This gene is found on chromosome 12.[4] The coding region in PFKM only shares a 68% similarity with that of the liver-type PFKL.[5]
Protein
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 common prokaryotic ancestor via gene duplication and mutation events. Generally, the N-terminal of the subunits carries out their catalytic activity while the C-terminal contains allosteric ligand binding sites.[10] In particular, the binding site for the PFK inhibitor citrate is found in the PFKL C-terminal region.[11]
Function
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 the heart, brain, and testis.[13]
Clinical significance
As the erythrocyte PFK is composed of both PFKL and PFKM, this heterogeneic composition is attributed with the differential PFK activity and organ involvement observed in some inherited PFK deficiency states in which myopathy or hemolysis or both can occur, such as glycogenosis type VII, also known as Tarui disease.[6][9][14] Notably, mutations in PFKM 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 with type 2 diabetes and insulin resistance in skeletal muscle. One possible explanation suggests that the overexpression is meant to compensate for the allosteric inhibition of PFK1 as a result of excess oxidation of free fatty acids and accumulation of citrate and acetyl-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, 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.
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.
Hamaguchi T, Nakajima H, Noguchi T, Nakagawa C, Kuwajima M, Kono N, Tarui S, Matsuzawa Y (1997). "Novel missense mutation (W686C) of the phosphofructokinase-M gene in a Japanese patient with a mild form of glycogenosis VII". Human Mutation. 8 (3): 273–5. doi:10.1002/(SICI)1098-1004(1996)8:3<273::AID-HUMU13>3.0.CO;2-#. PMID8889589. S2CID196597214.
