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   22-FEB-2023, entry version 141.
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; Evidence={ECO:0000255|HAMAP-
CC         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   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; cd04601; CBS_pair_IMPDH; 1.
DR   CDD; cd00381; IMPDH; 1.
DR   DisProt; DP00399; -.
DR   Gene3D; 3.20.20.70; Aldolase class I; 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:SF111; INOSINE-5'-MONOPHOSPHATE DEHYDROGENASE; 1.
DR   PANTHER; PTHR11911; INOSINE-5-MONOPHOSPHATE DEHYDROGENASE RELATED; 1.
DR   Pfam; PF00571; CBS; 1.
DR   Pfam; PF00478; IMPDH; 1.
DR   PIRSF; PIRSF000130; IMPDH; 1.
DR   SMART; SM01240; IMPDH; 1.
DR   SUPFAM; SSF54631; CBS-domain pair; 1.
DR   SUPFAM; SSF51412; Inosine monophosphate dehydrogenase (IMPDH); 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
//