This 85-kDa protein is one of two subunit types that comprise the seven tetrameric PFK isozymes.[6][7] The muscle isozyme (PFK-1) is composed solely of PFKM.[6][8][9]The liver PFK (PFK-5) contains solely the second subunit type, PFKL, while the erythrocyte PFK includes five isozymes composed of different combinations of PFKM and PFKL.[6][7][9] These subunits evolved from a commonprokaryotic ancestor viagene duplication and mutation events. Generally, theN-terminal of the subunits carries out their catalytic activity while theC-terminal contains allostericligand binding sites.[10] In particular, the binding site for the PFK inhibitorcitrate is found in the PFKL C-terminal region.[11]
This gene encodes one of three protein subunits of PFK, which are expressed and combined to form the tetrameric PFK in a tissue-specific manner. As a PFK subunit, PFKL is involved in catalyzing the phosphorylation of fructose 6-phosphate to fructose 1,6-bisphosphate. This irreversible reaction serves as the major rate-limiting step of glycolysis.[6][9][10][12]
Though the PFKM subunit majorly incorporates into muscle and erythrocyte PFKs, PFKM also is expressed in theheart,brain, andtestis.[13]
As the erythrocyte PFK is composed of both PFKL and PFKM, thisheterogeneic composition is attributed with the differential PFK activity and organ involvement observed in some inherited PFK deficiency states in whichmyopathy orhemolysis or both can occur, such as glycogenosis type VII, also known as Tarui disease.[6][9][14] Notably, mutations inPFKM have been shown to cause Tarui disease due to homozygosity for catalytically inactive M subunits.[7][14] PFKM is confirmed to be involved in muscle PFK deficiency with early-onset hyperuricemia.[7]
Even though PFKM functions to drive glycolysis, its overexpression has been associated withtype 2 diabetes andinsulin resistance in skeletal muscle. One possible explanation suggests that the overexpression is meant to compensate for theallosteric inhibition ofPFK1 as a result of excessoxidation of freefatty acids and accumulation of citrate andacetyl-CoA.[14]
^Levanon D, Danciger E, Dafni N, Bernstein Y, Elson A, Moens W, Brandeis M, Groner Y (Dec 1989). "The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK".DNA.8 (10):733–43.doi:10.1089/dna.1989.8.733.PMID2533063.
^Koster JF, Slee RG, Van Berkel TJ (Apr 1980). "Isoenzymes of human phosphofructokinase".Clinica Chimica Acta; International Journal of Clinical Chemistry.103 (2):169–73.doi:10.1016/0009-8981(80)90210-7.PMID6445244.
^abcdMusumeci O, Bruno C, Mongini T, Rodolico C, Aguennouz M, Barca E, Amati A, Cassandrini D, Serlenga L, Vita G, Toscano A (Apr 2012). "Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII)".Neuromuscular Disorders.22 (4):325–30.doi:10.1016/j.nmd.2011.10.022.PMID22133655.S2CID20133199.
^Kahn A, Meienhofer MC, Cottreau D, Lagrange JL, Dreyfus JC (Apr 1979). "Phosphofructokinase (PFK) isozymes in man. I. Studies of adult human tissues".Human Genetics.48 (1):93–108.doi:10.1007/bf00273280.PMID156693.S2CID23300861.
Kahn A, Etiemble J, Meienhofer MC, Bovin P (Jun 1975). "Erythrocyte phosphofructokinase deficiency associated with an unstable variant of muscle phosphofructokinase".Clinica Chimica Acta; International Journal of Clinical Chemistry.61 (3):415–9.doi:10.1016/0009-8981(75)90434-9.PMID125160.
Zhao ZZ, Malencik DA, Anderson SR (Feb 1991). "Protein-induced inactivation and phosphorylation of rabbit muscle phosphofructokinase".Biochemistry.30 (8):2204–16.doi:10.1021/bi00222a026.PMID1825608.
Yamasaki T, Nakajima H, Kono N, Hotta K, Yamada K, Imai E, Kuwajima M, Noguchi T, Tanaka T, Tarui S (Aug 1991). "Structure of the entire human muscle phosphofructokinase-encoding gene: a two-promoter system".Gene.104 (2):277–82.doi:10.1016/0378-1119(91)90262-A.PMID1833270.
Valdez BC, Chen Z, Sosa MG, Younathan ES, Chang SH (Mar 1989). "Human 6-phosphofructo-1-kinase gene has an additional intron upstream of start codon".Gene.76 (1):167–9.doi:10.1016/0378-1119(89)90019-X.PMID2526044.
Sharma PM, Reddy GR, Vora S, Babior BM, McLachlan A (Apr 1989). "Cloning and expression of a human muscle phosphofructokinase cDNA".Gene.77 (1):177–83.doi:10.1016/0378-1119(89)90372-7.PMID2526045.
Kahn A, Weil D, Cottreau D, Dreyfus JC (Feb 1981). "Muscle phosphofructokinase deficiency in man: expression of the defect in blood cells and cultured fibroblasts".Annals of Human Genetics.45 (Pt 1):5–14.doi:10.1111/j.1469-1809.1981.tb00300.x.PMID6459054.S2CID39444994.
Howard TD, Akots G, Bowden DW (May 1996). "Physical and genetic mapping of the muscle phosphofructokinase gene (PFKM): reassignment to human chromosome 12q".Genomics.34 (1):122–7.doi:10.1006/geno.1996.0250.PMID8661033.
