ID   GLSK_RAT                Reviewed;         674 AA.
AC   P13264; Q8R421;
DT   01-JAN-1990, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-1992, sequence version 2.
DT   24-JAN-2024, entry version 175.
DE   RecName: Full=Glutaminase kidney isoform, mitochondrial;
DE            Short=GLS;
DE            EC=3.5.1.2 {ECO:0000269|PubMed:1991024, ECO:0000269|PubMed:22228304};
DE   AltName: Full=K-glutaminase;
DE   AltName: Full=L-glutamine amidohydrolase;
DE   Contains:
DE     RecName: Full=Glutaminase kidney isoform, mitochondrial 68 kDa chain {ECO:0000303|PubMed:1918000};
DE   Contains:
DE     RecName: Full=Glutaminase kidney isoform, mitochondrial 65 kDa chain {ECO:0000303|PubMed:1918000};
DE   Flags: Precursor;
GN   Name=Gls;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), PROTEIN SEQUENCE OF 73-90, AND
RP   PROTEOLYTIC PROCESSING.
RC   STRAIN=Sprague-Dawley; TISSUE=Kidney;
RX   PubMed=1918000; DOI=10.1016/s0021-9258(18)55132-2;
RA   Shapiro R.A., Farrell L., Srinivasan M., Curthoys N.P.;
RT   "Isolation, characterization, and in vitro expression of a cDNA that
RT   encodes the kidney isoenzyme of the mitochondrial glutaminase.";
RL   J. Biol. Chem. 266:18792-18796(1991).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-133.
RC   STRAIN=Sprague-Dawley;
RX   PubMed=11267668; DOI=10.1016/s0167-4781(01)00183-x;
RA   Taylor L., Liu X., Newsome W., Shapiro R.A., Srinivasan M., Curthoys N.P.;
RT   "Isolation and characterization of the promoter region of the rat kidney-
RT   type glutaminase gene.";
RL   Biochim. Biophys. Acta 1518:132-136(2001).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 299-674 (ISOFORM 2).
RX   PubMed=12045296; DOI=10.1152/physiolgenomics.00017.2002;
RA   Porter L.D., Ibrahim H., Taylor L., Curthoys N.P.;
RT   "Complexity and species variation of the kidney-type glutaminase gene.";
RL   Physiol. Genomics 9:157-166(2002).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 349-651 (ISOFORM 1).
RC   TISSUE=Brain;
RX   PubMed=3401701; DOI=10.1016/0169-328x(88)90047-2;
RA   Banner C., Hwang J.-J., Shapiro R.A., Wenthold R.J., Nakatani Y.,
RA   Lample K.A., Thomas J.W., Huie D., Curthoys N.P.;
RT   "Isolation of a cDNA for rat brain glutaminase.";
RL   Brain Res. 427:247-254(1988).
RN   [5]
RP   CATALYTIC ACTIVITY, ACTIVITY REGULATION, PROTEOLYTIC PROCESSING, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=1991024; DOI=10.1042/bj2730265;
RA   Perera S.Y., Voith D.M., Curthoys N.P.;
RT   "Biosynthesis and processing of mitochondrial glutaminase in HTC hepatoma
RT   cells.";
RL   Biochem. J. 273:265-270(1991).
RN   [6]
RP   PROTEOLYTIC PROCESSING, AND SUBCELLULAR LOCATION.
RX   PubMed=7836378; DOI=10.1074/jbc.270.3.1185;
RA   Srinivasan M., Kalousek F., Curthoys N.P.;
RT   "In vitro characterization of the mitochondrial processing and the
RT   potential function of the 68-kDa subunit of renal glutaminase.";
RL   J. Biol. Chem. 270:1185-1190(1995).
RN   [7]
RP   IDENTIFICATION BY MASS SPECTROMETRY, AND INTERACTION WITH ATCAY.
RX   PubMed=16899818; DOI=10.1242/jcs.03061;
RA   Buschdorf J.P., Li Chew L., Zhang B., Cao Q., Liang F.Y., Liou Y.C.,
RA   Zhou Y.T., Low B.C.;
RT   "Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to
RT   neurite terminals and reduces glutamate levels.";
RL   J. Cell Sci. 119:3337-3350(2006).
RN   [8]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-657, AND IDENTIFICATION BY
RP   MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=22673903; DOI=10.1038/ncomms1871;
RA   Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA   Olsen J.V.;
RT   "Quantitative maps of protein phosphorylation sites across 14 different rat
RT   organs and tissues.";
RL   Nat. Commun. 3:876-876(2012).
RN   [9]
RP   CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX   PubMed=22228304; DOI=10.1073/pnas.1112495109;
RA   Cassago A., Ferreira A.P., Ferreira I.M., Fornezari C., Gomes E.R.,
RA   Greene K.S., Pereira H.M., Garratt R.C., Dias S.M., Ambrosio A.L.;
RT   "Mitochondrial localization and structure-based phosphate activation
RT   mechanism of glutaminase C with implications for cancer metabolism.";
RL   Proc. Natl. Acad. Sci. U.S.A. 109:1092-1097(2012).
RN   [10]
RP   SUBUNIT.
RX   PubMed=23935106; DOI=10.1074/jbc.m113.501346;
RA   Ferreira A.P., Cassago A., Goncalves Kde A., Dias M.M., Adamoski D.,
RA   Ascencao C.F., Honorato R.V., de Oliveira J.F., Ferreira I.M.,
RA   Fornezari C., Bettini J., Oliveira P.S., Paes Leme A.F., Portugal R.V.,
RA   Ambrosio A.L., Dias S.M.;
RT   "Active glutaminase C self-assembles into a supratetrameric oligomer that
RT   can be disrupted by an allosteric inhibitor.";
RL   J. Biol. Chem. 288:28009-28020(2013).
CC   -!- FUNCTION: Catalyzes the first reaction in the primary pathway for the
CC       renal catabolism of glutamine. Plays a role in maintaining acid-base
CC       homeostasis. Regulates the levels of the neurotransmitter glutamate,
CC       the main excitatory neurotransmitter in the brain.
CC       {ECO:0000250|UniProtKB:D3Z7P3}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H2O + L-glutamine = L-glutamate + NH4(+);
CC         Xref=Rhea:RHEA:15889, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938,
CC         ChEBI:CHEBI:29985, ChEBI:CHEBI:58359; EC=3.5.1.2;
CC         Evidence={ECO:0000269|PubMed:1991024, ECO:0000269|PubMed:22228304};
CC   -!- ACTIVITY REGULATION: Enzyme activity is increased by phosphate, due to
CC       increased kcat and increased substrate affinity.
CC       {ECO:0000269|PubMed:1991024, ECO:0000269|PubMed:22228304}.
CC   -!- SUBUNIT: Homotetramer, dimer of dimers. Tetramer composed of 68 and 65
CC       kDa peptides in a 1:3 ratio. Can assemble into higher oligomers (in
CC       vitro), but the physiological significance of this is not clear
CC       (PubMed:23935106). Interacts with RAF1 and MAP2K2 (By similarity).
CC       Interacts with ATCAY; the interaction is direct and may control GLS
CC       localization, negatively regulating its activity.
CC       {ECO:0000250|UniProtKB:O94925, ECO:0000269|PubMed:16899818,
CC       ECO:0000269|PubMed:23935106}.
CC   -!- SUBCELLULAR LOCATION: [Isoform 1]: Mitochondrion
CC       {ECO:0000269|PubMed:1991024}. Cytoplasm, cytosol
CC       {ECO:0000269|PubMed:1991024}. Note=The 74-kDa cytosolic precursor is
CC       translocated into the mitochondria and processed via a 72-kDa
CC       intermediate to yield the mature 68 and 65-kDa subunits.
CC       {ECO:0000269|PubMed:1991024}.
CC   -!- SUBCELLULAR LOCATION: [Glutaminase kidney isoform, mitochondrial 68 kDa
CC       chain]: Mitochondrion matrix {ECO:0000269|PubMed:1991024,
CC       ECO:0000269|PubMed:7836378}. Note=Produced by the proteolytic
CC       processing of the 74-kDa cytosolic precursor.
CC       {ECO:0000269|PubMed:1991024, ECO:0000269|PubMed:7836378}.
CC   -!- SUBCELLULAR LOCATION: [Glutaminase kidney isoform, mitochondrial 65 kDa
CC       chain]: Mitochondrion matrix {ECO:0000269|PubMed:1991024,
CC       ECO:0000269|PubMed:7836378}. Note=Produced by the proteolytic
CC       processing of the 74-kDa cytosolic precursor.
CC       {ECO:0000269|PubMed:1991024, ECO:0000269|PubMed:7836378}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1; Synonyms=KGA {ECO:0000303|PubMed:22228304};
CC         IsoId=P13264-1; Sequence=Displayed;
CC       Name=2; Synonyms=GAC;
CC         IsoId=P13264-2; Sequence=VSP_041992;
CC   -!- TISSUE SPECIFICITY: Kidney, brain, and intestine.
CC   -!- DOMAIN: The C-terminal ANK repeats prevent the assembly of the supra-
CC       tetrameric filaments. {ECO:0000250|UniProtKB:O94925}.
CC   -!- DOMAIN: A highly mobile activation loop at the dimer-dimer interface is
CC       important for enzyme activity. {ECO:0000250|UniProtKB:D3Z7P3}.
CC   -!- PTM: Synthesized as a 74-kDa cytosolic precursor which is
CC       proteolytically processed by the mitochondrial-processing peptidase
CC       (MPP) via a 72-kDa intermediate to yield the mature mitochondrial
CC       68- and 65-kDa subunits. {ECO:0000269|PubMed:1918000,
CC       ECO:0000269|PubMed:1991024, ECO:0000269|PubMed:7836378}.
CC   -!- SIMILARITY: Belongs to the glutaminase family. {ECO:0000305}.
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DR   EMBL; M65150; AAA41247.1; -; mRNA.
DR   EMBL; AF302091; AAG30873.1; -; Genomic_DNA.
DR   EMBL; AY083459; AAM00020.1; -; mRNA.
DR   EMBL; M22586; AAA41234.1; -; mRNA.
DR   PIR; A41009; A41009.
DR   RefSeq; NP_001103438.1; NM_001109968.1.
DR   RefSeq; NP_036701.2; NM_012569.2.
DR   AlphaFoldDB; P13264; -.
DR   SMR; P13264; -.
DR   BioGRID; 246565; 1.
DR   DIP; DIP-60007N; -.
DR   IntAct; P13264; 1.
DR   STRING; 10116.ENSRNOP00000071972; -.
DR   BindingDB; P13264; -.
DR   ChEMBL; CHEMBL4523186; -.
DR   GlyGen; P13264; 1 site, 1 O-linked glycan (1 site).
DR   iPTMnet; P13264; -.
DR   PhosphoSitePlus; P13264; -.
DR   SwissPalm; P13264; -.
DR   jPOST; P13264; -.
DR   PaxDb; 10116-ENSRNOP00000038205; -.
DR   GeneID; 24398; -.
DR   KEGG; rno:24398; -.
DR   UCSC; RGD:2707; rat. [P13264-1]
DR   AGR; RGD:2707; -.
DR   CTD; 2744; -.
DR   RGD; 2707; Gls.
DR   eggNOG; KOG0506; Eukaryota.
DR   InParanoid; P13264; -.
DR   OrthoDB; 537490at2759; -.
DR   PhylomeDB; P13264; -.
DR   BRENDA; 3.5.1.2; 5301.
DR   Reactome; R-RNO-210500; Glutamate Neurotransmitter Release Cycle.
DR   Reactome; R-RNO-5628897; TP53 Regulates Metabolic Genes.
DR   Reactome; R-RNO-8964539; Glutamate and glutamine metabolism.
DR   PRO; PR:P13264; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR   GO; GO:0005759; C:mitochondrial matrix; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; ISO:RGD.
DR   GO; GO:0045202; C:synapse; IEA:GOC.
DR   GO; GO:0004359; F:glutaminase activity; ISS:UniProtKB.
DR   GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR   GO; GO:0007268; P:chemical synaptic transmission; ISO:RGD.
DR   GO; GO:0006537; P:glutamate biosynthetic process; ISS:UniProtKB.
DR   GO; GO:0006543; P:glutamine catabolic process; ISS:UniProtKB.
DR   GO; GO:0090461; P:intracellular glutamate homeostasis; ISO:RGD.
DR   GO; GO:0051289; P:protein homotetramerization; ISS:UniProtKB.
DR   GO; GO:0002087; P:regulation of respiratory gaseous exchange by nervous system process; ISO:RGD.
DR   GO; GO:0001967; P:suckling behavior; ISO:RGD.
DR   Gene3D; 1.10.238.210; -; 1.
DR   Gene3D; 1.25.40.20; Ankyrin repeat-containing domain; 1.
DR   Gene3D; 3.40.710.10; DD-peptidase/beta-lactamase superfamily; 1.
DR   HAMAP; MF_00313; Glutaminase; 1.
DR   InterPro; IPR002110; Ankyrin_rpt.
DR   InterPro; IPR036770; Ankyrin_rpt-contain_sf.
DR   InterPro; IPR012338; Beta-lactam/transpept-like.
DR   InterPro; IPR015868; Glutaminase.
DR   InterPro; IPR041541; Glutaminase_EF-hand.
DR   NCBIfam; TIGR03814; Gln_ase; 1.
DR   PANTHER; PTHR12544; GLUTAMINASE; 1.
DR   PANTHER; PTHR12544:SF49; GLUTAMINASE KIDNEY ISOFORM, MITOCHONDRIAL; 1.
DR   Pfam; PF12796; Ank_2; 1.
DR   Pfam; PF17959; EF-hand_14; 1.
DR   Pfam; PF04960; Glutaminase; 1.
DR   SMART; SM00248; ANK; 2.
DR   SUPFAM; SSF48403; Ankyrin repeat; 1.
DR   SUPFAM; SSF56601; beta-lactamase/transpeptidase-like; 1.
DR   PROSITE; PS50297; ANK_REP_REGION; 1.
DR   PROSITE; PS50088; ANK_REPEAT; 1.
PE   1: Evidence at protein level;
KW   Acetylation; Alternative splicing; ANK repeat; Cytoplasm;
KW   Direct protein sequencing; Hydrolase; Mitochondrion; Phosphoprotein;
KW   Reference proteome; Repeat; Transit peptide.
FT   TRANSIT         1..54
FT                   /note="Mitochondrion"
FT                   /evidence="ECO:0000255"
FT   CHAIN           55..674
FT                   /note="Glutaminase kidney isoform, mitochondrial 68 kDa
FT                   chain"
FT                   /id="PRO_0000011623"
FT   CHAIN           73..674
FT                   /note="Glutaminase kidney isoform, mitochondrial 65 kDa
FT                   chain"
FT                   /evidence="ECO:0000305|PubMed:1918000"
FT                   /id="PRO_0000011624"
FT   REPEAT          590..619
FT                   /note="ANK 1"
FT   REPEAT          624..653
FT                   /note="ANK 2"
FT   REGION          56..123
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          320..327
FT                   /note="Highly mobile activation loop"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   REGION          652..674
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        70..102
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   BINDING         291
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   BINDING         340
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   BINDING         386
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   BINDING         393
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   BINDING         419
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   BINDING         471
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   BINDING         489
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   SITE            72..73
FT                   /note="Cleavage; MPP"
FT                   /evidence="ECO:0000269|PubMed:1918000"
FT   MOD_RES         135
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   MOD_RES         169
FT                   /note="N6-succinyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:D3Z7P3"
FT   MOD_RES         316
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:O94925"
FT   MOD_RES         657
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:22673903"
FT   VAR_SEQ         556..674
FT                   /note="VKSVINLLFAAYTGDVSALRRFALSAMDMEQRDYDSRTALHVAAAEGHVEVV
FT                   KFLLEACKVNPFPKDRWNNTPMDEALHFGHHDVFKILQEYQVQYTPQGDSDDGKENQTV
FT                   HKNLDGLL -> HSFGPLDYESLQQELALKDTVWKKVSPESSDDTSTTIVYRMESLGER
FT                   S (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:12045296"
FT                   /id="VSP_041992"
FT   CONFLICT        28
FT                   /note="T -> A (in Ref. 2; AAG30873)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        349..351
FT                   /note="LIK -> EFG (in Ref. 4; AAA41234)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   674 AA;  74024 MW;  4B2524A45D3678CA CRC64;
     MMRLRGSAML RELLLRPPAA VGGVLRRTQP LGTLCRRPRG GSRPAAGLVA AARLHPWWGG
     GGRAKGPGSG GLSSSPSEIL QELGKGGTPP QQQQQQQQQP GASPPAAPGP KDSPGETDAF
     GNSEGKEMVA AGDNKVKQGL LPSLEDLLFY TIAEGQEKIP VHKFITALKS TGLRTSDPRL
     KECMDMLRLT LQTTSDGVML DKDLFKKCVQ SNIVLLTQAF RRKFVIPDFM SFTSHIDELY
     ESAKKQSGGK VADYIPQLAK FSPDLWGVSV CTVDGQRHSI GDTKVPFCLQ SCVKPLKYAI
     AVNDLGTEYV HRYVGKEPSG LRFNKLFLNE DDKPHNPMVN AGAIVVTSLI KQGVNNAEKF
     DYVMQFLNKM AGNEYVGFSN ATFQSERESG DRNFAIGYYL KEKKCFPEGT DMVGILDFYF
     QLCSIEVTCE SASVMAATLA NGGFCPITGE RVLSPEAVRN TLSLMHSCGM YDFSGQFAFH
     VGLPAKSGVA GGILLVVPNV MGMMCWSPPL DKMGNSVKGI HFCHDLVSLC NFHNYDNLRH
     FAKKLDPRRE GGDQRVKSVI NLLFAAYTGD VSALRRFALS AMDMEQRDYD SRTALHVAAA
     EGHVEVVKFL LEACKVNPFP KDRWNNTPMD EALHFGHHDV FKILQEYQVQ YTPQGDSDDG
     KENQTVHKNL DGLL
//