[8] Alternative splicing of the variable, COOH-terminal domain has been observed, leading to 6 different isoforms termed UBI2K1 to UBI2K6 in humans.

Expression of the promoter is shown to be induce by phorbol esters and cyclic-AMP-dependent protein kinase signaling.

[10] The four PFKFB isoforms share high (85%) ‘2-Kase/2-Pase core’ sequence homology, but have different properties based on variable N- and C- terminal regulatory domains and variation in residues surrounding the active sites.

[14] However, overexcitation of N-methyl-D-aspartate subtype of glutamate receptors (NMDAR), known as excitotoxicity, stabilizes PFKFB3 protein in neurons, resulting in a redirection of glucose flux from PPP to glycolysis, followed by low NADPH(H+) availability for proper GSH regeneration; this ultimately leads to oxidative stress and neuronal death.

Silencing of PFKFB3 with small interfering RNA in neurons in vitro prevents the increase in ROS and apoptotic death induced by excitotoxic stimulus.

[15] Pharmacological inhibition of PFKFB3 in vitro also protects neurons from apoptosis induced by NMDAR overexcitation as well as from amyloid-ß peptide-induced neurotoxicity.

When used in vivo in a mouse model of ischaemic stroke, PFKFB3 inhibitor alleviates motor discoordination and brain infarct injury [16] The Warburg effect, proposed by Otto Warbug in 1956,[17] describes the upregulation of glycolysis in most cancer cells, even in the presence of oxygen.

The high rate of glycolysis is accompanied by increased lactic acid fermentation, providing additional nutrients for cancer cell growth and tumorigenesis.

[21] Hypoxia signaling via HIF-1α stabilization upregulates the transcription of genes that permit survival in low oxygen conditions.

These genes include glycolysis enzymes, like PFKFB3, that permit ATP synthesis without oxygen, and vascular endothelial growth factor (VEGF), which promotes angiogenesis.

[29] It appears, however, that further development has been discontinued following disappointing Phase I results (see also the discussion of ACT compounds in § Small molecule inhibitors of PFKFB3).

The efficacy of two known PFKFB3 inhibitors, namely AZ67 (from AstraZeneca and CRT Discovery Laboratories [26]), and PFK158, an improved but structurally close derivative of 3PO, were recently investigated for their ability to reduce F2,6BP production in A549 cells.

[36] It was found that RA T cell fail to upregulate autophagy, and knockout experiments placed PFKFB3 as an upstream regulator of this process.

Suppression of PFKFB3 was found to decrease insulin-stimulated glucose uptake, GLUT4 translocation, and Akt signaling in 3T3-L1 adipocytes.