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}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
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
//
