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Protein

Fructose-2,6-bisphosphatase TIGAR

Gene

TIGAR

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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

Caution

Not expected to have any kinase activity.Curated

Catalytic activityi

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

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei11Tele-phosphohistidine intermediateBy similarity1
Active sitei89Proton donor/acceptorBy similarity1
Sitei198Transition state stabilizerBy similarity1

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 mitophagy 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

Keywordsi

Molecular functionHydrolase
Biological processApoptosis, Autophagy

Enzyme and pathway databases

BioCyciMetaCyc:HS01277-MONOMER
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

EuPathDBiHostDB:ENSG00000078237.6
HGNCiHGNC:1185 TIGAR
MIMi610775 gene
neXtProtiNX_Q9NQ88

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Mitochondrion, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi11H → 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 Publications1
Mutagenesisi102E → 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 Publications1
Mutagenesisi198H → 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 Publications1
Mutagenesisi258 – 261Missing : 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 Publication4

Organism-specific databases

DisGeNETi57103
OpenTargetsiENSG00000078237
PharmGKBiPA25506

Polymorphism and mutation databases

BioMutaiTIGAR
DMDMi74734311

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001799571 – 270Fructose-2,6-bisphosphatase TIGARAdd BLAST270

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei50N6-acetyllysineCombined sources1

Keywords - PTMi

Acetylation

Proteomic databases

EPDiQ9NQ88
MaxQBiQ9NQ88
PaxDbiQ9NQ88
PeptideAtlasiQ9NQ88
PRIDEiQ9NQ88
ProteomicsDBi82106

PTM databases

DEPODiQ9NQ88
iPTMnetiQ9NQ88
PhosphoSitePlusiQ9NQ88

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
ExpressionAtlasiQ9NQ88 baseline and differential
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

Binary interactionsi

WithEntry#Exp.IntActNotes
HK2P527893EBI-3920747,EBI-741469

Protein-protein interaction databases

BioGridi121369, 10 interactors
DIPiDIP-60093N
IntActiQ9NQ88, 4 interactors
STRINGi9606.ENSP00000179259

Structurei

Secondary structure

1270
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi2 – 10Combined sources9
Helixi15 – 19Combined sources5
Beta strandi24 – 27Combined sources4
Helixi33 – 45Combined sources13
Turni46 – 48Combined sources3
Beta strandi52 – 56Combined sources5
Helixi60 – 70Combined sources11
Beta strandi81 – 83Combined sources3
Helixi85 – 87Combined sources3
Helixi93 – 95Combined sources3
Helixi100 – 109Combined sources10
Turni114 – 116Combined sources3
Helixi125 – 149Combined sources25
Helixi161 – 167Combined sources7
Beta strandi192 – 197Combined sources6
Helixi199 – 211Combined sources13
Helixi223 – 227Combined sources5
Beta strandi235 – 242Combined sources8
Beta strandi244 – 247Combined sources4
Beta strandi251 – 259Combined sources9

3D structure databases

ProteinModelPortaliQ9NQ88
SMRiQ9NQ88
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, 1 hit
InterProiView protein in InterPro
IPR013078 His_Pase_superF_clade-1
IPR029033 His_PPase_superfam
IPR001345 PG/BPGM_mutase_AS
PfamiView protein in Pfam
PF00300 His_Phos_1, 1 hit
SMARTiView protein in SMART
SM00855 PGAM, 1 hit
SUPFAMiSSF53254 SSF53254, 2 hits
PROSITEiView protein in PROSITE
PS00175 PG_MUTASE, 1 hit

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

Similar proteinsi

Entry informationi

Entry nameiTIGAR_HUMAN
AccessioniPrimary (citable) accession number: Q9NQ88
Secondary accession number(s): B2R840
Entry historyiIntegrated into UniProtKB/Swiss-Prot: December 6, 2005
Last sequence update: October 1, 2000
Last modified: July 18, 2018
This is version 139 of the entry and version 1 of the sequence. See 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

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

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