PFKM explained

6-phosphofructokinase, muscle type is an enzyme that in humans is encoded by the PFKM gene on chromosome 12. Three phosphofructokinase isozymes exist in humans: muscle, liver and platelet. These isozymes function as subunits of the mammalian tetramer phosphofructokinase, which catalyzes the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. Tetramer composition varies depending on tissue type. This gene encodes the muscle-type isozyme. Mutations in this gene have been associated with glycogen storage disease type VII, also known as Tarui disease. Alternatively spliced transcript variants have been described.[provided by RefSeq, Nov 2009]^[1]

Structure

Gene

This gene is found on chromosome 12.^[1] The coding region in PFKM only shares a 68% similarity with that of the liver-type PFKL.^[2]

Protein

This 85-kDa protein is one of two subunit types that comprise the seven tetrameric PFK isozymes.^{[3] [4]} The muscle isozyme (PFK-1) is composed solely of PFKM.^{[3] [5] [6]} 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.^{[3] [4] [6]} 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.^[7] In particular, the binding site for the PFK inhibitor citrate is found in the PFKL C-terminal region.^[8]

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.^{[3] [6] [7] [9]}

Though the PFKM subunit majorly incorporates into muscle and erythrocyte PFKs, PFKM also is expressed in the heart, brain, and testis.^[10]

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.^{[3] [6] [11]} Notably, mutations in PFKM have been shown to cause Tarui disease due to homozygosity for catalytically inactive M subunits.^{[4] [11]} PFKM is confirmed to be involved in muscle PFK deficiency with early-onset hyperuricemia.^[4]

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.^[11]

Interactions

PFKM has been shown to interact with ATP6V0A4.^[12]

See also

• PFK
• PFK-1
• PFKL
• PFKP

Further reading

• Raben N, Sherman JB . Mutations in muscle phosphofructokinase gene . Human Mutation . 6 . 1 . 1–6 . 1995 . 7550225 . 10.1002/humu.1380060102 . 46649815 . free .
• Kahn A, Etiemble J, Meienhofer MC, Bovin P . Erythrocyte phosphofructokinase deficiency associated with an unstable variant of muscle phosphofructokinase . Clinica Chimica Acta; International Journal of Clinical Chemistry . 61 . 3 . 415–9 . Jun 1975 . 125160 . 10.1016/0009-8981(75)90434-9 .
• Zhao ZZ, Malencik DA, Anderson SR . Protein-induced inactivation and phosphorylation of rabbit muscle phosphofructokinase . Biochemistry . 30 . 8 . 2204–16 . Feb 1991 . 1825608 . 10.1021/bi00222a026 .
• Yamasaki T, Nakajima H, Kono N, Hotta K, Yamada K, Imai E, Kuwajima M, Noguchi T, Tanaka T, Tarui S . Structure of the entire human muscle phosphofructokinase-encoding gene: a two-promoter system . Gene . 104 . 2 . 277–82 . Aug 1991 . 1833270 . 10.1016/0378-1119(91)90262-A .
• Sharma PM, Reddy GR, Babior BM, McLachlan A . Alternative splicing of the transcript encoding the human muscle isoenzyme of phosphofructokinase . The Journal of Biological Chemistry . 265 . 16 . 9006–10 . Jun 1990 . 10.1016/S0021-9258(19)38803-9 . 2140567 . free .
• Nakajima H, Kono N, Yamasaki T, Hotta K, Kawachi M, Kuwajima M, Noguchi T, Tanaka T, Tarui S . Genetic defect in muscle phosphofructokinase deficiency. Abnormal splicing of the muscle phosphofructokinase gene due to a point mutation at the 5'-splice site . The Journal of Biological Chemistry . 265 . 16 . 9392–5 . Jun 1990 . 10.1016/S0021-9258(19)38861-1 . 2140573 . free .
• Valdez BC, Chen Z, Sosa MG, Younathan ES, Chang SH . Human 6-phosphofructo-1-kinase gene has an additional intron upstream of start codon . Gene . 76 . 1 . 167–9 . Mar 1989 . 2526044 . 10.1016/0378-1119(89)90019-X .
• Sharma PM, Reddy GR, Vora S, Babior BM, McLachlan A . Cloning and expression of a human muscle phosphofructokinase cDNA . Gene . 77 . 1 . 177–83 . Apr 1989 . 2526045 . 10.1016/0378-1119(89)90372-7 .
• Nakajima H, Noguchi T, Yamasaki T, Kono N, Tanaka T, Tarui S . Cloning of human muscle phosphofructokinase cDNA . FEBS Letters . 223 . 1 . 113–6 . Oct 1987 . 2822475 . 10.1016/0014-5793(87)80519-7 . 42849336 . free .
• Vora S, Seaman C, Durham S, Piomelli S . Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system . Proceedings of the National Academy of Sciences of the United States of America . 77 . 1 . 62–6 . Jan 1980 . 6444721 . 348208 . 10.1073/pnas.77.1.62 . 1980PNAS...77...62V . free .
• Kahn A, Weil D, Cottreau D, Dreyfus JC . Muscle phosphofructokinase deficiency in man: expression of the defect in blood cells and cultured fibroblasts . Annals of Human Genetics . 45 . Pt 1 . 5–14 . Feb 1981 . 6459054 . 10.1111/j.1469-1809.1981.tb00300.x . 39444994 .
• Vasconcelos O, Sivakumar K, Dalakas MC, Quezado M, Nagle J, Leon-Monzon M, Dubnick M, Gajdusek DC, Goldfarb LG . Nonsense mutation in the phosphofructokinase muscle subunit gene associated with retention of intron 10 in one of the isolated transcripts in Ashkenazi Jewish patients with Tarui disease . Proceedings of the National Academy of Sciences of the United States of America . 92 . 22 . 10322–6 . Oct 1995 . 7479776 . 40788 . 10.1073/pnas.92.22.10322 . 1995PNAS...9210322V . free .
• Tsujino S, Servidei S, Tonin P, Shanske S, Azan G, DiMauro S . Identification of three novel mutations in non-Ashkenazi Italian patients with muscle phosphofructokinase deficiency . American Journal of Human Genetics . 54 . 5 . 812–9 . May 1994 . 7513946 . 1918246 .
• Raben N, Exelbert R, Spiegel R, Sherman JB, Nakajima H, Plotz P, Heinisch J . Functional expression of human mutant phosphofructokinase in yeast: genetic defects in French Canadian and Swiss patients with phosphofructokinase deficiency . American Journal of Human Genetics . 56 . 1 . 131–41 . Jan 1995 . 7825568 . 1801305 .
• Raben N, Sherman J, Miller F, Mena H, Plotz P . A 5' splice junction mutation leading to exon deletion in an Ashkenazic Jewish family with phosphofructokinase deficiency (Tarui disease) . The Journal of Biological Chemistry . 268 . 7 . 4963–7 . Mar 1993 . 10.1016/S0021-9258(18)53489-X . 8444874 . free .
• Howard TD, Akots G, Bowden DW . Physical and genetic mapping of the muscle phosphofructokinase gene (PFKM): reassignment to human chromosome 12q . Genomics . 34 . 1 . 122–7 . May 1996 . 8661033 . 10.1006/geno.1996.0250 .
• Hamaguchi T, Nakajima H, Noguchi T, Nakagawa C, Kuwajima M, Kono N, Tarui S, Matsuzawa Y . 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 . 1997 . 8889589 . 10.1002/(SICI)1098-1004(1996)8:3<273::AID-HUMU13>3.0.CO;2-# . 196597214 .
• Scherer PE, Lisanti MP . Association of phosphofructokinase-M with caveolin-3 in differentiated skeletal myotubes. Dynamic regulation by extracellular glucose and intracellular metabolites . The Journal of Biological Chemistry . 272 . 33 . 20698–705 . Aug 1997 . 9252390 . 10.1074/jbc.272.33.20698 . free.
• Ristow M, Vorgerd M, Möhlig M, Schatz H, Pfeiffer A . Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance . The Journal of Clinical Investigation . 100 . 11 . 2833–41 . Dec 1997 . 9389749 . 508489 . 10.1172/JCI119831 .

Notes and References

1. Web site: Entrez Gene: PFKM phosphofructokinase, muscle.
2. Levanon D, Danciger E, Dafni N, Bernstein Y, Elson A, Moens W, Brandeis M, Groner Y . The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK . DNA . 8 . 10 . 733–43 . Dec 1989 . 2533063 . 10.1089/dna.1989.8.733.
3. Vora S, Seaman C, Durham S, Piomelli S . Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system . Proceedings of the National Academy of Sciences of the United States of America . 77 . 1 . 62–6 . Jan 1980 . 6444721 . 10.1073/pnas.77.1.62 . 348208. 1980PNAS...77...62V . free .
4. Vora S, Davidson M, Seaman C, Miranda AF, Noble NA, Tanaka KR, Frenkel EP, Dimauro S . Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency . The Journal of Clinical Investigation . 72 . 6 . 1995–2006 . Dec 1983 . 6227635 . 10.1172/JCI111164 . 437040.
5. Koster JF, Slee RG, Van Berkel TJ . Isoenzymes of human phosphofructokinase . Clinica Chimica Acta; International Journal of Clinical Chemistry . 103 . 2 . 169–73 . Apr 1980 . 6445244 . 10.1016/0009-8981(80)90210-7.
6. Musumeci O, Bruno C, Mongini T, Rodolico C, Aguennouz M, Barca E, Amati A, Cassandrini D, Serlenga L, Vita G, Toscano A . Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII) . Neuromuscular Disorders . 22 . 4 . 325–30 . Apr 2012 . 22133655 . 10.1016/j.nmd.2011.10.022 . 20133199 .
7. Brüser A, Kirchberger J, Kloos M, Sträter N, Schöneberg T . Functional linkage of adenine nucleotide binding sites in mammalian muscle 6-phosphofructokinase . The Journal of Biological Chemistry . 287 . 21 . 17546–53 . May 2012 . 22474333 . 10.1074/jbc.M112.347153 . 3366854. free .
8. Usenik A, Legiša M . Evolution of allosteric citrate binding sites on 6-phosphofructo-1-kinase . PLOS ONE . 5 . 11 . e15447 . 23 November 2010 . 21124851 . 10.1371/journal.pone.0015447 . 2990764. 2010PLoSO...515447U . free .
9. Graham DB, Becker CE, Doan A, Goel G, Villablanca EJ, Knights D, Mok A, Ng AC, Doench JG, Root DE, Clish CB, Xavier RJ . Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst . Nature Communications . 6 . 7838 . 21 July 2015 . 26194095 . 10.1038/ncomms8838 . 4518307. 2015NatCo...6.7838G .
10. Kahn A, Meienhofer MC, Cottreau D, Lagrange JL, Dreyfus JC . Phosphofructokinase (PFK) isozymes in man. I. Studies of adult human tissues . Human Genetics . 48 . 1 . 93–108 . Apr 1979 . 156693 . 10.1007/bf00273280. 23300861 .
11. Keildson S, Fadista J, Ladenvall C, Hedman ÅK, Elgzyri T, Small KS, Grundberg E, Nica AC, Glass D, Richards JB, Barrett A, Nisbet J, Zheng HF, Rönn T, Ström K, Eriksson KF, Prokopenko I, Spector TD, Dermitzakis ET, Deloukas P, McCarthy MI, Rung J, Groop L, Franks PW, Lindgren CM, Hansson O . Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity . Diabetes . 63 . 3 . 1154–65 . Mar 2014 . 24306210 . 10.2337/db13-1301 . 3931395.
12. Su Y, Zhou A, Al-Lamki RS, Karet FE . The a-subunit of the V-type H+-ATPase interacts with phosphofructokinase-1 in humans . The Journal of Biological Chemistry . 278 . 22 . 20013–8 . May 2003 . 12649290 . 10.1074/jbc.M210077200 . free .