Disease relevance of PFKM

• The PFKM-associated microsatellite will be a valuable tool in the evaluation of PFKM in diabetic populations as well as in linkage analysis in families with Tarui disease [1].
• Expression of PFK isoform mRNA species was examined by RT-PCR in rat islets, in purified populations of beta-cells prepared by fluorescence-activated cell sorting (FACS), and in RIN-m5F insulinoma cells, all of which expressed mRNA species for PFK-A, -B, and -C isoforms [2].
• Mutations in the human phosphofructokinase muscle subunit gene (PFKM) are known to cause myopathy classified as glycogenosis type VII (Tarui disease) [3].
• Erythrocyte membrane leakage of Ca2+ in familial phosphofructokinase deficiency results in a compensatory increase of Ca2+-ATPase activity that depletes ATP and leads to diminished erythrocyte deformability and a higher rate of hemolysis [4].
• The genetic defect in muscle phosphofructokinase deficiency (type VII glycogenosis, Tarui disease) was investigated [5].

High impact information on PFKM

• The binding of phosphoenolpyruvate (PEP) to the single allosteric site on phosphofructokinase (EC ) from Bacillus stearothermophilus (BsPFK) diminishes the ability of the enzyme to bind the substrate fructose 6-phosphate (Fru-6-P) [6].
• Using a reverse transcription PCR assay, PFKM subunit transcripts differing by length were detected in skeletal muscle tissue of all three affected subjects [3].
• We have identified three novel mutations in four non-Ashkenazi Italian patients with muscle phosphofructokinase (PFK-M) deficiency (Tarui disease) [7].
• Association of phosphofructokinase-M with caveolin-3 in differentiated skeletal myotubes. Dynamic regulation by extracellular glucose and intracellular metabolites [8].
• A deficiency of the muscle isoform of the enzyme, phosphofructokinase (PFK, EC 2.7.1.11), leads to an illness (glycogenosis, Type VII) characterized by myopathy and hemolysis [9].

Chemical compound and disease context of PFKM

• Although this pathophysiological condition has been observed not only in glycolytic defects but also in mitochondrial diseases affecting lipid and carbohydrate oxidation, it is most common and prominent in muscle phosphofructokinase deficiency, in which neither glycogen nor glucose can be used as metabolic fuels [10].
• Exercise intolerance syndromes are well known to be associated with inborn errors of metabolism affecting glycolysis (phosphorylase and phosphofructokinase deficiency) and fatty acid oxidation (palmitoyl carnitine transferase deficiency) [11].

Biological context of PFKM

• Based on physical and genetic mapping, we have found that the gene for PFKM does not map to chromosome 1 as previously described, but instead maps to chromosome 12 [1].
• The rat PFK-A deduced amino-acid sequence is 96% identical to that of human PFK-A, and all residues thought to participate in substrate or allosteric effector binding are conserved between the two sequences [2].
• Using as probe a PCR product generated from rat islet RNA with primers designed from the human PFK-A sequence, we have cloned a full-length PFK-A cDNA from a rat islet cDNA library [2].
• Tissue specificity in expression and alternative RNA splicing of human phosphofructokinase-M and -L genes [12].
• Genetic defect in muscle phosphofructokinase deficiency. Abnormal splicing of the muscle phosphofructokinase gene due to a point mutation at the 5'-splice site [5].

Anatomical context of PFKM

• PCR analysis with a somatic cell hybrid mapping panel using primers derived from intron 6 and exon 18 of the PFKM gene showed consistent amplification of cell lines containing chromosome 12 (concordance, 100%) [1].
• Using somatic cell hybrids and subunit-specific antibodies, the PFKM, PFKP, and PFKL loci have been assigned to chromosomes I (region cen leads to q32), 10p and 21, respectively [13].
• It was found that while relative amount of PFKL mRNA in adult brain was one-fourth of that detected in fetal brain the level of PFKM mRNA in adult brain was slightly higher than in fetal tissue, suggesting that PFK expression might be controlled at the transcriptional level [14].
• Muscle phosphofructokinase deficiency in man: expression of the defect in blood cells and cultured fibroblasts [15].
• The localization of aldolase (ALD) was also shifted towards the plasma membrane (and colocalized with PFK) in CAV-1 over-expressing cells [16].

Associations of PFKM with chemical compounds

• Interleukin-1 impairs islet glucose metabolism and insulin secretion and was found to induce a specific decline in islet expression of PFK-A mRNA [2].
• In fresh human blood samples, ammonium was found to relieve phosphofructokinase from inhibition by increased ATP concentrations, to have no significant effect on adenine phosphoribosyl transferase activity, and, unexpectedly, to increase the activity of AMP deaminase [17].
• The phosphoryl donor for phosphofructokinase was only PPi [18].
• Phosphofructokinase, malate dehydrogenase, creatine kinase, and glucose-6-phosphate dehydrogenase recovered only after cardioversion [19].
• The determination of fructolytic intermediates and cofactors and calculation of mass action ratios for each enzymic step revealed that hexokinase, phosphofructokinase, fructose-biphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase catalysed reactions far removed from the equilibrium [20].

Other interactions of PFKM

• The gene for muscle phosphofructokinase, PFKM, is mutated in Tarui disease and conceivably contributes to non-insulin-dependent diabetes mellitus (NIDDM) [1].
• Results of analysis of a pig-rodent somatic cell hybrid panel by PCR allowed the assignments of ATP1A2 to porcine chromosome (chr) 4 and of PFKM to porcine chr 5 [21].
• Exposure to a calmodulin antagonist significantly slows IMP accumulation during experimental energy imbalance in patients' cells to levels that are similar to those in untreated controls, implying that Ca2+-calmodulin is involved in erythrocyte AMP deaminase activation in familial phosphofructokinase deficiency [4].
• Inside the muscle these could include glucose uptake (GLUT4) and phosphorylation (hexokinase), glycogenolysis (glycogen phosphorylase), glycolysis (phosphofructokinase) and conversion to acetyl CoA (pyruvate dehydrogenase) [22].
• The clinical manifestations may resemble myophosphorylase deficiency (McArdle's disease: glycogenosis Type V) and muscle phosphofructokinase deficiency (Tarui's disease: glycogenosis Type VII) [23].

Analytical, diagnostic and therapeutic context of PFKM

• Using specific immunoprecipitation of M-type phosphofructokinase and assay of immunoprecipitate enzyme activity, it was possible to detect some M-type enzyme in normal blood cells and fibroblasts, although this isoenzyme represents a very small part of total phosphofructokinase [15].
• Confocal immunofluorescence microscopy was used to study the distribution of phosphofructokinase (PFK) and CAV-1 in the transfected cells [16].
• Compared to the control group, the mouse in the group treated with the PO extracts by 1 g/d had significantly higher activities of PF, PFK, LDH and higher levels of ATP in the cortices, especially under the hypoxic environment for 24 hours [24].

References