IMDH_TRIFO
ID IMDH_TRIFO Reviewed; 503 AA.
AC P50097;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Inosine-5'-monophosphate dehydrogenase {ECO:0000255|HAMAP-Rule:MF_03156};
DE Short=IMP dehydrogenase {ECO:0000255|HAMAP-Rule:MF_03156};
DE Short=IMPD {ECO:0000255|HAMAP-Rule:MF_03156};
DE Short=IMPDH {ECO:0000255|HAMAP-Rule:MF_03156};
DE EC=1.1.1.205 {ECO:0000255|HAMAP-Rule:MF_03156};
GN Name=IMPDH {ECO:0000255|HAMAP-Rule:MF_03156};
OS Tritrichomonas foetus (Trichomonas foetus) (Tritrichomonas suis).
OC Eukaryota; Metamonada; Parabasalia; Tritrichomonadida; Tritrichomonadidae;
OC Tritrichomonas.
OX NCBI_TaxID=56690;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=UNK;
RX PubMed=7905423; DOI=10.1006/expr.1994.1010;
RA Beck J.T., Zhao S., Wang C.C.;
RT "Cloning, sequencing, and structural analysis of the DNA encoding inosine
RT monophosphate dehydrogenase (EC 1.1.1.205) from Tritrichomonas foetus.";
RL Exp. Parasitol. 78:101-112(1994).
RN [2]
RP SEQUENCE REVISION.
RA Wang C.C.;
RL Submitted (FEB-1996) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP ACTIVITY REGULATION.
RX PubMed=1967525; DOI=10.1016/0006-2952(90)90659-9;
RA Hedstrom L., Cheung K.S., Wang C.C.;
RT "A novel mechanism of mycophenolic acid resistance in the protozoan
RT parasite Tritrichomonas foetus.";
RL Biochem. Pharmacol. 39:151-160(1990).
RN [4]
RP CHARACTERIZATION.
RX PubMed=7577983; DOI=10.1021/bi00042a021;
RA Huete-Perez J.A., Wu J.C., Whitby F.G., Wang C.C.;
RT "Identification of the IMP binding site in the IMP dehydrogenase from
RT Tritrichomonas foetus.";
RL Biochemistry 34:13889-13894(1995).
RN [5]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND MUTAGENESIS OF CYS-319.
RX PubMed=10029522; DOI=10.1021/bi982305k;
RA Digits J.A., Hedstrom L.;
RT "Kinetic mechanism of Tritrichomonas foetus inosine 5'-monophosphate
RT dehydrogenase.";
RL Biochemistry 38:2295-2306(1999).
RN [6]
RP NUCLEIC ACID-BINDING.
RX PubMed=14766016; DOI=10.1042/bj20031585;
RA McLean J.E., Hamaguchi N., Belenky P., Mortimer S.E., Stanton M.,
RA Hedstrom L.;
RT "Inosine 5'-monophosphate dehydrogenase binds nucleic acids in vitro and in
RT vivo.";
RL Biochem. J. 379:243-251(2004).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS).
RX PubMed=9271497; DOI=10.1021/bi9708850;
RA Whitby F.G., Luecke H., Kuhn P., Somoza J.R., Huete-Perez J.A.,
RA Phillips J.D., Hill C.P., Fletterick R.J., Wang C.C.;
RT "Crystal structure of Tritrichomonas foetus inosine-5'-monophosphate
RT dehydrogenase and the enzyme-product complex.";
RL Biochemistry 36:10666-10674(1997).
RN [8]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 4-377 IN COMPLEX WITH SUBSTRATE
RP AND INHIBITOR, AND POTASSIUM-BINDING.
RX PubMed=12403633; DOI=10.1021/bi0203785;
RA Gan L., Petsko G.A., Hedstrom L.;
RT "Crystal structure of a ternary complex of Tritrichomonas foetus inosine
RT 5'-monophosphate dehydrogenase: NAD+ orients the active site loop for
RT catalysis.";
RL Biochemistry 41:13309-13317(2002).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) IN COMPLEX WITH INHIBITOR, AND
RP ACTIVE SITE.
RX PubMed=12235158; DOI=10.1074/jbc.m208330200;
RA Prosise G.L., Wu J.Z., Luecke H.;
RT "Crystal structure of Tritrichomonas foetus inosine monophosphate
RT dehydrogenase in complex with the inhibitor ribavirin monophosphate reveals
RT a catalysis-dependent ion-binding site.";
RL J. Biol. Chem. 277:50654-50659(2002).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 4-377 IN COMPLEX WITH INHIBITOR
RP (MIZORIBINE MONOPHOSPHATE; MZP) AND POTASSIUM, AND ACTIVE SITE.
RX PubMed=12549902; DOI=10.1021/bi0271401;
RA Gan L., Seyedsayamdost M.R., Shuto S., Matsuda A., Petsko G.A.,
RA Hedstrom L.;
RT "The immunosuppressive agent mizoribine monophosphate forms a transition
RT state analogue complex with inosine monophosphate dehydrogenase.";
RL Biochemistry 42:857-863(2003).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-483 IN COMPLEX WITH SUBSTRATE;
RP PRODUCT; INHIBITOR (MYCOPHENOLIC ACID; MPA) AND NAD(+).
RX PubMed=12559919; DOI=10.1016/s0022-2836(02)01383-9;
RA Prosise G.L., Luecke H.;
RT "Crystal structures of Tritrichomonas foetus inosine monophosphate
RT dehydrogenase in complex with substrate, cofactor and analogs: a structural
RT basis for the random-in ordered-out kinetic mechanism.";
RL J. Mol. Biol. 326:517-527(2003).
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. {ECO:0000255|HAMAP-Rule:MF_03156,
CC ECO:0000269|PubMed:10029522}.
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:0000255|HAMAP-Rule:MF_03156};
CC -!- COFACTOR:
CC Name=K(+); Xref=ChEBI:CHEBI:29103;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03156};
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 ECO:0000269|PubMed:1967525}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.7 uM for Inosine 5'-phosphate {ECO:0000269|PubMed:10029522};
CC KM=150 uM for NAD(+) {ECO:0000269|PubMed:10029522};
CC -!- PATHWAY: Purine metabolism; XMP biosynthesis via de novo pathway; XMP
CC from IMP: step 1/1. {ECO:0000255|HAMAP-Rule:MF_03156}.
CC -!- SUBUNIT: Homotetramer. {ECO:0000255|HAMAP-Rule:MF_03156,
CC ECO:0000269|PubMed:12235158, ECO:0000269|PubMed:12403633,
CC ECO:0000269|PubMed:12549902, ECO:0000269|PubMed:12559919}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03156}.
CC -!- MISCELLANEOUS: Contains 2 potassium ions bound at each subunit
CC interface. The second potassium binding site is not conserved and not
CC observed in crystal structures of IMPDHs from other organisms
CC (PubMed:12403633). {ECO:0000305|PubMed:12403633}.
CC -!- SIMILARITY: Belongs to the IMPDH/GMPR family. {ECO:0000255|HAMAP-
CC Rule:MF_03156}.
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DR EMBL; L18917; AAB01581.1; -; Genomic_DNA.
DR PIR; A58910; A58910.
DR PDB; 1AK5; X-ray; 2.30 A; A=1-503.
DR PDB; 1LRT; X-ray; 2.20 A; A/B/C/D=2-503.
DR PDB; 1ME7; X-ray; 2.15 A; A=1-503.
DR PDB; 1ME8; X-ray; 1.90 A; A=1-503.
DR PDB; 1ME9; X-ray; 2.20 A; A=1-503.
DR PDB; 1MEH; X-ray; 1.95 A; A=1-503.
DR PDB; 1MEI; X-ray; 2.20 A; A=1-503.
DR PDB; 1MEW; X-ray; 2.15 A; A=1-503.
DR PDB; 1PVN; X-ray; 2.00 A; A/B/C/D=2-503.
DR PDBsum; 1AK5; -.
DR PDBsum; 1LRT; -.
DR PDBsum; 1ME7; -.
DR PDBsum; 1ME8; -.
DR PDBsum; 1ME9; -.
DR PDBsum; 1MEH; -.
DR PDBsum; 1MEI; -.
DR PDBsum; 1MEW; -.
DR PDBsum; 1PVN; -.
DR AlphaFoldDB; P50097; -.
DR SMR; P50097; -.
DR PRIDE; P50097; -.
DR VEuPathDB; TrichDB:TRFO_05937; -.
DR SABIO-RK; P50097; -.
DR UniPathway; UPA00601; UER00295.
DR EvolutionaryTrace; P50097; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0032991; C:protein-containing complex; IDA:CAFA.
DR GO; GO:0042802; F:identical protein binding; IDA:CAFA.
DR GO; GO:0003938; F:IMP dehydrogenase activity; IEA:UniProtKB-UniRule.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-UniRule.
DR GO; GO:0000166; F:nucleotide binding; IDA:UniProtKB.
DR GO; GO:0006177; P:GMP biosynthetic process; IEA:UniProtKB-UniRule.
DR CDD; cd00381; IMPDH; 1.
DR DisProt; DP00399; -.
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; IPR046342; CBS_dom_sf.
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; 1.
DR Pfam; PF00478; IMPDH; 1.
DR PIRSF; PIRSF000130; IMPDH; 1.
DR SUPFAM; SSF54631; SSF54631; 1.
DR PROSITE; PS51371; CBS; 2.
DR PROSITE; PS00487; IMP_DH_GMP_RED; 1.
PE 1: Evidence at protein level;
KW 3D-structure; CBS domain; Cytoplasm; GMP biosynthesis; Metal-binding; NAD;
KW Oxidoreductase; Potassium; Purine biosynthesis; Repeat.
FT CHAIN 1..503
FT /note="Inosine-5'-monophosphate dehydrogenase"
FT /id="PRO_0000093676"
FT DOMAIN 103..163
FT /note="CBS 1"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT DOMAIN 167..228
FT /note="CBS 2"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT ACT_SITE 319
FT /note="Thioimidate intermediate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156,
FT ECO:0000269|PubMed:12235158, ECO:0000269|PubMed:12549902"
FT ACT_SITE 418
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03156"
FT BINDING 20
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="2"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 22
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="2"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 261..263
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT BINDING 264
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="2"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 266
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="2"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 312..314
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT BINDING 314
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="1"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 316
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="1"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 317
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 319
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="1"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 358..360
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 381..382
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 405..409
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 431
FT /ligand="IMP"
FT /ligand_id="ChEBI:CHEBI:58053"
FT BINDING 460
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="2"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /note="in other chain"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 485
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="1"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 486
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="1"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /evidence="ECO:0000269|PubMed:12549902"
FT BINDING 487
FT /ligand="K(+)"
FT /ligand_id="ChEBI:CHEBI:29103"
FT /ligand_label="1"
FT /ligand_note="ligand shared between two tetrameric
FT partners"
FT /evidence="ECO:0000269|PubMed:12549902"
FT MUTAGEN 319
FT /note="C->S: Has less than 0.06% of the wild-type
FT activity."
FT /evidence="ECO:0000269|PubMed:10029522"
FT HELIX 12..14
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 15..17
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 28..30
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 49..56
FT /evidence="ECO:0007829|PDB:1ME8"
FT TURN 60..62
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 65..73
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 77..80
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 82..84
FT /evidence="ECO:0007829|PDB:1ME7"
FT HELIX 86..97
FT /evidence="ECO:0007829|PDB:1ME8"
FT TURN 98..100
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 235..238
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 240..242
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 243..253
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 256..260
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 268..281
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 282..284
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 287..292
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 295..304
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 307..311
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 317..321
FT /evidence="ECO:0007829|PDB:1MEH"
FT TURN 322..325
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 331..349
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 350..352
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 355..359
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 364..372
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 376..381
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 382..385
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 390..392
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 394..397
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 400..406
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 411..414
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 416..419
FT /evidence="ECO:0007829|PDB:1PVN"
FT STRAND 421..423
FT /evidence="ECO:0007829|PDB:1PVN"
FT STRAND 434..438
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 443..460
FT /evidence="ECO:0007829|PDB:1ME8"
FT HELIX 466..472
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 475..477
FT /evidence="ECO:0007829|PDB:1ME8"
FT TURN 480..482
FT /evidence="ECO:0007829|PDB:1MEH"
FT TURN 484..486
FT /evidence="ECO:0007829|PDB:1ME8"
FT STRAND 490..493
FT /evidence="ECO:0007829|PDB:1PVN"
SQ SEQUENCE 503 AA; 55473 MW; E204EADE7ECC4134 CRC64;
MAKYYNEPCH TFNEYLLIPG LSTVDCIPSN VNLSTPLVKF QKGQQSEINL KIPLVSAIMQ
SVSGEKMAIA LAREGGISFI FGSQSIESQA AMVHAVKNFK AGFVVSDSNV KPDQTFADVL
AISQRTTHNT VAVTDDGTPH GVLLGLVTQR DYPIDLTQTE TKVSDMMTPF SKLVTAHQDT
KLSEANKIIW EKKLNALPII DDDQHLRYIV FRKDYDRSQV CHNELVDSQK RYLVGAGINT
RDFRERVPAL VEAGADVLCI DSSDGFSEWQ KITIGWIREK YGDKVKVGAG NIVDGEGFRY
LADAGADFIK IGIGGGSICI TREQKGIGRG QATAVIDVVA ERNKYFEETG IYIPVCSDGG
IVYDYHMTLA LAMGADFIML GRYFARFEES PTRKVTINGS VMKEYWGEGS SRARNWQRYD
LGGKQKLSFE EGVDSYVPYA GKLKDNVEAS LNKVKSTMCN CGALTIPQLQ SKAKITLVSS
VSIVEGGAHD VIVKDRINDY HPK
