HINT2_HUMAN
ID HINT2_HUMAN Reviewed; 163 AA.
AC Q9BX68; Q5TCW3;
DT 31-AUG-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2001, sequence version 1.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Adenosine 5'-monophosphoramidase HINT2 {ECO:0000305|PubMed:16762638};
DE EC=3.9.1.- {ECO:0000269|PubMed:16762638, ECO:0000269|PubMed:31990367};
DE AltName: Full=HINT-3 {ECO:0000303|Ref.4};
DE AltName: Full=HIT-17kDa {ECO:0000303|Ref.1};
DE AltName: Full=Histidine triad nucleotide-binding protein 2, mitochondrial {ECO:0000305};
DE Short=HINT-2 {ECO:0000303|Ref.3};
DE AltName: Full=PKCI-1-related HIT protein {ECO:0000303|Ref.2};
DE Flags: Precursor;
GN Name=HINT2 {ECO:0000312|HGNC:HGNC:18344};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RA Magnino F., Dufour J.-F.;
RT "HIT-17kDa is a new protein from the HIT family with high homology to PKCI-
RT 1.";
RL Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Takada F., Lugus J.J., Beggs A.H.;
RT "PKCI-1-related HIT protein.";
RL Submitted (APR-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Takada F., Lugus J.J., Beggs A.H.;
RT "Hint-2 genomic sequence.";
RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Kidney;
RA Chen H., Peng J., Huang C.-H.;
RT "HINT-3 is a novel member of the histidine triad protein family.";
RL Submitted (MAR-2001) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E., Howe K.L.,
RA Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C., Ainscough R.,
RA Almeida J.P., Ambrose K.D., Ashwell R.I.S., Babbage A.K., Babbage S.,
RA Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K.,
RA Beasley H., Beasley O., Bird C.P., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C.,
RA Chen Y., Clarke G., Clark S.Y., Clee C.M., Clegg S., Collier R.E.,
RA Corby N., Crosier M., Cummings A.T., Davies J., Dhami P., Dunn M.,
RA Dutta I., Dyer L.W., Earthrowl M.E., Faulkner L., Fleming C.J.,
RA Frankish A., Frankland J.A., French L., Fricker D.G., Garner P.,
RA Garnett J., Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C., Lawlor S.,
RA Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M., Lovell J.,
RA Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S., McLay K.E.,
RA McMurray A., Milne S., Nickerson T., Nisbett J., Nordsiek G., Pearce A.V.,
RA Peck A.I., Porter K.M., Pandian R., Pelan S., Phillimore B., Povey S.,
RA Ramsey Y., Rand V., Scharfe M., Sehra H.K., Shownkeen R., Sims S.K.,
RA Skuce C.D., Smith M., Steward C.A., Swarbreck D., Sycamore N., Tester J.,
RA Thorpe A., Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M.,
RA West A.P., Whitehead S.L., Willey D.L., Williams S.A., Wilming L.,
RA Wray P.W., Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S., Rogers J.,
RA Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, ACTIVE SITE, MUTAGENESIS OF HIS-149, AND CATALYTIC ACTIVITY.
RX PubMed=16762638; DOI=10.1053/j.gastro.2006.03.024;
RA Martin J., Magnino F., Schmidt K., Piguet A.-C., Lee J.S., Semela D.,
RA St-Pierre M.V., Ziemiecki A., Cassio D., Brenner C., Thorgeirsson S.S.,
RA Dufour J.-F.;
RT "Hint2, a mitochondrial apoptotic sensitizer down-regulated in
RT hepatocellular carcinoma.";
RL Gastroenterology 130:2179-2188(2006).
RN [9]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=18653718; DOI=10.1210/en.2008-0400;
RA Lenglet S., Antigny F., Vetterli L., Dufour J.-F., Rossier M.F.;
RT "Hint2 is expressed in the mitochondria of H295R cells and is involved in
RT steroidogenesis.";
RL Endocrinology 149:5461-5469(2008).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [13]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=31990367; DOI=10.1002/1873-3468.13745;
RA Strom A., Tong C.L., Wagner C.R.;
RT "Histidine triad nucleotide-binding proteins HINT1 and HINT2 share similar
RT substrate specificities and little affinity for the signaling dinucleotide
RT Ap4A.";
RL FEBS Lett. 594:1497-1505(2020).
RN [14] {ECO:0007744|PDB:4INC, ECO:0007744|PDB:4INI}
RP X-RAY CRYSTALLOGRAPHY (1.19 ANGSTROMS) OF 37-163 IN COMPLEX WITH AMP.
RX PubMed=23659632; DOI=10.1111/febs.12330;
RA Maize K.M., Wagner C.R., Finzel B.C.;
RT "Structural characterization of human histidine triad nucleotide-binding
RT protein 2, a member of the histidine triad superfamily.";
RL FEBS J. 280:3389-3398(2013).
RN [15] {ECO:0007744|PDB:6YI0, ECO:0007744|PDB:6YPR, ECO:0007744|PDB:6YPX, ECO:0007744|PDB:6YQD}
RP X-RAY CRYSTALLOGRAPHY (1.32 ANGSTROMS).
RA Dolot R.M., Wlodarczyk A., Bujacz G.D., Nawrot B.;
RT "Human histidine triad nucleotide-binding protein 2 (hHINT2) in H32 space
RT group at 1.32 A.";
RL Submitted (NOV-2013) to the PDB data bank.
RN [16] {ECO:0007744|PDB:5KM5, ECO:0007744|PDB:5KM8, ECO:0007744|PDB:5KM9}
RP X-RAY CRYSTALLOGRAPHY (1.45 ANGSTROMS) OF 26-163.
RX PubMed=28968488; DOI=10.1021/acs.molpharmaceut.7b00664;
RA Maize K.M., Shah R., Strom A., Kumarapperuma S., Zhou A., Wagner C.R.,
RA Finzel B.C.;
RT "A Crystal Structure Based Guide to the Design of Human Histidine Triad
RT Nucleotide Binding Protein 1 (hHint1) Activated ProTides.";
RL Mol. Pharm. 14:3987-3997(2017).
CC -!- FUNCTION: Exhibits adenosine 5'-monophosphoramidase activity,
CC hydrolyzing purine nucleotide phosphoramidates with a single phosphate
CC group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP
CC and NH2 (PubMed:16762638, PubMed:31990367). Hydrolyzes adenosine 5'-O-
CC p-nitrophenylphosphoramidate (AMP-pNA) (PubMed:16762638). Hydrolyzes
CC fluorogenic purine nucleoside tryptamine phosphoramidates in vitro
CC (PubMed:31990367). May be involved in steroid biosynthesis
CC (PubMed:18653718). May play a role in apoptosis (PubMed:16762638).
CC {ECO:0000269|PubMed:16762638, ECO:0000269|PubMed:18653718,
CC ECO:0000269|PubMed:31990367}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosine 5'-phosphoramidate + H2O = AMP + NH4(+);
CC Xref=Rhea:RHEA:67916, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:57890, ChEBI:CHEBI:456215;
CC Evidence={ECO:0000269|PubMed:16762638, ECO:0000269|PubMed:31990367};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=128 uM for adenosine 5'-O-p-nitrophenylphosphoramidate
CC {ECO:0000269|PubMed:16762638};
CC pH dependence:
CC Optimum pH is 7-8. {ECO:0000269|PubMed:31990367};
CC -!- SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:16762638,
CC ECO:0000269|PubMed:18653718}.
CC -!- TISSUE SPECIFICITY: High expression in liver and pancreas. Expression
CC is significantly down-regulated in hepatocellular carcinoma (HCC)
CC patients. {ECO:0000269|PubMed:16762638}.
CC -!- SIMILARITY: Belongs to the HINT family. {ECO:0000305}.
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DR EMBL; AF356515; AAK37562.1; -; mRNA.
DR EMBL; AY033094; AAK53455.1; -; mRNA.
DR EMBL; AF490476; AAM09526.1; -; Genomic_DNA.
DR EMBL; AF356875; AAM00221.1; -; mRNA.
DR EMBL; AL133410; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471071; EAW58332.1; -; Genomic_DNA.
DR EMBL; BC047737; AAH47737.1; -; mRNA.
DR CCDS; CCDS6594.1; -.
DR RefSeq; NP_115982.1; NM_032593.2.
DR PDB; 4INC; X-ray; 1.19 A; A/B=37-163.
DR PDB; 4INI; X-ray; 1.65 A; A/B=37-163.
DR PDB; 5KM5; X-ray; 2.10 A; A/B=26-163.
DR PDB; 5KM8; X-ray; 2.00 A; A/B=26-163.
DR PDB; 5KM9; X-ray; 1.45 A; A/B=26-163.
DR PDB; 6YI0; X-ray; 1.65 A; AAA/BBB/CCC/DDD=1-163.
DR PDB; 6YPR; X-ray; 1.26 A; AAA=1-163.
DR PDB; 6YPX; X-ray; 2.11 A; AAA/BBB/CCC/DDD=1-163.
DR PDB; 6YQD; X-ray; 1.41 A; AAA/BBB=1-163.
DR PDB; 6YVP; X-ray; 2.77 A; AAA/BBB=1-163.
DR PDBsum; 4INC; -.
DR PDBsum; 4INI; -.
DR PDBsum; 5KM5; -.
DR PDBsum; 5KM8; -.
DR PDBsum; 5KM9; -.
DR PDBsum; 6YI0; -.
DR PDBsum; 6YPR; -.
DR PDBsum; 6YPX; -.
DR PDBsum; 6YQD; -.
DR PDBsum; 6YVP; -.
DR AlphaFoldDB; Q9BX68; -.
DR SMR; Q9BX68; -.
DR BioGRID; 124200; 338.
DR IntAct; Q9BX68; 9.
DR MINT; Q9BX68; -.
DR STRING; 9606.ENSP00000259667; -.
DR iPTMnet; Q9BX68; -.
DR PhosphoSitePlus; Q9BX68; -.
DR BioMuta; HINT2; -.
DR DMDM; 51701612; -.
DR OGP; Q9BX68; -.
DR EPD; Q9BX68; -.
DR jPOST; Q9BX68; -.
DR MassIVE; Q9BX68; -.
DR MaxQB; Q9BX68; -.
DR PaxDb; Q9BX68; -.
DR PeptideAtlas; Q9BX68; -.
DR PRIDE; Q9BX68; -.
DR ProteomicsDB; 79368; -.
DR TopDownProteomics; Q9BX68; -.
DR Antibodypedia; 11787; 136 antibodies from 19 providers.
DR DNASU; 84681; -.
DR Ensembl; ENST00000259667.6; ENSP00000259667.5; ENSG00000137133.11.
DR GeneID; 84681; -.
DR KEGG; hsa:84681; -.
DR MANE-Select; ENST00000259667.6; ENSP00000259667.5; NM_032593.3; NP_115982.1.
DR UCSC; uc003zyh.4; human.
DR CTD; 84681; -.
DR DisGeNET; 84681; -.
DR GeneCards; HINT2; -.
DR HGNC; HGNC:18344; HINT2.
DR HPA; ENSG00000137133; Low tissue specificity.
DR MIM; 609997; gene.
DR neXtProt; NX_Q9BX68; -.
DR OpenTargets; ENSG00000137133; -.
DR PharmGKB; PA29287; -.
DR VEuPathDB; HostDB:ENSG00000137133; -.
DR eggNOG; KOG3275; Eukaryota.
DR GeneTree; ENSGT00940000157905; -.
DR HOGENOM; CLU_056776_8_0_1; -.
DR InParanoid; Q9BX68; -.
DR OMA; SDCLFCK; -.
DR OrthoDB; 1190598at2759; -.
DR PhylomeDB; Q9BX68; -.
DR TreeFam; TF314862; -.
DR PathwayCommons; Q9BX68; -.
DR Reactome; R-HSA-9013405; RHOD GTPase cycle.
DR SABIO-RK; Q9BX68; -.
DR SignaLink; Q9BX68; -.
DR BioGRID-ORCS; 84681; 12 hits in 1082 CRISPR screens.
DR ChiTaRS; HINT2; human.
DR GenomeRNAi; 84681; -.
DR Pharos; Q9BX68; Tbio.
DR PRO; PR:Q9BX68; -.
DR Proteomes; UP000005640; Chromosome 9.
DR RNAct; Q9BX68; protein.
DR Bgee; ENSG00000137133; Expressed in apex of heart and 94 other tissues.
DR Genevisible; Q9BX68; HS.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0043530; F:adenosine 5'-monophosphoramidase activity; IDA:UniProtKB.
DR GO; GO:0016787; F:hydrolase activity; IBA:GO_Central.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0016042; P:lipid catabolic process; IEA:Ensembl.
DR GO; GO:2000757; P:negative regulation of peptidyl-lysine acetylation; IEA:Ensembl.
DR GO; GO:0006694; P:steroid biosynthetic process; IEA:UniProtKB-KW.
DR Gene3D; 3.30.428.10; -; 1.
DR InterPro; IPR019808; Histidine_triad_CS.
DR InterPro; IPR001310; Histidine_triad_HIT.
DR InterPro; IPR011146; HIT-like.
DR InterPro; IPR036265; HIT-like_sf.
DR PANTHER; PTHR23089; PTHR23089; 1.
DR Pfam; PF01230; HIT; 1.
DR PRINTS; PR00332; HISTRIAD.
DR SUPFAM; SSF54197; SSF54197; 1.
DR PROSITE; PS00892; HIT_1; 1.
DR PROSITE; PS51084; HIT_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Apoptosis; Hydrolase; Lipid biosynthesis;
KW Lipid metabolism; Mitochondrion; Nucleotide-binding; Reference proteome;
KW Steroid biosynthesis; Transit peptide.
FT TRANSIT 1..17
FT /note="Mitochondrion"
FT /evidence="ECO:0000255"
FT CHAIN 18..163
FT /note="Adenosine 5'-monophosphoramidase HINT2"
FT /id="PRO_0000109786"
FT DOMAIN 55..163
FT /note="HIT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00464"
FT MOTIF 147..151
FT /note="Histidine triad motif"
FT ACT_SITE 149
FT /note="Tele-AMP-histidine intermediate"
FT /evidence="ECO:0000269|PubMed:16762638"
FT BINDING 63
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:23659632,
FT ECO:0007744|PDB:4INI"
FT BINDING 80
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:23659632,
FT ECO:0007744|PDB:4INI"
FT BINDING 136
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:23659632,
FT ECO:0007744|PDB:4INI"
FT BINDING 142..145
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:23659632,
FT ECO:0007744|PDB:4INI"
FT BINDING 149..151
FT /ligand="AMP"
FT /ligand_id="ChEBI:CHEBI:456215"
FT /evidence="ECO:0000269|PubMed:23659632,
FT ECO:0007744|PDB:4INI"
FT MOD_RES 119
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9D0S9"
FT MOD_RES 139
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q9D0S9"
FT MUTAGEN 149
FT /note="H->A: Loss of adenosine phosphoramidase activity."
FT /evidence="ECO:0000269|PubMed:16762638"
FT HELIX 56..60
FT /evidence="ECO:0007829|PDB:4INC"
FT HELIX 65..67
FT /evidence="ECO:0007829|PDB:4INC"
FT STRAND 68..71
FT /evidence="ECO:0007829|PDB:4INC"
FT STRAND 73..79
FT /evidence="ECO:0007829|PDB:4INC"
FT STRAND 84..95
FT /evidence="ECO:0007829|PDB:4INC"
FT HELIX 100..102
FT /evidence="ECO:0007829|PDB:4INC"
FT HELIX 105..107
FT /evidence="ECO:0007829|PDB:4INC"
FT HELIX 108..124
FT /evidence="ECO:0007829|PDB:4INC"
FT STRAND 131..137
FT /evidence="ECO:0007829|PDB:4INC"
FT TURN 138..142
FT /evidence="ECO:0007829|PDB:4INC"
FT STRAND 145..147
FT /evidence="ECO:0007829|PDB:4INC"
FT STRAND 150..156
FT /evidence="ECO:0007829|PDB:4INC"
SQ SEQUENCE 163 AA; 17162 MW; 63A0C15D13749F99 CRC64;
MAAAVVLAAG LRAARRAVAA TGVRGGQVRG AAGVTDGNEV AKAQQATPGG AAPTIFSRIL
DKSLPADILY EDQQCLVFRD VAPQAPVHFL VIPKKPIPRI SQAEEEDQQL LGHLLLVAKQ
TAKAEGLGDG YRLVINDGKL GAQSVYHLHI HVLGGRQLQW PPG
