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PFKFB3
PFKFB3 is a gene that encodes the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme in humans. It is one of 4 tissue-specific PFKFB isoenzymes identified currently (PFKFB1-4).
The PFKFB3 gene is mapped to single locus on chromosome 10 (10p15-p14). It spans a region of 32.5kb with an open reading frame that is 5,675bp long. It is estimated to consist of 19 exons, of which 15 are regularly expressed. Alternative splicing of the variable, COOH-terminal domain has been observed, leading to 6 different isoforms termed UBI2K1 to UBI2K6 in humans. Different nomenclature also recognizes two broad categories of PFKFB3 isoforms, termed 'inducible' and 'ubiquitous'. The inducible protein isoform, iPFK2, is named as such because its expression has been shown to be induced by hypoxic conditions.
The PFKFB3 promoter is predicted to contain multiple binding sites, including Sp-1 and AP-2 binding sites. It also contains motifs for the binding of E-box, nuclear factor-1 (NF-1), and progesterone response element. Expression of the promoter is shown to be induce by phorbol esters and cyclic-AMP-dependent protein kinase signaling.
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. The PFKFB3 inducible isoform has higher '2-Kase' (kinase) activity than other isoforms, due to phosphorylation of Ser-460 by PKA or AMP-dependent protein kinase. The high '2-Kase' activity of PFKFB3 is also due to the lack of a specific Ser that is phosphorylated in the other PFKFB isoforms to decrease kinase activity.
The primary protein encoded by PFKFB3, iPFK2, consists of 590 amino acids. It has a predicted molecular weight of 66.9 kDa and an isoelectric point of 8.64. The crystal structure was determined in 2006:
iPFK2 converts fructose-6-phosphate to fructose-2,6-bisP (F2,6BP). F2,6BP is a 'potent' allosteric activator of 6-phosphofructokinase-1 (PFK-1), stimulating glycolysis. Click to see image of PFFKB3 function[permanent dead link].
In neurons, glucose metabolism via glycolysis is usually low when compared to astrocytes. According Astrocyte-to-Neuron Lactate Shuttle Hypothesis, glucose uptake by the brain parenchyma occurs predominantly into astrocytes which subsequently release lactate for the use of neurons. In neurons, glucose is mainly metabolized through the pentose–phosphate pathway (PPP), which is required for NADPH(H+) regeneration and maintenance of neuronal redox status. This neuronal metabolic switch is dictated by the PFKFB3 activity. In neurons, PFKFB3 protein abundance is negligible due to the continuous proteasomal degradation of the enzyme. 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. 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
The Warburg effect, proposed by Otto Warbug in 1956, 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.
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PFKFB3
PFKFB3 is a gene that encodes the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme in humans. It is one of 4 tissue-specific PFKFB isoenzymes identified currently (PFKFB1-4).
The PFKFB3 gene is mapped to single locus on chromosome 10 (10p15-p14). It spans a region of 32.5kb with an open reading frame that is 5,675bp long. It is estimated to consist of 19 exons, of which 15 are regularly expressed. Alternative splicing of the variable, COOH-terminal domain has been observed, leading to 6 different isoforms termed UBI2K1 to UBI2K6 in humans. Different nomenclature also recognizes two broad categories of PFKFB3 isoforms, termed 'inducible' and 'ubiquitous'. The inducible protein isoform, iPFK2, is named as such because its expression has been shown to be induced by hypoxic conditions.
The PFKFB3 promoter is predicted to contain multiple binding sites, including Sp-1 and AP-2 binding sites. It also contains motifs for the binding of E-box, nuclear factor-1 (NF-1), and progesterone response element. Expression of the promoter is shown to be induce by phorbol esters and cyclic-AMP-dependent protein kinase signaling.
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. The PFKFB3 inducible isoform has higher '2-Kase' (kinase) activity than other isoforms, due to phosphorylation of Ser-460 by PKA or AMP-dependent protein kinase. The high '2-Kase' activity of PFKFB3 is also due to the lack of a specific Ser that is phosphorylated in the other PFKFB isoforms to decrease kinase activity.
The primary protein encoded by PFKFB3, iPFK2, consists of 590 amino acids. It has a predicted molecular weight of 66.9 kDa and an isoelectric point of 8.64. The crystal structure was determined in 2006:
iPFK2 converts fructose-6-phosphate to fructose-2,6-bisP (F2,6BP). F2,6BP is a 'potent' allosteric activator of 6-phosphofructokinase-1 (PFK-1), stimulating glycolysis. Click to see image of PFFKB3 function[permanent dead link].
In neurons, glucose metabolism via glycolysis is usually low when compared to astrocytes. According Astrocyte-to-Neuron Lactate Shuttle Hypothesis, glucose uptake by the brain parenchyma occurs predominantly into astrocytes which subsequently release lactate for the use of neurons. In neurons, glucose is mainly metabolized through the pentose–phosphate pathway (PPP), which is required for NADPH(H+) regeneration and maintenance of neuronal redox status. This neuronal metabolic switch is dictated by the PFKFB3 activity. In neurons, PFKFB3 protein abundance is negligible due to the continuous proteasomal degradation of the enzyme. 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. 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
The Warburg effect, proposed by Otto Warbug in 1956, 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.
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