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Protein

Fructose-2,6-bisphosphatase TIGAR

Gene

TIGAR

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate (PubMed:19015259). Acts as a negative regulator of glycolysis by lowering intracellular levels of fructose-2,6-bisphosphate in a p53/TP53-dependent manner, resulting in the pentose phosphate pathway (PPP) activation and NADPH production (PubMed:16839880, PubMed:22887998). Contributes to the generation of reduced glutathione to cause a decrease in intracellular reactive oxygen species (ROS) content, correlating with its ability to protect cells from oxidative or metabolic stress-induced cell death (PubMed:16839880, PubMed:19713938, PubMed:23726973, PubMed:22887998, PubMed:23817040). Plays a role in promoting protection against cell death during hypoxia by decreasing mitochondria ROS levels in a HK2-dependent manner through a mechanism that is independent of its fructose-bisphosphatase activity (PubMed:23185017). In response to cardiac damage stress, mediates p53-induced inhibition of myocyte mitophagy through ROS levels reduction and the subsequent inactivation of BNIP3. Reduced mitophagy results in an enhanced apoptotic myocyte cell death, and exacerbates cardiac damage (By similarity). Plays a role in adult intestinal regeneration; contributes to the growth, proliferation and survival of intestinal crypts following tissue ablation (PubMed:23726973). Plays a neuroprotective role against ischemic brain damage by enhancing PPP flux and preserving mitochondria functions (By similarity). Protects glioma cells from hypoxia- and ROS-induced cell death by inhibiting glycolysis and activating mitochondrial energy metabolism and oxygen consumption in a TKTL1-dependent and p53/TP53-independent manner (PubMed:22887998). Plays a role in cancer cell survival by promoting DNA repair through activating PPP flux in a CDK5-ATM-dependent signaling pathway during hypoxia and/or genome stress-induced DNA damage responses (PubMed:25928429). Involved in intestinal tumor progression (PubMed:23726973).By similarity8 Publications

Catalytic activityi

Beta-D-fructose 2,6-bisphosphate + H2O = D-fructose 6-phosphate + phosphate.1 Publication

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei11 – 111Tele-phosphohistidine intermediateBy similarity
Active sitei89 – 891Proton donor/acceptorBy similarity
Sitei198 – 1981Transition state stabilizerBy similarity

GO - Molecular functioni

  • bisphosphoglycerate 2-phosphatase activity Source: UniProtKB
  • fructose-2,6-bisphosphate 2-phosphatase activity Source: UniProtKB

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • autophagy Source: UniProtKB-KW
  • cellular response to cobalt ion Source: UniProtKB
  • cellular response to DNA damage stimulus Source: UniProtKB
  • cellular response to hypoxia Source: UniProtKB
  • fructose 1,6-bisphosphate metabolic process Source: UniProtKB
  • fructose 2,6-bisphosphate metabolic process Source: UniProtKB
  • intestinal epithelial cell development Source: Ensembl
  • negative regulation of glucose catabolic process to lactate via pyruvate Source: Ensembl
  • negative regulation of glycolytic process Source: Ensembl
  • negative regulation of macromitophagy Source: Ensembl
  • negative regulation of neuron death Source: Ensembl
  • negative regulation of programmed cell death Source: UniProtKB
  • negative regulation of reactive oxygen species metabolic process Source: Ensembl
  • positive regulation of cardiac muscle cell apoptotic process Source: Ensembl
  • positive regulation of DNA repair Source: UniProtKB
  • positive regulation of hexokinase activity Source: UniProtKB
  • regulation of pentose-phosphate shunt Source: UniProtKB
  • regulation of response to DNA damage checkpoint signaling Source: UniProtKB
  • response to gamma radiation Source: Ensembl
  • response to ischemia Source: UniProtKB
  • response to xenobiotic stimulus Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase

Keywords - Biological processi

Apoptosis, Autophagy

Enzyme and pathway databases

ReactomeiR-HSA-5628897. TP53 Regulates Metabolic Genes.

Names & Taxonomyi

Protein namesi
Recommended name:
Fructose-2,6-bisphosphatase TIGARCurated (EC:3.1.3.461 Publication)
Alternative name(s):
TP53-induced glycolysis and apoptosis regulator1 Publication
TP53-induced glycolysis regulatory phosphataseImported
Gene namesi
Name:TIGAR1 Publication
Synonyms:C12orf5
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:1185. TIGAR.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: GO_Central
  • intracellular Source: LIFEdb
  • mitochondrial outer membrane Source: UniProtKB
  • nucleus Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi11 – 111H → A: Abolishes the ability to lower cellular fructose-2,6-bisphosphate levels, to inhibit the glycolytic activity, to reduce levels of ROS, to increase oxygen consumption and to protect toward hypoxic cell death; when associated with A-11 and A-102. Retains the ability to interact and enhance HK2 activity, to localize to the mitochondria, to limit mitochondrial ROS level increase during hypoxia and to rescued partially crypt growth; when associated with A-102 and A-198. Loss of the ability to protect against cell death during hypoxia; when associated with A-102; A-198 and 258-N--D-261 Del. 4 Publications
Mutagenesisi102 – 1021E → A: Abolishes the ability to lower cellular fructose-2,6-bisphosphate levels, to inhibit the glycolytic activity, to reduce levels of ROS, to increase oxygen consumption and to protect toward hypoxic cell death; when associated with A-11 and A-198. Retains the ability to interact and enhance HK2 activity, to localize to the mitochondria, to limit mitochondrial ROS level increase during hypoxia and to rescued partially crypt growth; when associated with A-11 and A-198. Loss of the ability to protect against cell death during hypoxia; when associated with A-11; A-198 and 258-N--D-261 Del. 4 Publications
Mutagenesisi198 – 1981H → A: Abolishes the ability to lower cellular fructose-2,6-bisphosphate levels, to inhibit the glycolytic activity, to reduce levels of ROS, to increase oxygen consumption and to protect toward hypoxic cell death; when associated with A-11 and A-102. Retains the ability to interact and enhance HK2 activity, to localize to the mitochondria, to limit mitochondrial ROS level increase during hypoxia and to rescued partially crypt growth; when associated with A-11 and A-102. Loss of the ability to protect against cell death during hypoxia; when associated with A-11; A-102 and 258-N--D-261 Del. 4 Publications
Mutagenesisi258 – 2614Missing : Inhibits the ability to interact and enhance HK2 activity, to localize to the mitochondria, to protect against the decrease of mitochondrial membrane potential and to limit mitochondrial ROS level increase during hypoxia. Does not abolish the ability to lower cellular fructose-2,6-bisphosphate levels during hypoxia. Loss of the ability to protect against cell death during hypoxia; when associated with A-11; A-102 and A-198. 1 Publication

Organism-specific databases

PharmGKBiPA25506.

Polymorphism and mutation databases

BioMutaiTIGAR.
DMDMi74734311.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 270270Fructose-2,6-bisphosphatase TIGARPRO_0000179957Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei50 – 501N6-acetyllysineCombined sources

Keywords - PTMi

Acetylation

Proteomic databases

EPDiQ9NQ88.
MaxQBiQ9NQ88.
PaxDbiQ9NQ88.
PeptideAtlasiQ9NQ88.
PRIDEiQ9NQ88.

PTM databases

DEPODiQ9NQ88.
iPTMnetiQ9NQ88.
PhosphoSiteiQ9NQ88.

Expressioni

Tissue specificityi

Expressed in the brain (PubMed:22887998). Expressed in breast tumors (PubMed:21820150). Expressed in glioblastomas (PubMed:22887998).2 Publications

Inductioni

Up-regulated by p53/TP53 (at protein level) (PubMed:16839880). Rapidly up-regulated by p53/TP53 (PubMed:16140933, PubMed:16839880, PubMed:19713938). Up-regulated in glioma cell line in a p53/TP53-independent manner (PubMed:22887998).4 Publications

Gene expression databases

BgeeiENSG00000078237.
CleanExiHS_C12orf5.
GenevisibleiQ9NQ88. HS.

Organism-specific databases

HPAiCAB034010.
HPA040354.
HPA044111.

Interactioni

Subunit structurei

Interacts with HK2; the interaction increases hexokinase HK2 activity in a hypoxia- and HIF1A-dependent manner, resulting in the regulation of mitochondrial membrane potential, thus increasing NADPH production and decreasing intracellular ROS levels (PubMed:23185017).1 Publication

Protein-protein interaction databases

BioGridi121369. 9 interactions.
DIPiDIP-60093N.
IntActiQ9NQ88. 2 interactions.
MINTiMINT-5003605.
STRINGi9606.ENSP00000179259.

Structurei

Secondary structure

1
270
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi2 – 109Combined sources
Helixi15 – 195Combined sources
Beta strandi24 – 274Combined sources
Helixi33 – 4513Combined sources
Turni46 – 483Combined sources
Beta strandi52 – 565Combined sources
Helixi60 – 7011Combined sources
Beta strandi81 – 833Combined sources
Helixi85 – 873Combined sources
Helixi93 – 953Combined sources
Helixi100 – 10910Combined sources
Turni114 – 1163Combined sources
Helixi125 – 14925Combined sources
Helixi161 – 1677Combined sources
Beta strandi192 – 1976Combined sources
Helixi199 – 21113Combined sources
Helixi223 – 2275Combined sources
Beta strandi235 – 2428Combined sources
Beta strandi244 – 2474Combined sources
Beta strandi251 – 2599Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3DCYX-ray1.75A2-270[»]
ProteinModelPortaliQ9NQ88.
SMRiQ9NQ88. Positions 2-264.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ9NQ88.

Family & Domainsi

Sequence similaritiesi

Belongs to the phosphoglycerate mutase family.Curated

Phylogenomic databases

eggNOGiENOG410IUDB. Eukaryota.
COG0406. LUCA.
GeneTreeiENSGT00390000013224.
HOGENOMiHOG000060277.
HOVERGENiHBG108569.
InParanoidiQ9NQ88.
KOiK14634.
OMAiNFEEGRE.
OrthoDBiEOG091G0W1L.
PhylomeDBiQ9NQ88.
TreeFamiTF329053.

Family and domain databases

CDDicd07067. HP_PGM_like. 1 hit.
Gene3Di3.40.50.1240. 2 hits.
InterProiIPR013078. His_Pase_superF_clade-1.
IPR029033. His_PPase_superfam.
IPR001345. PG/BPGM_mutase_AS.
[Graphical view]
PfamiPF00300. His_Phos_1. 1 hit.
[Graphical view]
SMARTiSM00855. PGAM. 1 hit.
[Graphical view]
SUPFAMiSSF53254. SSF53254. 2 hits.
PROSITEiPS00175. PG_MUTASE. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9NQ88-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MARFALTVVR HGETRFNKEK IIQGQGVDEP LSETGFKQAA AAGIFLNNVK
60 70 80 90 100
FTHAFSSDLM RTKQTMHGIL ERSKFCKDMT VKYDSRLRER KYGVVEGKAL
110 120 130 140 150
SELRAMAKAA REECPVFTPP GGETLDQVKM RGIDFFEFLC QLILKEADQK
160 170 180 190 200
EQFSQGSPSN CLETSLAEIF PLGKNHSSKV NSDSGIPGLA ASVLVVSHGA
210 220 230 240 250
YMRSLFDYFL TDLKCSLPAT LSRSELMSVT PNTGMSLFII NFEEGREVKP
260 270
TVQCICMNLQ DHLNGLTETR
Length:270
Mass (Da):30,063
Last modified:October 1, 2000 - v1
Checksum:iB85D59659AD96E39
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ272206 mRNA. Translation: CAC01127.1.
AY425618 mRNA. Translation: AAQ98969.1.
AK313226 mRNA. Translation: BAG36037.1.
CH471116 Genomic DNA. Translation: EAW88849.1.
BC012340 mRNA. Translation: AAH12340.1.
CCDSiCCDS8525.1.
RefSeqiNP_065108.1. NM_020375.2.
UniGeneiHs.504545.

Genome annotation databases

EnsembliENST00000179259; ENSP00000179259; ENSG00000078237.
GeneIDi57103.
KEGGihsa:57103.
UCSCiuc001qmp.4. human.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AJ272206 mRNA. Translation: CAC01127.1.
AY425618 mRNA. Translation: AAQ98969.1.
AK313226 mRNA. Translation: BAG36037.1.
CH471116 Genomic DNA. Translation: EAW88849.1.
BC012340 mRNA. Translation: AAH12340.1.
CCDSiCCDS8525.1.
RefSeqiNP_065108.1. NM_020375.2.
UniGeneiHs.504545.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
3DCYX-ray1.75A2-270[»]
ProteinModelPortaliQ9NQ88.
SMRiQ9NQ88. Positions 2-264.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi121369. 9 interactions.
DIPiDIP-60093N.
IntActiQ9NQ88. 2 interactions.
MINTiMINT-5003605.
STRINGi9606.ENSP00000179259.

PTM databases

DEPODiQ9NQ88.
iPTMnetiQ9NQ88.
PhosphoSiteiQ9NQ88.

Polymorphism and mutation databases

BioMutaiTIGAR.
DMDMi74734311.

Proteomic databases

EPDiQ9NQ88.
MaxQBiQ9NQ88.
PaxDbiQ9NQ88.
PeptideAtlasiQ9NQ88.
PRIDEiQ9NQ88.

Protocols and materials databases

DNASUi57103.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000179259; ENSP00000179259; ENSG00000078237.
GeneIDi57103.
KEGGihsa:57103.
UCSCiuc001qmp.4. human.

Organism-specific databases

CTDi57103.
GeneCardsiTIGAR.
HGNCiHGNC:1185. TIGAR.
HPAiCAB034010.
HPA040354.
HPA044111.
MIMi610775. gene.
neXtProtiNX_Q9NQ88.
PharmGKBiPA25506.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IUDB. Eukaryota.
COG0406. LUCA.
GeneTreeiENSGT00390000013224.
HOGENOMiHOG000060277.
HOVERGENiHBG108569.
InParanoidiQ9NQ88.
KOiK14634.
OMAiNFEEGRE.
OrthoDBiEOG091G0W1L.
PhylomeDBiQ9NQ88.
TreeFamiTF329053.

Enzyme and pathway databases

ReactomeiR-HSA-5628897. TP53 Regulates Metabolic Genes.

Miscellaneous databases

ChiTaRSiC12orf5. human.
EvolutionaryTraceiQ9NQ88.
GeneWikiiC12orf5.
GenomeRNAii57103.
PROiQ9NQ88.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000078237.
CleanExiHS_C12orf5.
GenevisibleiQ9NQ88. HS.

Family and domain databases

CDDicd07067. HP_PGM_like. 1 hit.
Gene3Di3.40.50.1240. 2 hits.
InterProiIPR013078. His_Pase_superF_clade-1.
IPR029033. His_PPase_superfam.
IPR001345. PG/BPGM_mutase_AS.
[Graphical view]
PfamiPF00300. His_Phos_1. 1 hit.
[Graphical view]
SMARTiSM00855. PGAM. 1 hit.
[Graphical view]
SUPFAMiSSF53254. SSF53254. 2 hits.
PROSITEiPS00175. PG_MUTASE. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTIGAR_HUMAN
AccessioniPrimary (citable) accession number: Q9NQ88
Secondary accession number(s): B2R840
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 6, 2005
Last sequence update: October 1, 2000
Last modified: September 7, 2016
This is version 127 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (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.

Miscellaneousi

Caution

Not expected to have any kinase activity.Curated

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.