DB code: S00639

RLCP classification	3.717.19970.25 : Transfer
CATH domain	3.40.50.150 : Rossmann fold	Catalytic domain
E.C.	2.1.1.77
CSA
M-CSA
MACiE

CATH domain	Related DB codes (homologues)
3.40.50.150 : Rossmann fold	S00637 S00262 S00261 S00291 S00412 D00075 D00076 D00079 D00080 D00082 D00083 D00823

Uniprot Enzyme Name
UniprotKB	Protein name	Synonyms	RefSeq	Pfam
Q57636	Protein-L-isoaspartate O-methyltransferase	EC 2.1.1.77 Protein-beta-aspartate methyltransferase PIMT Protein L-isoaspartyl methyltransferase L-isoaspartyl protein carboxyl methyltransferase	NP_247140.1 (Protein) NC_000909.1 (DNA/RNA sequence)	PF01135 (PCMT) [Graphical View]
Q8TZR3	Protein-L-isoaspartate O-methyltransferase	EC 2.1.1.77 Protein-beta-aspartate methyltransferase PIMT Protein L-isoaspartyl methyltransferase L-isoaspartyl protein carboxyl methyltransferase	NP_579651.1 (Protein) NC_003413.1 (DNA/RNA sequence)	PF01135 (PCMT) [Graphical View]
Q8ILD5		Protein-L-isoaspartate O-methyltransferase beta-aspartate methyltransferase, putative	XP_001348483.1 (Protein) XM_001348447.1 (DNA/RNA sequence)	PF01135 (PCMT) [Graphical View]
Q27869	Protein-L-isoaspartate(D-aspartate) O-methyltransferase	PIMT EC 2.1.1.77 Protein-beta-aspartate methyltransferase dPIMT Protein L-isoaspartyl/D-aspartyl methyltransferase L-isoaspartyl protein carboxyl methyltransferase	NP_536756.1 (Protein) NM_080508.4 (DNA/RNA sequence)	PF01135 (PCMT) [Graphical View]
P22061	Protein-L-isoaspartate(D-aspartate) O-methyltransferase	PIMT EC 2.1.1.77 Protein-beta-aspartate methyltransferase Protein L-isoaspartyl/D-aspartyl methyltransferase L-isoaspartyl protein carboxyl methyltransferase	NP_001238978.1 (Protein) NM_001252049.1 (DNA/RNA sequence) NP_001238982.1 (Protein) NM_001252053.1 (DNA/RNA sequence)	PF01135 (PCMT) [Graphical View]

KEGG enzyme name
Protein-L-isoaspartate(D-aspartate) O-methyltransferase Protein-L-isoaspartate O-methyltransferase Protein-beta-aspartate O-methyltransferase D-Aspartyl/L-isoaspartyl methyltransferase L-Isoaspartyl/D-aspartyl protein carboxyl methyltransferase Protein (D-aspartate) methyltransferase Protein D-aspartate methyltransferase Protein L-isoaspartate methyltransferase Protein L-isoaspartyl methyltransferase Protein O-methyltransferase (L-isoaspartate) L-Aspartyl/L-isoaspartyl protein methyltransferase

KEGG enzyme name

Protein-L-isoaspartate(D-aspartate) O-methyltransferase
Protein-L-isoaspartate O-methyltransferase
Protein-beta-aspartate O-methyltransferase
D-Aspartyl/L-isoaspartyl methyltransferase
L-Isoaspartyl/D-aspartyl protein carboxyl methyltransferase
Protein (D-aspartate) methyltransferase
Protein D-aspartate methyltransferase
Protein L-isoaspartate methyltransferase
Protein L-isoaspartyl methyltransferase
Protein O-methyltransferase (L-isoaspartate)
L-Aspartyl/L-isoaspartyl protein methyltransferase

UniprotKB: Accession Number	Entry name	Activity	Subunit	Subcellular location
Q57636	PIMT_METJA	S-adenosyl-L-methionine + protein L-isoaspartate = S-adenosyl-L-homocysteine + protein L-isoaspartate alpha-methyl ester.		Cytoplasm (By similarity).
Q8TZR3	PIMT_PYRFU	S-adenosyl-L-methionine + protein L-isoaspartate = S-adenosyl-L-homocysteine + protein L-isoaspartate alpha-methyl ester.	Monomer.	Cytoplasm (By similarity).
Q8ILD5	Q8ILD5_PLAF7
Q27869	PIMT_DROME	S-adenosyl-L-methionine + protein L-isoaspartate = S-adenosyl-L-homocysteine + protein L-isoaspartate alpha-methyl ester.	Monomer.	Cytoplasm (By similarity).
P22061	PIMT_HUMAN	S-adenosyl-L-methionine + protein L-isoaspartate = S-adenosyl-L-homocysteine + protein L-isoaspartate alpha-methyl ester.	Monomer.	Cytoplasm.

KEGG Pathways
Map code	Pathways	E.C.

Compound table
	Substrates		Products		Intermediates
KEGG-id	C00019	C03306	C00021	C04311
E.C.
Compound	S-adenosyl-L-methionine	protein L-isoaspartate	S-adenosyl-L-homocysteine	protein L-isoaspartate alpha-methyl ester
Type	amino acids,amine group,nucleoside,sulfonium ion	carboxyl group,peptide/protein	amino acids,amine group,nucleoside,sulfide group	carbohydrate,peptide/protein
ChEBI	67040 67040		16680 57856 16680 57856
PubChem	34755 34755		25246222 439155 25246222 439155

2yxeA00	Unbound	Unbound	Unbound	Unbound
2yxeB00	Unbound	Unbound	Unbound	Unbound
1jg1A00	Unbound	Unbound	Bound:SAH	Unbound
1jg2A00	Unbound	Unbound	Analogue:ADN	Unbound
1jg3A00	Unbound	Bound:VAL-TYR-PRO-ASP-HIS-ALA (chain C)	Analogue:ADN	Unbound
1jg3B00	Unbound	Bound:VAL-TYR-PRO-ASP-HIS-ALA (chain D)	Analogue:ADN	Unbound
1jg4A00	Bound:SAM	Unbound	Unbound	Unbound
2pbfA00	Unbound	Unbound	Bound:SAH	Unbound
2pbfB00	Unbound	Unbound	Bound:SAH	Unbound
1r18A00	Unbound	Unbound	Bound:SAH	Unbound
1i1nA00	Unbound	Unbound	Bound:SAH	Unbound
1kr5A00	Unbound	Unbound	Bound:SAH	Unbound

Reference for Active-site residues
resource	references	E.C.
literature [2], [7] & Swiss;Q57636, Q8TZR3, P22061, Q27869

Active-site residues
PDB	Catalytic residues	Cofactor-binding residues	Modified residues	Main-chain involved in catalysis	Comment

2yxeA00	SER 61
2yxeB00	SER 61
1jg1A00	SER 75
1jg2A00	SER 75
1jg3A00	SER 75
1jg3B00	SER 75
1jg4A00	SER 75
2pbfA00	SER 62
2pbfB00	SER 62
1r18A00	SER 60
1i1nA00	SER 59
1kr5A00	SER 59

References for Catalytic Mechanism
References	Sections	No. of steps in catalysis
[2]	Fig.5c, p.1196-1198
[7]	p.12850-12852

References
[1]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 11-284
Medline ID
PubMed ID	9115443
Journal	Structure
Year	1997
Volume	5
Pages	545-58
Authors	Djordjevic S, Stock AM
Title	Crystal structure of the chemotaxis receptor methyltransferase CheR suggests a conserved structural motif for binding S-adenosylmethionine.
Related PDB	1af7
Related UniProtKB	P07801
[2]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
Medline ID
PubMed ID	11080641
Journal	Structure
Year	2000
Volume	8
Pages	1189-201
Authors	Skinner MM, Puvathingal JM, Walter RL, Friedman AM
Title	Crystal structure of protein isoaspartyl methyltransferase: a catalyst for protein repair.
Related PDB	1dl5
Related UniProtKB	Q56308
[3]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS).
Medline ID
PubMed ID	11700066
Journal	J Mol Biol
Year	2001
Volume	313
Pages	1103-16
Authors	Griffith SC, Sawaya MR, Boutz DR, Thapar N, Katz JE, Clarke S, Yeates TO
Title	Crystal structure of a protein repair methyltransferase from Pyrococcus furiosus with its L-isoaspartyl peptide substrate.
Related PDB	1jg1 1jg2 1jg3 1jg4
Related UniProtKB	Q8TZR3
[4]
Resource
Comments
Medline ID
PubMed ID	12504684
Journal	Curr Opin Struct Biol
Year	2002
Volume	12
Pages	783-93
Authors	Martin JL, McMillan FM
Title	SAM (dependent) I AM: the S-adenosylmethionine-dependent methyltransferase fold. Curr Opin Struct Biol. 2002 Dec;12(6):783-93. Review.
Related PDB
Related UniProtKB
[5]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
Medline ID
PubMed ID	11792715
Journal	J Biol Chem
Year	2002
Volume	277
Pages	10642-6
Authors	Ryttersgaard C, Griffith SC, Sawaya MR, MacLaren DC, Clarke S, Yeates TO
Title	Crystal structure of human L-isoaspartyl methyltransferase.
Related PDB	1kr5
Related UniProtKB	P22061
[6]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS).
Medline ID
PubMed ID	11847284
Journal	Protein Sci
Year	2002
Volume	11
Pages	625-35
Authors	Smith CD, Carson M, Friedman AM, Skinner MM, Delucas L, Chantalat L, Weise L, Shirasawa T, Chattopadhyay D
Title	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.
Related PDB	1i1n
Related UniProtKB	P22061
[7]
Resource
Comments	X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-221, SUBUNIT, ACTIVE SITE, MUTAGENESIS OF SER-60.
Medline ID
PubMed ID	14596598
Journal	Biochemistry
Year	2003
Volume	42
Pages	12844-53
Authors	Bennett EJ, Bjerregaard J, Knapp JE, Chavous DA, Friedman AM, Royer WE Jr, O'Connor CM
Title	Catalytic implications from the Drosophila protein L-isoaspartyl methyltransferase structure and site-directed mutagenesis.
Related PDB	1r18
Related UniProtKB	Q27869

Comments
This enzyme catalyzes the repair of proteins, which are age-damaged by isomerized and racemized aspartyl residue leading to the isoaspartyl formation (L-isoAsp), by methylation of the alpha-carboxylate of isoAsp in the damaged peptide. The methyl ester product is unstable and rapidly converted to succinimide, which can form either the normal L-Asp residue or the L-isoAsp residue spontaneously. This enzyme has a homologous enzyme counterpart with two domains (see S00823 in EzCatDB). According to the literature [2] and [7], the reaction of this enzyme occurs as follows: (1) Ser75 (PDB;1jg3) modulates the nucleophilicity of the alpha-carboxylate of the substrate, by orienting the oxygen atom of the acceptor carboxylate group, and by creating aprotic environment that is favorable for an SN2 reaction. (2) The acceptor carboxylate group makes a nucleophilic attack on the methyl group on AdoMet. This is an SN2 reaction.

Comments

This enzyme catalyzes the repair of proteins, which are age-damaged by isomerized and racemized aspartyl residue leading to the isoaspartyl formation (L-isoAsp), by methylation of the alpha-carboxylate of isoAsp in the damaged peptide. The methyl ester product is unstable and rapidly converted to succinimide, which can form either the normal L-Asp residue or the L-isoAsp residue spontaneously.
This enzyme has a homologous enzyme counterpart with two domains (see S00823 in EzCatDB).
According to the literature [2] and [7], the reaction of this enzyme occurs as follows:
(1) Ser75 (PDB;1jg3) modulates the nucleophilicity of the alpha-carboxylate of the substrate, by orienting the oxygen atom of the acceptor carboxylate group, and by creating aprotic environment that is favorable for an SN2 reaction.
(2) The acceptor carboxylate group makes a nucleophilic attack on the methyl group on AdoMet. This is an SN2 reaction.

Created	Updated
2009-10-28	2010-08-19