[5][6][7] TIGAR is a recently discovered enzyme that primarily functions as a regulator of glucose breakdown in human cells.

Since its discovery in 2005 by Kuang-Yu Jen and Vivian G. Cheung, TIGAR has become of particular interest to the scientific community thanks to its active role in many cancers.

Normally, TIGAR manufactured by the body is activated by the p53 tumour suppressor protein after a cell has experienced a low level of DNA damage or stress.

[8][9][10] This gene is regulated as part of the p53 tumor suppressor pathway and encodes a protein with sequence similarity to the bisphosphate domain of the glycolytic enzyme that degrades fructose-2,6-bisphosphate.

[14] The core of TIGAR is made up of an α-β-α sandwich, which consists of a six-stranded β sheet surrounded by 4 α helices.

[14] Additional α helices and a long loop are built around the core to give the full enzyme.

The bis-phosphatase-like active site of TIGAR is positively charged, and catalyses the removal of phosphate groups from other molecules.

These 3 residues are known collectively as a catalytic triad,[9] and are found in all enzymes belonging to the phosphoglyceromutase branch of the histidine phosphatase superfamily.

TIGAR acts as a direct regulator of fructose-2,6-bisphosphate levels and hexokinase 2 activity, and this can lead indirectly to many changes within the cell in a chain of biochemical events.

[19] If the cell has undergone stress, certain proteins are expressed that will prevent the specific sequence of macromolecular interactions at the checkpoint required for progression to the next phase.

[17][18][19] TIGAR activity can prevent cells progressing into S phase through a checkpoint known in humans as the restriction point.

[20] TIGAR can indirectly prevent a cell passing through the Restriction Point by keeping Rb unphosphorylated.

[12] Under low oxygen conditions known as hypoxia, a small amount of TIGAR travels to the mitochondria and increases the activity of Hexokinase 2 (HK2) by binding to it[21] During hypoxia, a protein called Hif1α is activated and causes TIGAR to re-localise from the cytoplasm to the outer mitochondrial membrane.

[22] TIGAR does not re-localise to the mitochondria and bind HK2 under normal cellular conditions,[21] or if the cell is starved of glucose.

[21] Increased expression of TIGAR protects cells from oxidative-stress induced apoptosis [24] by decreasing the levels of ROS.

[9][25] GSH becomes the reducing agent, and passes electrons on to the ROS hydrogen peroxide to form harmless water in the reaction:

Under normal or glucose starved conditions, TIGAR mediated protection from apoptosis comes from its bis-phosphatase activity alone.

[26] When IL-3 dependent cell lines are deprived of IL-3 they die[26] due to decreased uptake and metabolism of glucose.

Autophagy is employed to remove damaged organelles, or under starvation conditions to provide additional nutrients.

[13][28][29][30] TIGAR can have some effect on three characteristics of cancer; the ability to evade apoptosis, uncontrolled cell division, and altered metabolism.

MUC-1 is an oncoprotein that is overexpressed in multiple myeloma and protects these cells from ROS-induced apoptosis by maintaining TIGAR activity.

[32] However, TIGAR may also have an inhibitory effect on cancer development by preventing cellular proliferation through its role in p53 -mediated cell cycle arrest.

This change affects glycolysis and the pentose phosphate pathway, potentially restoring apoptosis and reducing tumor resistance to treatments.