IMDH2_CRIGR
ID IMDH2_CRIGR Reviewed; 514 AA.
AC P12269; G3IB73;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1989, sequence version 1.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Inosine-5'-monophosphate dehydrogenase 2 {ECO:0000255|HAMAP-Rule:MF_03156};
DE Short=IMP dehydrogenase 2 {ECO:0000255|HAMAP-Rule:MF_03156};
DE Short=IMPD 2 {ECO:0000255|HAMAP-Rule:MF_03156};
DE Short=IMPDH 2 {ECO:0000255|HAMAP-Rule:MF_03156};
DE EC=1.1.1.205 {ECO:0000250|UniProtKB:P12268};
DE AltName: Full=IMPDH-II;
GN Name=IMPDH2 {ECO:0000255|HAMAP-Rule:MF_03156};
OS Cricetulus griseus (Chinese hamster) (Cricetulus barabensis griseus).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea;
OC Cricetidae; Cricetinae; Cricetulus.
OX NCBI_TaxID=10029;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 336-370.
RX PubMed=2902093; DOI=10.1016/s0021-9258(19)37654-9;
RA Collart F.R., Huberman E.;
RT "Cloning and sequence analysis of the human and Chinese hamster inosine-5'-
RT monophosphate dehydrogenase cDNAs.";
RL J. Biol. Chem. 263:15769-15772(1988).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=21804562; DOI=10.1038/nbt.1932;
RA Xu X., Nagarajan H., Lewis N.E., Pan S., Cai Z., Liu X., Chen W., Xie M.,
RA Wang W., Hammond S., Andersen M.R., Neff N., Passarelli B., Koh W.,
RA Fan H.C., Wang J., Gui Y., Lee K.H., Betenbaugh M.J., Quake S.R.,
RA Famili I., Palsson B.O., Wang J.;
RT "The genomic sequence of the Chinese hamster ovary (CHO)-K1 cell line.";
RL Nat. Biotechnol. 29:735-741(2011).
RN [3] {ECO:0007744|PDB:1JR1}
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEX WITH SUBSTRATE AND THE
RP INHIBITOR MYCOPHENOLIC ACID (MPA), AND MUTAGENESIS OF SER-275; SER-276;
RP SER-329; CYS-331; THR-333; ASP-364; GLN-368 AND GLN-441.
RX PubMed=8681386; DOI=10.1016/s0092-8674(00)81275-1;
RA Sintchak M.D., Fleming M.A., Futer O., Raybuck S.A., Chambers S.P.,
RA Caron P.R., Murcko M.A., Wilson K.P.;
RT "Structure and mechanism of inosine monophosphate dehydrogenase in complex
RT with the immunosuppressant mycophenolic acid.";
RL Cell 85:921-930(1996).
CC -!- FUNCTION: Catalyzes the conversion of inosine 5'-phosphate (IMP) to
CC xanthosine 5'-phosphate (XMP), the first committed and rate-limiting
CC step in the de novo synthesis of guanine nucleotides, and therefore
CC plays an important role in the regulation of cell growth. Could also
CC have a single-stranded nucleic acid-binding activity and could play a
CC role in RNA and/or DNA metabolism. It may also have a role in the
CC development of malignancy and the growth progression of some tumors.
CC {ECO:0000250|UniProtKB:P12268}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + IMP + NAD(+) = H(+) + NADH + XMP; Xref=Rhea:RHEA:11708,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:57464,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:57945, ChEBI:CHEBI:58053;
CC EC=1.1.1.205; Evidence={ECO:0000250|UniProtKB:P12268};
CC -!- COFACTOR:
CC Name=K(+); Xref=ChEBI:CHEBI:29103;
CC -!- ACTIVITY REGULATION: Mycophenolic acid (MPA) is a non-competitive
CC inhibitor that prevents formation of the closed enzyme conformation by
CC binding to the same site as the amobile flap. In contrast, mizoribine
CC monophosphate (MZP) is a competitive inhibitor that induces the closed
CC conformation. MPA is a potent inhibitor of mammalian IMPDHs but a poor
CC inhibitor of the bacterial enzymes. MZP is a more potent inhibitor of
CC bacterial IMPDH. {ECO:0000255|HAMAP-Rule:MF_03156}.
CC -!- PATHWAY: Purine metabolism; XMP biosynthesis via de novo pathway; XMP
CC from IMP: step 1/1. {ECO:0000250|UniProtKB:P12268}.
CC -!- SUBUNIT: Homotetramer (PubMed:8681386). Interacts with CLOCK; in a
CC circadian manner. Interacts with ANKRD9; leading to its ubiquitination
CC and degradation by the proteasome (By similarity).
CC {ECO:0000250|UniProtKB:P12268, ECO:0000269|PubMed:8681386}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:P12268}. Nucleus
CC {ECO:0000250|UniProtKB:P12268}. Cytoplasm, cytosol
CC {ECO:0000250|UniProtKB:P12268}. Note=Can form fiber-like subcellular
CC structures termed 'cytoophidia' in response to intracellular guanine-
CC nucleotide depletion. {ECO:0000250|UniProtKB:P12268}.
CC -!- PTM: Acetylated by CLOCK in a circadian manner.
CC {ECO:0000250|UniProtKB:P12268}.
CC -!- PTM: Ubiquitinated leading to its degradation by the proteasome.
CC {ECO:0000250|UniProtKB:P12268}.
CC -!- SIMILARITY: Belongs to the IMPDH/GMPR family. {ECO:0000255|HAMAP-
CC Rule:MF_03156}.
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DR EMBL; J04209; AAA36993.1; -; mRNA.
DR EMBL; JH001800; EGW10487.1; -; Genomic_DNA.
DR RefSeq; NP_001233751.1; NM_001246822.1.
DR PDB; 1JR1; X-ray; 2.60 A; A/B=1-514.
DR PDBsum; 1JR1; -.
DR AlphaFoldDB; P12269; -.
DR SMR; P12269; -.
DR STRING; 10029.NP_001233751.1; -.
DR Ensembl; ENSCGRT00001002522; ENSCGRP00001002027; ENSCGRG00001002016.
DR GeneID; 100689398; -.
DR KEGG; cge:100689398; -.
DR CTD; 3615; -.
DR eggNOG; KOG2550; Eukaryota.
DR GeneTree; ENSGT00940000157726; -.
DR InParanoid; P12269; -.
DR OMA; HDYHMTL; -.
DR UniPathway; UPA00601; UER00295.
DR EvolutionaryTrace; P12269; -.
DR PRO; PR:P12269; -.
DR Proteomes; UP000001075; Unassembled WGS sequence.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0003938; F:IMP dehydrogenase activity; ISS:UniProtKB.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-UniRule.
DR GO; GO:0000166; F:nucleotide binding; ISS:UniProtKB.
DR GO; GO:0097294; P:'de novo' XMP biosynthetic process; IEA:Ensembl.
DR GO; GO:0071353; P:cellular response to interleukin-4; IEA:Ensembl.
DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR GO; GO:0006177; P:GMP biosynthetic process; IEA:UniProtKB-UniRule.
DR GO; GO:0006183; P:GTP biosynthetic process; ISS:UniProtKB.
DR GO; GO:0046651; P:lymphocyte proliferation; IEA:Ensembl.
DR CDD; cd00381; IMPDH; 1.
DR Gene3D; 3.20.20.70; -; 1.
DR HAMAP; MF_01964; IMPDH; 1.
DR InterPro; IPR013785; Aldolase_TIM.
DR InterPro; IPR000644; CBS_dom.
DR InterPro; IPR005990; IMP_DH.
DR InterPro; IPR015875; IMP_DH/GMP_Rdtase_CS.
DR InterPro; IPR001093; IMP_DH_GMPRt.
DR PANTHER; PTHR11911; PTHR11911; 1.
DR Pfam; PF00571; CBS; 2.
DR Pfam; PF00478; IMPDH; 1.
DR PIRSF; PIRSF000130; IMPDH; 1.
DR SMART; SM00116; CBS; 2.
DR TIGRFAMs; TIGR01302; IMP_dehydrog; 1.
DR PROSITE; PS51371; CBS; 2.
DR PROSITE; PS00487; IMP_DH_GMP_RED; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; CBS domain; Cytoplasm;
KW Direct protein sequencing; GMP biosynthesis; Isopeptide bond;
KW Metal-binding; NAD; Nucleus; Oxidoreductase; Phosphoprotein; Potassium;
KW Purine biosynthesis; Reference proteome; Repeat; Ubl conjugation.
FT CHAIN 1..514
FT /note="Inosine-5'-monophosphate dehydrogenase 2"
FT /id="PRO_0000093672"
FT DOMAIN 114..173
FT /note="CBS 1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT DOMAIN 179..237
FT /note="CBS 2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT ACT_SITE 331
FT /note="Thioimidate intermediate"
FT ACT_SITE 429
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 274..276
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 276
FT /ligand="mycophenolate"
FT /ligand_id="ChEBI:CHEBI:62932"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:8681386,
FT ECO:0007744|PDB:1JR1"
FT BINDING 324..326
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 326
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 326
FT /ligand="mycophenolate"
FT /ligand_id="ChEBI:CHEBI:62932"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:8681386,
FT ECO:0007744|PDB:1JR1"
FT BINDING 328
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 329
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 331
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 333
FT /ligand="mycophenolate"
FT /ligand_id="ChEBI:CHEBI:62932"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:8681386,
FT ECO:0007744|PDB:1JR1"
FT BINDING 364..366
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 387..388
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 411..415
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 441
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 500
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 501
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 502
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT MOD_RES 122
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P12268"
FT MOD_RES 160
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P12268"
FT MOD_RES 400
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000250|UniProtKB:P12268"
FT MOD_RES 416
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P12268"
FT MOD_RES 511
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:P12268"
FT CROSSLNK 195
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P12268"
FT CROSSLNK 208
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P12268"
FT CROSSLNK 438
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO2)"
FT /evidence="ECO:0000250|UniProtKB:P12268"
FT MUTAGEN 275
FT /note="S->A: No effect."
FT /evidence="ECO:0000269|PubMed:8681386"
FT MUTAGEN 276
FT /note="S->A: Increases Ki for MPA 7-fold."
FT /evidence="ECO:0000269|PubMed:8681386"
FT MUTAGEN 329
FT /note="S->A: Reduces activity by 87%."
FT /evidence="ECO:0000269|PubMed:8681386"
FT MUTAGEN 331
FT /note="C->A: Loss of activity."
FT /evidence="ECO:0000269|PubMed:8681386"
FT MUTAGEN 333
FT /note="T->I: Increases Ki for MPA 300-fold."
FT /evidence="ECO:0000269|PubMed:8681386"
FT MUTAGEN 364
FT /note="D->A: Loss of activity."
FT /evidence="ECO:0000269|PubMed:8681386"
FT MUTAGEN 368
FT /note="Q->A: No effect."
FT /evidence="ECO:0000269|PubMed:8681386"
FT MUTAGEN 441
FT /note="Q->A: Reduces activity by over 95% and increases Ki
FT for MPA 25-fold."
FT /evidence="ECO:0000269|PubMed:8681386"
FT HELIX 20..23
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 32..34
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 35..37
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 46..48
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 53..58
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 60..63
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 65..67
FT /evidence="ECO:0007829|PDB:1JR1"
FT TURN 71..73
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 76..85
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 88..91
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 97..108
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 113..115
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 194..200
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 210..213
FT /evidence="ECO:0007829|PDB:1JR1"
FT TURN 214..216
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 217..222
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 224..232
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 247..250
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 255..266
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 270..273
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 281..293
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 298..304
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 307..316
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 319..323
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 333..337
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 343..354
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 355..357
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 361..365
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 370..378
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 382..387
FT /evidence="ECO:0007829|PDB:1JR1"
FT TURN 388..392
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 396..398
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 401..405
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 407..412
FT /evidence="ECO:0007829|PDB:1JR1"
FT TURN 417..419
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 444..448
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 453..470
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 476..485
FT /evidence="ECO:0007829|PDB:1JR1"
FT STRAND 490..492
FT /evidence="ECO:0007829|PDB:1JR1"
FT HELIX 495..501
FT /evidence="ECO:0007829|PDB:1JR1"
SQ SEQUENCE 514 AA; 55890 MW; 5FA0138FA41E8A02 CRC64;
MADYLISGGT SYVPDDGLTA QQLFNCGDGL TYNDFLILPG YIDFTADQVD LTSALTKKIT
LKTPLVSSPM DTVTEAGMAI AMALTGGIGF IHHNCTPEFQ ANEVRKVKKY EQGFITDPVV
LSPKDRVRDV FEAKARHGFC GIPITDTGRM GSRLVGIISS RDIDFLKEEE HDRFLEEIMT
KREDLVVAPA GITLKEANEI LQRSKKGKLP IVNENDELVA IIARTDLKKN RDYPLASKDA
KKQLLCGAAI GTHEDDKYRL DLLALAGVDV VVLDSSQGNS IFQINMIKYM KEKYPNLQVI
GGNVVTAAQA KNLIDAGVDA LRVGMGCGSI CITQEVLACG RPQATAVYKV SEYARRFGVP
VIADGGIQNV GHIAKALALG ASTVMMGSLL AATTEAPGEY FFSDGIRLKK YRGMGSLDAM
DKHLSSQNRY FSEADKIKVA QGVSGAVQDK GSIHKFVPYL IAGIQHSCQD IGAKSLTQVR
AMMYSGELKF EKRTSSAQVE GGVHSLHSYE KRLF
