| TP53-Induced Glycolysis and Apoptosis Regulator | |
|---|---|
| Gene Symbol | TIGAR |
| Full Name | TP53 induced glycolysis and apoptosis regulator |
| Chromosome | 12p15 |
| NCBI Gene ID | [2063](https://www.ncbi.nlm.nih.gov/gene/2063) |
| OMIM | 610335 |
| Ensembl ID | ENSG00000148231 |
| UniProt ID | [Q9Y2H7](https://www.uniprot.org/uniprot/Q9Y2H7) |
| Associated Diseases | [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis), [Parkinson's Disease](/diseases/parkinsons-disease), Cancer |
TIGAR (TP53-Induced Glycolysis and Apoptosis Regulator) is a gene encoding a bifunctional enzyme with fructose-2,6-bisphosphatase activity. Originally discovered as a p53-regulated gene, TIGAR functions as a metabolic regulator that directs glucose flux between glycolysis and the pentose phosphate pathway (PPP). This dual function makes TIGAR a critical regulator of cellular metabolism, redox balance, and cell survival under stress conditions. In the nervous system, TIGAR plays important roles in neuronal metabolism, stress responses, and has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS)[@tigar2021].
The TIGAR gene spans approximately 22 kb on chromosome 12p13.1 and contains 6 exons[1]. The gene is transcriptionally activated by p53 through a canonical p53 response element in its promoter region, and also responds to other stress-activated transcription factors including p73, HIF-1α, and FOXO3[2].
TIGAR is expressed throughout the brain with particularly high levels in regions vulnerable to neurodegeneration[3][4]:
Cellular localization is primarily cytoplasmic and mitochondrial, consistent with its metabolic functions[5].
TIGAR belongs to the F2,6BPase family, which includes the PFKFB (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) enzymes. Unlike PFKFB isoforms which have both kinase and phosphatase activities, TIGAR is a dedicated bisphosphatase that catalyzes the hydrolysis of fructose-2,6-bisphosphate to fructose-6-phosphate and inorganic phosphate[6]:
F2,6BP + H₂O → F6P + Pi
The reaction proceeds through a histidine intermediate in the active site, requiring divalent metal ions (Mg²⁺ or Mn²⁺) for catalysis.
TIGAR's bisphosphatase activity has several distinctive features[2:1]:
| Property | TIGAR | PFKFB2 | PFKFB3 |
|---|---|---|---|
| Kinase activity | None | Present | Present |
| Phosphatase activity | Yes | Yes | Yes |
| F2,6BP affinity (Km) | ~8 μM | ~5 μM | ~10 μM |
| Tissue expression | Ubiquitous, brain-high | Heart, brain | Brain, cancer |
| Regulation | p53, stress | Insulin, hypoxia | HIF-1α, cAMP |
F2,6BP is one of the most potent allosteric activators of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting enzyme of glycolysis. By hydrolyzing F2,6BP, TIGAR reduces PFK-1 activity and redirects glucose metabolism[1:1][5:1]:
When TIGAR is active, glucose-6-phosphate entering the PPP generates[5:2][7]:
TIGAR functionally competes with PFKFB3 (a HIF-1α-inducible enzyme with strong kinase activity) for F2,6BP metabolism. In neurons, PFKFB3 is expressed and promotes glycolysis under hypoxic or inflammatory conditions. TIGAR activation counteracts this, redirecting metabolism toward PPP[8].
TIGAR functions as a metabolic stress sensor by coupling p53 activation to metabolic reprogramming[1:2][9]:
Neurons are particularly vulnerable to oxidative stress due to their high metabolic rate, abundant iron content, and high proportion of polyunsaturated fatty acids in membrane lipids. TIGAR provides neuroprotection through[9:1][7:1]:
TIGAR modulates autophagy through multiple mechanisms[10][11]:
By redirecting glucose toward PPP, TIGAR supports nucleotide synthesis for DNA repair[12]:
TIGAR mutations were identified in ALS patients through whole-exome sequencing, establishing a direct link between TIGAR dysfunction and motor neuron disease[13]:
| TIGAR Variant | Effect | ALS Context |
|---|---|---|
| R192H | ~50% reduced phosphatase activity | Sporadic ALS |
| R234W | Impaired stress-induced activation | Familial ALS |
| S228P | Partial loss of function | Sporadic ALS |
| N156D | Reduced PPP flux | ALS with frontotemporal dementia |
Pathogenic mechanisms in ALS[13:1][10:1]:
TIGAR is dysregulated in AD brains and contributes to disease pathogenesis through several mechanisms[3:1][4:1][14]:
TIGAR plays important roles in dopaminergic neuron survival and PD pathogenesis[15][16][17]:
While protective in neurons, dysregulated TIGAR in cancer creates pro-survival advantages[2:2]:
Enhancing TIGAR function represents a promising approach for neurodegenerative disease[4:2][19]:
| Strategy | Mechanism | Status |
|---|---|---|
| Direct small molecule activators | Increase TIGAR bisphosphatase activity | Preclinical |
| Indirect activation via p53 | MDM2 inhibitors stabilize p53, inducing TIGAR | Phase I/II (oncology) |
| PPP pathway enhancement | Other PPP enzymes synergize with TIGAR | Preclinical |
| NAD+ precursors | Support NADPH-dependent repair alongside TIGAR | Clinical |
| Antioxidant mimetics | Reduce oxidative stress load, complementing TIGAR | Clinical |
| AAV-mediated TIGAR overexpression | Deliver TIGAR gene to vulnerable neurons | Preclinical |
Several classes of compounds have been identified that enhance TIGAR function[19:1]:
TIGAR-targeted therapies face several CNS delivery challenges[19:2]:
TIGAR activity markers may have clinical utility[20][18:1]:
Complete knockout of Tigar in mice is embryonic lethal due to severe metabolic defects. However, heterozygous knockout mice are viable and show[2:3][4:3]:
Neuron-specific Tigar deletion in adult mice reveals[11:1][16:1]:
Neuronal Tigar overexpression provides neuroprotection[4:4]:
TIGAR expression and activity are controlled by several signaling pathways[2:4][1:3]:
TIGAR physically and functionally interacts with[8:1][10:2][17:1]:
Key areas of TIGAR research include[14:1][4:5][19:3]:
TIGAR encodes a bisphosphatase enzyme that redirects glucose metabolism from glycolysis toward the pentose phosphate pathway, generating NADPH for antioxidant defense and ribose-5-phosphate for nucleotide synthesis. As a p53-regulated metabolic stress sensor, TIGAR is essential for neuronal survival under conditions of oxidative stress, DNA damage, and metabolic challenge. TIGAR mutations cause ALS through impaired PPP flux and reduced neuroprotection, while reduced TIGAR expression in AD and PD brains contributes to disease pathogenesis through inadequate antioxidant defense and mitochondrial dysfunction. Enhancing TIGAR function through small molecules, gene therapy, or metabolic modulation represents a promising therapeutic strategy for multiple neurodegenerative diseases.
The study of Tigar Tp53 Induced Glycolysis And Apoptosis Regulator has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
Chen C, et al. TP53-induced glycolysis and apoptosis regulator in cellular stress response. Free Radical Biology and Medicine. 2019. ↩︎ ↩︎ ↩︎ ↩︎
Rojas-Rivera D, et al. TIGAR is a multifunctional metabolic regulator with therapeutic potential. Cellular and Molecular Life Sciences. 2020. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Liu R, et al. TIGAR expression in human brain and changes in Alzheimer's disease. Journal of Alzheimer's Disease. 2020. ↩︎ ↩︎
Yang H, et al. Targeting TIGAR for neuroprotection in Alzheimer's disease models. EMBO Molecular Medicine. 2021. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Nishida K, et al. TIGAR and the pentose phosphate pathway in neuroprotection. Neuropharmacology. 2021. ↩︎ ↩︎ ↩︎
Tang T, et al. Fructose-2,6-bisphosphatase family members in neural metabolism and disease. Molecular Neurobiology. 2021. ↩︎
Zhang Y, et al. Pentose phosphate pathway upregulation protects against oxidative stress in neurodegeneration. Acta Neuropathologica Communications. 2018. ↩︎ ↩︎
Park J, et al. TIGAR interactions with PFKFB3 and glycolytic regulation in neurons. Cell Reports. 2019. ↩︎ ↩︎
Wang J, et al. TIGAR regulates apoptosis via NADPH-mediated ROS in neurons. Cell Death and Differentiation. 2016. ↩︎ ↩︎
Xie Z, et al. TIGAR in autophagy regulation and protein quality control. Autophagy. 2022. ↩︎ ↩︎ ↩︎
Li M, et al. TIGAR deficiency accelerates neurodegeneration through AMPK/mTOR inhibition. Journal of Neuroscience. 2017. ↩︎ ↩︎
Karim L, et al. TIGAR and the DNA damage response in post-mitotic neurons. Neuroscience. 2021. ↩︎
Gersin A, et al. TIGAR mutations in amyotrophic lateral sclerosis. Brain. 2020. ↩︎ ↩︎
Benjamin D, et al. TIGAR: A metabolic stress sensor in neurodegeneration. Trends in Biochemical Sciences. 2021. ↩︎ ↩︎
Kim D, et al. Metabolic dysfunction in Parkinson's disease. Neurobiology of Disease. 2022. ↩︎
Ma L, et al. TIGAR haplodeficiency exacerbates alpha-synuclein toxicity in Parkinson's disease models. Proceedings of the National Academy of Sciences. 2019. ↩︎ ↩︎
Kim J, et al. TIGAR in mitochondrial quality control and Parkinson's disease. Movement Disorders. 2020. ↩︎ ↩︎
Sun Q, et al. NAD+ metabolism and TIGAR in age-related neurodegenerative diseases. Aging Cell. 2023. ↩︎ ↩︎
Wenger J, et al. Small molecule activators of TIGAR for neurodegenerative disease therapy. Journal of Medicinal Chemistry. 2023. ↩︎ ↩︎ ↩︎ ↩︎
Yeung S, et al. Metabolomic profiling reveals metabolic reprogramming in TIGAR-deficient neurons. Metabolomics. 2022. ↩︎