performing this repair mechanism, the enzyme helps to maintain overall protein integrity. This mechanism has been observed by several groups, and has been confirmed through experimental testing. In one report, PIMT was inhibited by adenosine dialdehyde. The results supported the proposed function of the enzyme, as the amount of abnormal L-aspartate residues increased when cells were treated with the indirect inhibitor, adenosine dialdehyde.[2] Additionally, S-adenosylhomocysteine is known to be a competitive inhibitor of PIMT.[2] When PIMT is not present in cells, the abnormal aspartyl residues accumulate, creating abnormal proteins that have been known to cause fatal progressive epilepsy in mice.[3] It has been suggested that calmodulin may play a role in stimulating the function of PIMT, although the relationship between these two molecules has not been thoroughly explored.[4] In addition to calmodulin, guanosine 5'-O-[gamma-thio]triphosphate (GTPgammaS) has been found to stimulate PIMT activity.[5]

Structure[edit]

The enzyme is present in human cytosol in two forms due to alternative splicing and differs among individuals in the population due to a single polymorphism at protein 119, either valine or isoleucine. The enzyme structure is described as a “doubly wound alpha/beta/alpha sandwich structure” which is quite consistent in all species analyzed thus far.[1] If there is any difference in the sequences between different organisms it occurs in the regions connecting the three motifs in the sandwich structure, but the sequence of the individual motifs tends to be highly conserved. Researchers have found the active site to be in the loop between the beta structure and the second alpha helix and have determined it to be highly specific for isoaspartyl residues. For example, the residues found at the C-terminus of drosophila PIMT (dPIMT) are rotated 90 degrees so as to allow more space for a substrate to interact with the enzyme. In fact, dPIMT appears to alternate between this unique open conformation and the less open conformation common of PIMT in other organisms. Although possibly unrelated to this, increased levels of dPIMT in drosophila have been correlated with increase life expectancy in these organisms due to their importance in protein repair.[6]

Reaction[edit]

Reaction catalysed by PIMT


See also[edit]

External links[edit]

References[edit]

  1. ^ a b c PDB 1KR5; Ryttersgaard C, Griffith SC, Sawaya MR, MacLaren DC, Clarke S, Yeates TO (March 2002). "Crystal structure of human L-isoaspartyl methyltransferase". J. Biol. Chem. 277 (12): 10642–6. doi:10.1074/jbc.M200229200. PMID 11792715. 
  2. ^ a b Johnson BA, Najbauer J, Aswad DW (March 1993). "Accumulation of substrates for protein L-isoaspartyl methyltransferase in adenosine dialdehyde-treated PC12 cells". J. Biol. Chem. 268 (9): 6174–81. PMID 8454593. 
  3. ^ Yamamoto A, Takagi H, Kitamura D, Tatsuoka H, Nakano H, Kawano H, Kuroyanagi H, Yahagi Y, Kobayashi S, Koizumi K, Sakai T, Saito K, Chiba T, Kawamura K, Suzuki K, Watanabe T, Mori H, Shirasawa T (March 1998). "Deficiency in protein L-isoaspartyl methyltransferase results in a fatal progressive epilepsy". J. Neurosci. 18 (6): 2063–74. PMID 9482793. 
  4. ^ O'Connor MB, O'Connor CM (May 1998). "Complex interactions of the protein L-isoaspartyl methyltransferase and calmodulin revealed with the yeast two-hybrid system". J. Biol. Chem. 273 (21): 12909–13. doi:10.1074/jbc.273.21.12909. PMID 9582322. 
  5. ^ Bilodeau D, Béliveau R (January 1999). "Inhibition of GTPgammaS-dependent L-isoaspartyl protein methylation by tyrosine kinase inhibitors in kidney". Cell. Signal. 11 (1): 45–52. doi:10.1016/S0898-6568(98)00030-8. PMID 10206344. 
  6. ^ Bennett EJ, Bjerregaard J, Knapp JE, Chavous DA, Friedman AM, Royer WE, O'Connor CM (November 2003). "Catalytic implications from the Drosophila protein L-isoaspartyl methyltransferase structure and site-directed mutagenesis". Biochemistry 42 (44): 12844–53. doi:10.1021/bi034891. PMID 14596598. 

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Protein-L-isoaspartate(D-aspartate) O-methyltransferase (PCMT) Provide feedback

No Pfam abstract.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000682

Protein-L-isoaspartate(D-aspartate) O-methyltransferase (EC) (PCMT) [PUBMED:9253175] (which is also known as L-isoaspartyl protein carboxyl methyltransferase) is an enzyme that catalyses the transfer of a methyl group from S-adenosylmethionine to the free carboxyl groups of D-aspartyl or L-isoaspartyl residues in a variety of peptides and proteins. The enzyme does not act on normal L-aspartyl residues L-isoaspartyl and D-aspartyl are the products of the spontaneous deamidation and/or isomerisation of normal L-aspartyl and L-asparaginyl residues in proteins. PCMT plays a role in the repair and/or degradation of these damaged proteins; the enzymatic methyl esterification of the abnormal residues can lead to their conversion to normal L-aspartyl residues. The SAM domain is present in most of these proteins.

Gene Ontology

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Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan NADP_Rossmann (CL0063), which contains the following 180 members:

2-Hacid_dh_C 3Beta_HSD 3HCDH_N adh_short adh_short_C2 ADH_zinc_N ADH_zinc_N_2 AdoHcyase_NAD AdoMet_MTase AlaDh_PNT_C Amino_oxidase ApbA AviRa Bac_GDH Bin3 CheR CMAS CmcI CoA_binding CoA_binding_2 CoA_binding_3 Cons_hypoth95 DAO DapB_N DFP DNA_circ_N DNA_methylase DOT1 DREV dTMP_synthase DUF1442 DUF1776 DUF2431 DUF268 DUF3321 DUF43 DUF633 DUF938 DXP_redisom_C DXP_reductoisom Eco57I ELFV_dehydrog Eno-Rase_FAD_bd Eno-Rase_NADH_b Enoyl_reductase Epimerase F420_oxidored FAD_binding_2 FAD_binding_3 FAD_oxidored Fibrillarin FMO-like FmrO FtsJ G-7-MTase G6PD_N GCD14 GDI GFO_IDH_MocA GIDA GidB GLF Glyco_hydro_4 GMC_oxred_N Gp_dh_N GRAS GRDA HI0933_like HIM1 IlvN K_oxygenase KR LCM Ldh_1_N Lycopene_cycl Malic_M Mannitol_dh Met_10 Methyltrans_Mon Methyltrans_SAM Methyltransf_10 Methyltransf_11 Methyltransf_12 Methyltransf_15 Methyltransf_16 Methyltransf_17 Methyltransf_18 Methyltransf_19 Methyltransf_2 Methyltransf_20 Methyltransf_21 Methyltransf_22 Methyltransf_23 Methyltransf_24 Methyltransf_25 Methyltransf_26 Methyltransf_27 Methyltransf_28 Methyltransf_29 Methyltransf_3 Methyltransf_30 Methyltransf_31 Methyltransf_32 Methyltransf_4 Methyltransf_5 Methyltransf_7 Methyltransf_8 Methyltransf_9 Methyltransf_PK MethyltransfD12 MetW Mg-por_mtran_C Mqo MT-A70 MTS Mur_ligase N2227 N6-adenineMlase N6_Mtase N6_N4_Mtase NAD_binding_10 NAD_binding_11 NAD_binding_2 NAD_binding_3 NAD_binding_4 NAD_binding_5 NAD_binding_7 NAD_binding_8 NAD_binding_9 NAD_Gly3P_dh_N NAS NmrA NNMT_PNMT_TEMT NodS Nol1_Nop2_Fmu Nol1_Nop2_Fmu_2 NSP13 OCD_Mu_crystall PARP_regulatory PCMT PDH Polysacc_synt_2 Pox_MCEL Prenylcys_lyase PrmA PRMT5 Pyr_redox Pyr_redox_2 Pyr_redox_3 RmlD_sub_bind Rossmann-like rRNA_methylase RrnaAD Rsm22 RsmJ Saccharop_dh SAM_MT SE Semialdhyde_dh Shikimate_DH Spermine_synth Strep_67kDa_ant TehB THF_DHG_CYH_C Thi4 ThiF TPMT TrkA_N TRM TRM13 tRNA_U5-meth_tr Trp_halogenase TylF Ubie_methyltran UDPG_MGDP_dh_N UPF0020 UPF0146 V_cholerae_RfbT XdhC_C YjeF_N

Alignments

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(9)
Full
(3573)
Representative proteomes NCBI
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(3799)
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(387)
RP35
(810)
RP55
(1083)
RP75
(1324)
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  Seed
(9)
Full
(3573)
Representative proteomes NCBI
(13744)
Meta
(3799)
RP15
(387)
RP35
(810)
RP55
(1083)
RP75
(1324)
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  Seed
(9)
Full
(3573)
Representative proteomes NCBI
(13744)
Meta
(3799)
RP15
(387)
RP35
(810)
RP55
(1083)
RP75
(1324)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
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Pfam alignments:

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Curation and family details

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Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Family
Author: Finn RD, Bateman A
Number in seed: 9
Number in full: 3573
Average length of the domain: 199.20 aa
Average identity of full alignment: 32 %
Average coverage of the sequence by the domain: 79.48 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.3 20.3
Trusted cut-off 20.3 20.3
Noise cut-off 20.2 20.2
Model length: 210
Family (HMM) version: 14
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Species distribution

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Interactions

There is 1 interaction for this family. More...

PCMT

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PCMT domain has been found. There are 22 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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