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O94925 (GLSK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Glutaminase kidney isoform, mitochondrial

Short name=GLS
EC=3.5.1.2
Alternative name(s):
K-glutaminase
L-glutamine amidohydrolase
Gene names
Name:GLS
Synonyms:GLS1, KIAA0838
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length669 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate in the brain. Isoform 2 lacks catalytic activity. HAMAP-Rule MF_00313

Catalytic activity

L-glutamine + H2O = L-glutamate + NH3. Ref.14

Enzyme regulation

Isoform 1 and isoform 3 are activated by phosphate. Inhibited by BPTES. BPTES binds between subunits and favors dissociation of the tetramer into dimers. Ref.14

Subunit structure

Heterotetramer. Interacts with ATCAY; the interaction is direct and may control GLS localization, negatively regulating its activity. Ref.8 Ref.14

Subcellular location

Isoform 1: Cytoplasmcytosol Ref.8 Ref.13.

Isoform 3: Mitochondrion Ref.8 Ref.13.

Tissue specificity

Isoform 1 and isoform 3 are detected in brain cortex. Isoform 3 is highly expressed in astrocytoma, ganglioglioma and ependymoma. Isoform 1 is highly expressed in brain and kidney, but not detected in liver. Isoform 3 is highly expressed in heart and pancreas, detected at lower levels in placenta, lung, pancreas and kidney, but is not detected in liver. Isoform 2 is expressed in cardiac and skeletal muscle. Ref.1 Ref.9

Sequence similarities

Belongs to the glutaminase family.

Contains 2 ANK repeats.

Caution

Isoform 3 is predicted to be expressed at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay (Ref.7), but has been shown to be well expressed (Ref.9 and Ref.1) and the encoded protein is detected in mitochondria (Ref.13).

A report observed N-glycosylation at Asn-620 (Ref.10). However, as the protein is mitochondrial, additional evidences are required to confirm this result.

Biophysicochemical properties

Kinetic parameters:

KM=1.9 mM for glutamine (isoform 1) Ref.14

KM=1.4 mM for glutamine (isoform 3)

Sequence caution

The sequence BAA74861.2 differs from that shown. Reason: Erroneous initiation. Translation N-terminally shortened.

Ontologies

Keywords
   Cellular componentCytoplasm
Mitochondrion
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainANK repeat
Repeat
Transit peptide
   Molecular functionHydrolase
   PTMAcetylation
   Technical term3D-structure
Complete proteome
Direct protein sequencing
Reference proteome
Gene Ontology (GO)
   Biological_processcellular amino acid biosynthetic process

Traceable author statement. Source: Reactome

cellular nitrogen compound metabolic process

Traceable author statement. Source: Reactome

glutamate biosynthetic process

Inferred from direct assay Ref.8Ref.14. Source: UniProtKB

glutamate secretion

Traceable author statement. Source: Reactome

glutamine catabolic process

Inferred from direct assay Ref.14. Source: UniProtKB

neurotransmitter secretion

Traceable author statement. Source: Reactome

protein homotetramerization

Inferred from direct assay Ref.14. Source: UniProtKB

regulation of respiratory gaseous exchange by neurological system process

Inferred from electronic annotation. Source: Ensembl

small molecule metabolic process

Traceable author statement. Source: Reactome

suckling behavior

Inferred from electronic annotation. Source: Ensembl

synaptic transmission

Traceable author statement. Source: Reactome

   Cellular_componentcytosol

Inferred from electronic annotation. Source: UniProtKB-SubCell

mitochondrial matrix

Traceable author statement. Source: Reactome

mitochondrion

Inferred from direct assay Ref.8. Source: UniProtKB

   Molecular_functionglutaminase activity

Inferred from direct assay Ref.14. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: O94925-1)

Also known as: KGA;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: O94925-2)

Also known as: GAM;

The sequence of this isoform differs from the canonical sequence as follows:
     162-169: ALKSTGLR → VSFYIFLS
     170-669: Missing.
Isoform 3 (identifier: O94925-3)

Also known as: Glutaminase C; GAC;

The sequence of this isoform differs from the canonical sequence as follows:
     551-669: VKSVINLLFA...TVHKNLDGLL → HSFGPLDYES...YRMESLGEKS

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Transit peptide1 – 1616Mitochondrion By similarity
Chain17 – 669653Glutaminase kidney isoform, mitochondrial HAMAP-Rule MF_00313
PRO_0000011622

Regions

Repeat585 – 61430ANK 1 HAMAP-Rule MF_00313
Repeat619 – 64830ANK 2 HAMAP-Rule MF_00313

Sites

Binding site2861Substrate
Binding site3351Substrate
Binding site3811Substrate
Binding site3881Substrate
Binding site4141Substrate
Binding site4661Substrate
Binding site4841Substrate; via amide nitrogen

Amino acid modifications

Modified residue1301N6-succinyllysine By similarity
Modified residue1641N6-succinyllysine By similarity
Modified residue3111N6-acetyllysine Ref.11

Natural variations

Alternative sequence162 – 1698ALKSTGLR → VSFYIFLS in isoform 2.
VSP_001765
Alternative sequence170 – 669500Missing in isoform 2.
VSP_001766
Alternative sequence551 – 669119VKSVI…LDGLL → HSFGPLDYESLQQELALKET VWKKVSPESNEDISTTVVYR MESLGEKS in isoform 3.
VSP_001767
Natural variant2541A → P.
Corresponds to variant rs16833035 [ dbSNP | Ensembl ].
VAR_049188

Experimental info

Mutagenesis3181F → Y: No effect on catalytic activity. Loss of inhibition by BPTES; when associated with S-322. Ref.14
Mutagenesis3221F → S: No effect on catalytic activity. Loss of inhibition by BPTES; when associated with Y-318. Ref.14
Mutagenesis3941Y → L: No effect on catalytic activity. Loss of inhibition by BPTES. Ref.14
Sequence conflict61G → S in AAF00090. Ref.1
Sequence conflict661E → D in AAF00090. Ref.1
Sequence conflict2191F → L in AAG47842. Ref.4
Sequence conflict2681V → A in AAD47056. Ref.1

Secondary structure

................................................................... 669
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (KGA) [UniParc].

Last modified May 1, 1999. Version 1.
Checksum: 4E5E63505E84E0B7

FASTA66973,461
        10         20         30         40         50         60 
MMRLRGSGML RDLLLRSPAG VSATLRRAQP LVTLCRRPRG GGRPAAGPAA AARLHPWWGG 

        70         80         90        100        110        120 
GGWPAEPLAR GLSSSPSEIL QELGKGSTHP QPGVSPPAAP AAPGPKDGPG ETDAFGNSEG 

       130        140        150        160        170        180 
KELVASGENK IKQGLLPSLE DLLFYTIAEG QEKIPVHKFI TALKSTGLRT SDPRLKECMD 

       190        200        210        220        230        240 
MLRLTLQTTS DGVMLDKDLF KKCVQSNIVL LTQAFRRKFV IPDFMSFTSH IDELYESAKK 

       250        260        270        280        290        300 
QSGGKVADYI PQLAKFSPDL WGVSVCTVDG QRHSTGDTKV PFCLQSCVKP LKYAIAVNDL 

       310        320        330        340        350        360 
GTEYVHRYVG KEPSGLRFNK LFLNEDDKPH NPMVNAGAIV VTSLIKQGVN NAEKFDYVMQ 

       370        380        390        400        410        420 
FLNKMAGNEY VGFSNATFQS ERESGDRNFA IGYYLKEKKC FPEGTDMVGI LDFYFQLCSI 

       430        440        450        460        470        480 
EVTCESASVM AATLANGGFC PITGERVLSP EAVRNTLSLM HSCGMYDFSG QFAFHVGLPA 

       490        500        510        520        530        540 
KSGVAGGILL VVPNVMGMMC WSPPLDKMGN SVKGIHFCHD LVSLCNFHNY DNLRHFAKKL 

       550        560        570        580        590        600 
DPRREGGDQR VKSVINLLFA AYTGDVSALR RFALSAMDME QRDYDSRTAL HVAAAEGHVE 

       610        620        630        640        650        660 
VVKFLLEACK VNPFPKDRWN NTPMDEALHF GHHDVFKILQ EYQVQYTPQG DSDNGKENQT 


VHKNLDGLL 

« Hide

Isoform 2 (GAM) [UniParc].

Checksum: 869F0D4A9B2B3AEE
Show »

FASTA16917,738
Isoform 3 (Glutaminase C) (GAC) [UniParc].

Checksum: 3076ED034A79ABA5
Show »

FASTA59865,460

References

« Hide 'large scale' references
[1]"Cloning and analysis of unique human glutaminase isoforms generated by tissue-specific alternative splicing."
Elgadi K.M., Meguid R.A., Qian M., Souba W.W., Abcouwer S.F.
Physiol. Genomics 1:51-62(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 3), TISSUE SPECIFICITY, ALTERNATIVE SPLICING.
Tissue: Placenta.
[2]"Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro."
Nagase T., Ishikawa K., Suyama M., Kikuno R., Hirosawa M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 5:355-364(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Brain.
[3]"Identification and expression of human renal and hepatic glutaminase isoforms."
Chavez R.A., Wang C., Cong R., Hawkinson J.E., Forsayeth J.R.
Submitted (JAN-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Brain.
[4]"Isolation, characterization and expression of a human brain mitochondrial glutaminase cDNA."
Holcomb T., Taylor L., Trohkimoinen J., Curthoys N.P.
Brain Res. Mol. Brain Res. 76:56-63(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Brain.
[5]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
Tissue: Brain.
[6]"Adenoma and carcinoma cell lines derived from colorectal tumours express different isoforms of glutaminase."
Turner A., McGivan J.D.
Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 225-466.
Tissue: Colon carcinoma.
[7]"An unappreciated role for RNA surveillance."
Hillman R.T., Green R.E., Brenner S.E.
Genome Biol. 5:R8.1-R8.16(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
[8]"Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels."
Buschdorf J.P., Li Chew L., Zhang B., Cao Q., Liang F.Y., Liou Y.C., Zhou Y.T., Low B.C.
J. Cell Sci. 119:3337-3350(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ATCAY, SUBCELLULAR LOCATION.
[9]"Relative expression of mRNAs coding for glutaminase isoforms in CNS tissues and CNS tumors."
Szeliga M., Matyja E., Obara M., Grajkowska W., Czernicki T., Albrecht J.
Neurochem. Res. 33:808-813(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: TISSUE SPECIFICITY (ISOFORM 1 AND ISOFORM 3).
[10]"A strategy for precise and large scale identification of core fucosylated glycoproteins."
Jia W., Lu Z., Fu Y., Wang H.P., Wang L.H., Chi H., Yuan Z.F., Zheng Z.B., Song L.N., Han H.H., Liang Y.M., Wang J.L., Cai Y., Zhang Y.K., Deng Y.L., Ying W.T., He S.M., Qian X.H.
Mol. Cell. Proteomics 8:913-923(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION.
[11]"Lysine acetylation targets protein complexes and co-regulates major cellular functions."
Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.C., Olsen J.V., Mann M.
Science 325:834-840(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-311, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[12]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[13]"Mitochondrial localization and structure-based phosphate activation mechanism of glutaminase C with implications for cancer metabolism."
Cassago A., Ferreira A.P., Ferreira I.M., Fornezari C., Gomes E.R., Greene K.S., Pereira H.M., Garratt R.C., Dias S.M., Ambrosio A.L.
Proc. Natl. Acad. Sci. U.S.A. 109:1092-1097(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[14]"Full-length human glutaminase in complex with an allosteric inhibitor."
DeLaBarre B., Gross S., Fang C., Gao Y., Jha A., Jiang F., Song J.J., Wei W., Hurov J.B.
Biochemistry 50:10764-10770(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 71-550 (ISOFORM 3) IN COMPLEXES WITH GLUTAMATE AND SYNTHETIC INHIBITOR BPTES, PROTEIN SEQUENCE OF N-TERMINUS, CATALYTIC ACTIVITY, MUTAGENESIS OF PHE-318; PHE-322 AND TYR-394, BIOPHYSICOCHEMICAL PROPERTIES, ENZYME REGULATION, IDENTIFICATION BY MASS SPECTROMETRY, SUBUNIT.
[15]"Human glutaminase in complex with L-glutamate."
Structural genomics consortium (SGC)
Submitted (JUL-2011) to the PDB data bank
Cited for: X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 221-533 IN COMPLEX WITH GLUTAMATE.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF158555 mRNA. Translation: AAD47056.1.
AF097492 mRNA. Translation: AAF00088.1.
AF097493 mRNA. Translation: AAF00089.1.
AF097495 mRNA. Translation: AAF00090.1.
AB020645 mRNA. Translation: BAA74861.2. Different initiation.
AF223943 mRNA. Translation: AAF33825.1.
AF327434 mRNA. Translation: AAG47842.1.
BC038507 mRNA. Translation: AAH38507.2.
AF279697 mRNA. Translation: AAG17700.1.
RefSeqNP_001243239.1. NM_001256310.1.
NP_055720.3. NM_014905.4.
UniGeneHs.116448.
Hs.737608.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
3CZDX-ray2.40A221-533[»]
3UNWX-ray2.56A/B/C/D71-550[»]
3UO9X-ray2.30A/B/C/D71-550[»]
3VOYX-ray2.20A221-533[»]
3VOZX-ray2.40A221-533[»]
3VP0X-ray2.40A221-533[»]
3VP1X-ray2.30A221-533[»]
3VP2X-ray2.70A221-533[»]
3VP3X-ray2.70A221-533[»]
3VP4X-ray2.45A221-533[»]
ProteinModelPortalO94925.
SMRO94925. Positions 137-641.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid109006. 12 interactions.
DIPDIP-50591N.
IntActO94925. 2 interactions.
MINTMINT-4096121.
STRING9606.ENSP00000317379.

Chemistry

ChEMBLCHEMBL2146302.
DrugBankDB00142. L-Glutamic Acid.
DB00130. L-Glutamine.

PTM databases

PhosphoSiteO94925.

Proteomic databases

PaxDbO94925.
PeptideAtlasO94925.
PRIDEO94925.

Protocols and materials databases

DNASU2744.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000320717; ENSP00000317379; ENSG00000115419. [O94925-1]
ENST00000338435; ENSP00000340689; ENSG00000115419. [O94925-3]
GeneID2744.
KEGGhsa:2744.
UCSCuc002usd.2. human. [O94925-2]
uc002use.3. human. [O94925-3]
uc002usf.3. human. [O94925-1]

Organism-specific databases

CTD2744.
GeneCardsGC02P191709.
H-InvDBHIX0161645.
HGNCHGNC:4331. GLS.
HPAHPA036223.
MIM138280. gene.
neXtProtNX_O94925.
PharmGKBPA28734.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG2066.
HOGENOMHOG000216891.
HOVERGENHBG005856.
InParanoidO94925.
KOK01425.
OMACMEMLKV.
OrthoDBEOG7S4X5F.
PhylomeDBO94925.
TreeFamTF313359.

Enzyme and pathway databases

BRENDA3.5.1.2. 2681.
ReactomeREACT_111217. Metabolism.
REACT_13685. Neuronal System.

Gene expression databases

ArrayExpressO94925.
BgeeO94925.
CleanExHS_GLS.
GenevestigatorO94925.

Family and domain databases

Gene3D1.25.40.20. 1 hit.
3.40.710.10. 1 hit.
HAMAPMF_00313. Glutaminase.
InterProIPR002110. Ankyrin_rpt.
IPR020683. Ankyrin_rpt-contain_dom.
IPR012338. Beta-lactam/transpept-like.
IPR015868. Glutaminase.
[Graphical view]
PANTHERPTHR12544. PTHR12544. 1 hit.
PfamPF12796. Ank_2. 1 hit.
PF04960. Glutaminase. 1 hit.
[Graphical view]
SMARTSM00248. ANK. 2 hits.
[Graphical view]
SUPFAMSSF48403. SSF48403. 1 hit.
SSF56601. SSF56601. 1 hit.
TIGRFAMsTIGR03814. Gln_ase. 1 hit.
PROSITEPS50297. ANK_REP_REGION. 1 hit.
PS50088. ANK_REPEAT. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSGLS. human.
EvolutionaryTraceO94925.
GenomeRNAi2744.
NextBio10816.
PROO94925.
SOURCESearch...

Entry information

Entry nameGLSK_HUMAN
AccessionPrimary (citable) accession number: O94925
Secondary accession number(s): Q9UL05 expand/collapse secondary AC list , Q9UL06, Q9UL07, Q9UN40
Entry history
Integrated into UniProtKB/Swiss-Prot: January 24, 2001
Last sequence update: May 1, 1999
Last modified: April 16, 2014
This is version 142 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM