HGPRT_MYCTU
ID HGPRT_MYCTU Reviewed; 202 AA.
AC P9WHQ9; L0TER1; O06383; P0A5T0; P96906;
DT 16-APR-2014, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 58.
DE RecName: Full=Hypoxanthine-guanine phosphoribosyltransferase {ECO:0000303|PubMed:19362594, ECO:0000303|PubMed:28082125};
DE Short=HGPRT {ECO:0000303|PubMed:19362594};
DE Short=HGPRTase;
DE EC=2.4.2.8 {ECO:0000269|PubMed:19362594, ECO:0000269|PubMed:25915781, ECO:0000269|PubMed:28082125};
GN Name=hpt {ECO:0000303|PubMed:19362594}; Synonyms=hprT;
GN OrderedLocusNames=Rv3624c; ORFNames=MTCY15C10.28;
OS Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv).
OC Bacteria; Actinobacteria; Corynebacteriales; Mycobacteriaceae;
OC Mycobacterium; Mycobacterium tuberculosis complex.
OX NCBI_TaxID=83332;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RA Bergeson S.E., Barry R., Allen T., Hwang H., Ullman B.;
RL Submitted (FEB-1997) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=9634230; DOI=10.1038/31159;
RA Cole S.T., Brosch R., Parkhill J., Garnier T., Churcher C.M., Harris D.E.,
RA Gordon S.V., Eiglmeier K., Gas S., Barry C.E. III, Tekaia F., Badcock K.,
RA Basham D., Brown D., Chillingworth T., Connor R., Davies R.M., Devlin K.,
RA Feltwell T., Gentles S., Hamlin N., Holroyd S., Hornsby T., Jagels K.,
RA Krogh A., McLean J., Moule S., Murphy L.D., Oliver S., Osborne J.,
RA Quail M.A., Rajandream M.A., Rogers J., Rutter S., Seeger K., Skelton S.,
RA Squares S., Squares R., Sulston J.E., Taylor K., Whitehead S.,
RA Barrell B.G.;
RT "Deciphering the biology of Mycobacterium tuberculosis from the complete
RT genome sequence.";
RL Nature 393:537-544(1998).
RN [3]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 25618 / H37Rv;
RX PubMed=21969609; DOI=10.1074/mcp.m111.011627;
RA Kelkar D.S., Kumar D., Kumar P., Balakrishnan L., Muthusamy B., Yadav A.K.,
RA Shrivastava P., Marimuthu A., Anand S., Sundaram H., Kingsbury R.,
RA Harsha H.C., Nair B., Prasad T.S., Chauhan D.S., Katoch K., Katoch V.M.,
RA Kumar P., Chaerkady R., Ramachandran S., Dash D., Pandey A.;
RT "Proteogenomic analysis of Mycobacterium tuberculosis by high resolution
RT mass spectrometry.";
RL Mol. Cell. Proteomics 10:M111.011627-M111.011627(2011).
RN [4]
RP REVIEW.
RX PubMed=17346177; DOI=10.2174/138161207780162863;
RA Parker W.B., Long M.C.;
RT "Purine metabolism in Mycobacterium tuberculosis as a target for drug
RT development.";
RL Curr. Pharm. Des. 13:599-608(2007).
RN [5]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, SUBSTRATE
RP SPECIFICITY, AND PATHWAY.
RC STRAIN=H37Rv;
RX PubMed=19362594; DOI=10.1016/j.pep.2009.04.001;
RA Biazus G., Schneider C.Z., Palma M.S., Basso L.A., Santos D.S.;
RT "Hypoxanthine-guanine phosphoribosyltransferase from Mycobacterium
RT tuberculosis H37Rv: cloning, expression, and biochemical
RT characterization.";
RL Protein Expr. Purif. 66:185-190(2009).
RN [6]
RP REVIEW, AND PATHWAY.
RX PubMed=21366536; DOI=10.2174/092986711795029627;
RA Ducati R.G., Breda A., Basso L.A., Santos D.S.;
RT "Purine Salvage Pathway in Mycobacterium tuberculosis.";
RL Curr. Med. Chem. 18:1258-1275(2011).
RN [7]
RP CATALYTIC ACTIVITY, AND SUBUNIT.
RX PubMed=28082125; DOI=10.1016/j.biochi.2016.12.020;
RA Eng W.S., Keough D.T., Hockova D., Winzor D.J., Guddat L.W.;
RT "Oligomeric state of hypoxanthine-guanine phosphoribosyltransferase from
RT Mycobacterium tuberculosis.";
RL Biochimie 135:6-14(2017).
RN [8] {ECO:0007744|PDB:4RHT, ECO:0007744|PDB:4RHU, ECO:0007744|PDB:4RHX, ECO:0007744|PDB:4RHY}
RP X-RAY CRYSTALLOGRAPHY (2.03 ANGSTROMS) IN COMPLEXES WITH MAGNESIUM; GMP;
RP DIPHOSPHATE AND ACYCLIC NUCLEOSIDE PHOSPHONATE INHIBITORS, FUNCTION,
RP CATALYTIC ACTIVITY, COFACTOR, BIOPHYSICOCHEMICAL PROPERTIES, AND ACTIVITY
RP REGULATION.
RX PubMed=25915781; DOI=10.1021/acs.jmedchem.5b00611;
RA Eng W.S., Hockova D., Spacek P., Janeba Z., West N.P., Woods K.,
RA Naesens L.M., Keough D.T., Guddat L.W.;
RT "First Crystal Structures of Mycobacterium tuberculosis 6-Oxopurine
RT Phosphoribosyltransferase: Complexes with GMP and Pyrophosphate and with
RT Acyclic Nucleoside Phosphonates Whose Prodrugs Have Antituberculosis
RT Activity.";
RL J. Med. Chem. 58:4822-4838(2015).
RN [9] {ECO:0007744|PDB:5KNP, ECO:0007744|PDB:5KNQ, ECO:0007744|PDB:5KNY}
RP X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) IN COMPLEXES WITH PYRROLIDINE
RP NUCLEOSIDE BISPHOSPHONATE INHIBITORS AND DIPHOSPHATE, AND ACTIVITY
RP REGULATION.
RX PubMed=30265958; DOI=10.1016/j.ejmech.2018.09.039;
RA Eng W.S., Rejman D., Pohl R., West N.P., Woods K., Naesens L.M.J.,
RA Keough D.T., Guddat L.W.;
RT "Pyrrolidine nucleoside bisphosphonates as antituberculosis agents
RT targeting hypoxanthine-guanine phosphoribosyltransferase.";
RL Eur. J. Med. Chem. 159:10-22(2018).
CC -!- FUNCTION: Purine salvage pathway enzyme that catalyzes the transfer of
CC the ribosyl-5-phosphate group from 5-phospho-alpha-D-ribose 1-
CC diphosphate (PRPP) to the N9 position of the 6-oxopurines hypoxanthine
CC and guanine to form the corresponding ribonucleotides IMP (inosine 5'-
CC monophosphate) and GMP (guanosine 5'-monophosphate), with the release
CC of PPi (PubMed:19362594, PubMed:25915781). Thus, specifically recycles
CC hypoxanthine and guanine imported from the external medium, and
CC converts them to IMP and GMP, respectively. Cannot use xanthine as
CC substrate (PubMed:19362594). {ECO:0000269|PubMed:19362594,
CC ECO:0000269|PubMed:25915781}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=diphosphate + IMP = 5-phospho-alpha-D-ribose 1-diphosphate +
CC hypoxanthine; Xref=Rhea:RHEA:17973, ChEBI:CHEBI:17368,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:58017, ChEBI:CHEBI:58053; EC=2.4.2.8;
CC Evidence={ECO:0000269|PubMed:19362594, ECO:0000269|PubMed:25915781};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:17975;
CC Evidence={ECO:0000305|PubMed:19362594};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=diphosphate + GMP = 5-phospho-alpha-D-ribose 1-diphosphate +
CC guanine; Xref=Rhea:RHEA:25424, ChEBI:CHEBI:16235, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58017, ChEBI:CHEBI:58115; EC=2.4.2.8;
CC Evidence={ECO:0000269|PubMed:19362594, ECO:0000269|PubMed:25915781,
CC ECO:0000269|PubMed:28082125};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:25426;
CC Evidence={ECO:0000305|PubMed:19362594};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000305|PubMed:25915781};
CC -!- ACTIVITY REGULATION: Competitively inhibited by acyclic nucleoside
CC phosphonates (ANPs) with Ki values as low as 0.69 uM. Prodrugs of these
CC compounds arrest the growth of a virulent strain of M.tuberculosis with
CC MIC50 values as low as 4.5 uM and possess low cytotoxicity in mammalian
CC cells (PubMed:25915781). Inhibited by pyrrolidine nucleoside
CC bisphosphonates, which are also able to arrest the growth of virulent
CC M.tuberculosis not only in its replicating phase but also in its latent
CC phase, and to arrest the growth of M.tuberculosis in infected
CC macrophages while having low cytotoxicity in mammalian cells
CC (PubMed:30265958). {ECO:0000269|PubMed:25915781,
CC ECO:0000269|PubMed:30265958}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=25 uM for guanine (at pH 7.4 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:19362594};
CC KM=50 uM for hypoxanthine (at pH 7.4 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:19362594};
CC KM=4.4 uM for guanine (at pH 7.4 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:25915781};
CC KM=8.3 uM for hypoxanthine (at pH 7.4 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:25915781};
CC KM=360 uM for 5-phospho-alpha-D-ribose 1-diphosphate (with guanine as
CC cosubstrate, at pH 7.4 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:19362594};
CC KM=2039 uM for 5-phospho-alpha-D-ribose 1-diphosphate (with
CC hypoxanthine as cosubstrate, at pH 7.4 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:19362594};
CC KM=465 uM for 5-phospho-alpha-D-ribose 1-diphosphate (with guanine as
CC cosubstrate, at pH 7.4 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:25915781};
CC KM=1443 uM for 5-phospho-alpha-D-ribose 1-diphosphate (with
CC hypoxanthine as cosubstrate, at pH 7.4 and 25 degrees Celsius)
CC {ECO:0000269|PubMed:25915781};
CC Vmax=0.37 umol/min/mg enzyme with guanine as substrate (at pH 7.4 and
CC 25 degrees Celsius) {ECO:0000269|PubMed:19362594};
CC Vmax=0.37 umol/min/mg enzyme with hypoxanthine as substrate (at pH
CC 7.4 and 25 degrees Celsius) {ECO:0000269|PubMed:19362594};
CC Note=kcat is 0.14 sec(-1) with guanine as substrate. kcat is 0.9
CC sec(-1) with hypoxanthine as substrate (at pH 7.4 and 25 degrees
CC Celsius) (PubMed:19362594). kcat is 0.62 sec(-1) with guanine as
CC substrate. kcat is 0.55 sec(-1) with hypoxanthine as substrate (at pH
CC 7.4 and 25 degrees Celsius) (PubMed:25915781).
CC {ECO:0000269|PubMed:19362594, ECO:0000269|PubMed:25915781};
CC -!- PATHWAY: Purine metabolism; IMP biosynthesis via salvage pathway; IMP
CC from hypoxanthine: step 1/1. {ECO:0000303|PubMed:21366536,
CC ECO:0000305|PubMed:19362594}.
CC -!- PATHWAY: Purine metabolism; GMP biosynthesis via salvage pathway; GMP
CC from guanine: step 1/1. {ECO:0000303|PubMed:21366536,
CC ECO:0000305|PubMed:19362594}.
CC -!- SUBUNIT: Homodimer and homotetramer in equilibrium. The presence or
CC absence of divalent metal ions, as well as phosphate, can affect the
CC oligomerization state of the enzyme. Likely functions as a tetramer
CC (rather than a dimer) in its biological environment, which is the most
CC active form. The dimeric structure is also active though ~50% of that
CC of the tetramer. {ECO:0000269|PubMed:28082125}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000305}.
CC -!- MISCELLANEOUS: Is a target for anti-TB drug development.
CC {ECO:0000303|PubMed:17346177, ECO:0000305|PubMed:30265958}.
CC -!- SIMILARITY: Belongs to the purine/pyrimidine phosphoribosyltransferase
CC family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CCP46447.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; U88876; AAB48624.1; -; Genomic_DNA.
DR EMBL; AL123456; CCP46447.1; ALT_INIT; Genomic_DNA.
DR PIR; A70561; A70561.
DR RefSeq; NP_218141.1; NC_000962.3.
DR PDB; 4RHT; X-ray; 2.76 A; A/B/C/D=2-202.
DR PDB; 4RHU; X-ray; 2.57 A; A/B/C/D/E/F=2-202.
DR PDB; 4RHX; X-ray; 2.03 A; A/B/C/D=2-202.
DR PDB; 4RHY; X-ray; 2.32 A; A/B/C/D=2-202.
DR PDB; 5KNP; X-ray; 2.45 A; A/B/C/D=2-202.
DR PDB; 5KNQ; X-ray; 2.55 A; A/B/C/D=2-202.
DR PDB; 5KNY; X-ray; 2.91 A; A/B/C/D=2-202.
DR PDBsum; 4RHT; -.
DR PDBsum; 4RHU; -.
DR PDBsum; 4RHX; -.
DR PDBsum; 4RHY; -.
DR PDBsum; 5KNP; -.
DR PDBsum; 5KNQ; -.
DR PDBsum; 5KNY; -.
DR AlphaFoldDB; P9WHQ9; -.
DR SMR; P9WHQ9; -.
DR STRING; 83332.Rv3624c; -.
DR BindingDB; P9WHQ9; -.
DR ChEMBL; CHEMBL4295584; -.
DR PaxDb; P9WHQ9; -.
DR DNASU; 885398; -.
DR GeneID; 885398; -.
DR KEGG; mtu:Rv3624c; -.
DR PATRIC; fig|83332.12.peg.4040; -.
DR TubercuList; Rv3624c; -.
DR eggNOG; COG0634; Bacteria.
DR OMA; TMDWMAV; -.
DR BRENDA; 2.4.2.8; 3445.
DR UniPathway; UPA00591; UER00648.
DR UniPathway; UPA00909; UER00887.
DR Proteomes; UP000001584; Chromosome.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0052657; F:guanine phosphoribosyltransferase activity; IDA:MTBBASE.
DR GO; GO:0004422; F:hypoxanthine phosphoribosyltransferase activity; IDA:MTBBASE.
DR GO; GO:0000287; F:magnesium ion binding; IBA:GO_Central.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0006177; P:GMP biosynthetic process; IDA:MTBBASE.
DR GO; GO:0032263; P:GMP salvage; IBA:GO_Central.
DR GO; GO:0006178; P:guanine salvage; IBA:GO_Central.
DR GO; GO:0046100; P:hypoxanthine metabolic process; IBA:GO_Central.
DR GO; GO:0006188; P:IMP biosynthetic process; IDA:MTBBASE.
DR GO; GO:0032264; P:IMP salvage; IBA:GO_Central.
DR GO; GO:0006166; P:purine ribonucleoside salvage; IEA:UniProtKB-KW.
DR GO; GO:0043101; P:purine-containing compound salvage; IDA:MTBBASE.
DR CDD; cd06223; PRTases_typeI; 1.
DR Gene3D; 3.40.50.2020; -; 1.
DR InterPro; IPR005904; Hxn_phspho_trans.
DR InterPro; IPR000836; PRibTrfase_dom.
DR InterPro; IPR029057; PRTase-like.
DR Pfam; PF00156; Pribosyltran; 1.
DR SUPFAM; SSF53271; SSF53271; 1.
DR TIGRFAMs; TIGR01203; HGPRTase; 1.
DR PROSITE; PS00103; PUR_PYR_PR_TRANSFER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytoplasm; Glycosyltransferase; Magnesium; Metal-binding;
KW Nucleotide-binding; Purine salvage; Reference proteome; Transferase.
FT CHAIN 1..202
FT /note="Hypoxanthine-guanine phosphoribosyltransferase"
FT /id="PRO_0000139609"
FT REGION 66..67
FT /note="Diphosphate"
FT /evidence="ECO:0000269|PubMed:25915781,
FT ECO:0007744|PDB:4RHT, ECO:0007744|PDB:5KNP"
FT ACT_SITE 126
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:P0A9M2"
FT BINDING 122
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:25915781,
FT ECO:0007744|PDB:4RHT"
FT BINDING 123
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:25915781,
FT ECO:0007744|PDB:4RHT"
FT BINDING 154
FT /ligand="GMP"
FT /ligand_id="ChEBI:CHEBI:58115"
FT /evidence="ECO:0000269|PubMed:25915781,
FT ECO:0007744|PDB:4RHT"
FT BINDING 175..176
FT /ligand="GMP"
FT /ligand_id="ChEBI:CHEBI:58115"
FT /evidence="ECO:0000269|PubMed:25915781,
FT ECO:0007744|PDB:4RHT"
FT BINDING 182
FT /ligand="GMP"
FT /ligand_id="ChEBI:CHEBI:58115"
FT /evidence="ECO:0000269|PubMed:25915781,
FT ECO:0007744|PDB:4RHT"
FT BINDING 188
FT /ligand="diphosphate"
FT /ligand_id="ChEBI:CHEBI:33019"
FT /evidence="ECO:0000269|PubMed:25915781,
FT ECO:0007744|PDB:4RHT, ECO:0007744|PDB:5KNP"
FT CONFLICT 173..174
FT /note="ND -> KT (in Ref. 1; AAB48624)"
FT /evidence="ECO:0000305"
FT TURN 20..22
FT /evidence="ECO:0007829|PDB:4RHX"
FT STRAND 23..28
FT /evidence="ECO:0007829|PDB:4RHX"
FT HELIX 30..47
FT /evidence="ECO:0007829|PDB:4RHX"
FT TURN 48..50
FT /evidence="ECO:0007829|PDB:4RHX"
FT HELIX 51..55
FT /evidence="ECO:0007829|PDB:4RHX"
FT STRAND 59..64
FT /evidence="ECO:0007829|PDB:4RHX"
FT TURN 65..68
FT /evidence="ECO:0007829|PDB:4RHX"
FT HELIX 69..78
FT /evidence="ECO:0007829|PDB:4RHX"
FT STRAND 79..81
FT /evidence="ECO:0007829|PDB:5KNP"
FT STRAND 83..90
FT /evidence="ECO:0007829|PDB:4RHX"
FT HELIX 97..100
FT /evidence="ECO:0007829|PDB:5KNQ"
FT STRAND 105..107
FT /evidence="ECO:0007829|PDB:4RHX"
FT STRAND 117..128
FT /evidence="ECO:0007829|PDB:4RHX"
FT HELIX 129..139
FT /evidence="ECO:0007829|PDB:4RHX"
FT STRAND 144..153
FT /evidence="ECO:0007829|PDB:4RHX"
FT HELIX 155..159
FT /evidence="ECO:0007829|PDB:4RHX"
FT STRAND 165..170
FT /evidence="ECO:0007829|PDB:4RHX"
FT STRAND 176..178
FT /evidence="ECO:0007829|PDB:4RHX"
FT STRAND 191..196
FT /evidence="ECO:0007829|PDB:4RHX"
FT TURN 198..200
FT /evidence="ECO:0007829|PDB:4RHX"
SQ SEQUENCE 202 AA; 22251 MW; 17AD6817A2F8ED90 CRC64;
MHVTQSSSAI TPGQTAELYP GDIKSVLLTA EQIQARIAEL GEQIGNDYRE LSATTGQDLL
LITVLKGAVL FVTDLARAIP VPTQFEFMAV SSYGSSTSSS GVVRILKDLD RDIHGRDVLI
VEDVVDSGLT LSWLSRNLTS RNPRSLRVCT LLRKPDAVHA NVEIAYVGFD IPNDFVVGYG
LDYDERYRDL SYIGTLDPRV YQ
