PFKL explained

6-phosphofructokinase, liver type (PFKL) is an enzyme that in humans is encoded by the PFKL gene on chromosome 21.^[1] This gene encodes the liver (L) isoform of phosphofructokinase-1, an enzyme that catalyzes the conversion of D-fructose 6-phosphate to D-fructose 1,6-bisphosphate, which is a key step in glucose metabolism (glycolysis). This enzyme is a tetramer that may be composed of different subunits encoded by distinct genes in different tissues. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

Structure

Gene

The PFKL mRNA sequence includes 55 nucleotides at the 5' and 515 nucleotides at the 3' noncoding regions, as well as 2,337 nucleotides in the coding region, encoding 779 amino acids. This coding region only shares a 68% similarity between PFKL and the muscle-type PFKM.^[2]

Protein

This 80-kDa protein is one of three subunit types that comprise the five tetrameric PFK isozymes. The liver PFK (PFK-5) contains solely PFKL, while the erythrocyte PFK includes five isozymes composed of different combinations of PFKL and the second subunit type, PFKM.^{[3] [4]} The muscle isozyme (PFK-1) is composed solely of PFKM.^{[3] [5] [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]

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] [8]} Notably, knockdown of PFKL has been shown to impair glycolysis and promote metabolism via the pentose phosphate pathway. Moreover, PFKL regulates NADPH oxidase activity through the pentose phosphate pathway and according to NADPH levels.^[8]

PFKL has also been detected in leukocytes, kidney, and brain.^[5]

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 (Tarui disease).^{[3] [4]}

Overexpression of PFKL has been associated with Down's syndrome (DS) erythrocytes and fibroblasts and attributed with biochemical changes in PFK that enhance its glycolytic function. Moreover, the PFKL gene maps to the triplicated region of chromosome 21 responsible for DS, indicating that this gene, too, has been triplicated.^[9]

See also

• PFK
• PFKM
• PFKP

Further reading

• 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 . April 1979 . 156693 . 10.1007/bf00273280 . 23300861 .
• Kristensen T, Lopez R, Prydz H . An estimate of the sequencing error frequency in the DNA sequence databases . DNA Sequence . 2 . 6 . 343–6 . 1992 . 1446073 . 10.3109/10425179209020815 .
• Wang D, Fang H, Cantor CR, Smith CL . A contiguous Not I restriction map of band q22.3 of human chromosome 21 . Proceedings of the National Academy of Sciences of the United States of America . 89 . 8 . 3222–6 . April 1992 . 1565613 . 48838 . 10.1073/pnas.89.8.3222 . 1992PNAS...89.3222W . free .
• Elson A, Levanon D, Brandeis M, Dafni N, Bernstein Y, Danciger E, Groner Y . The structure of the human liver-type phosphofructokinase gene . Genomics . 7 . 1 . 47–56 . May 1990 . 2139864 . 10.1016/0888-7543(90)90517-X .
• 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 . December 1989 . 2533063 . 10.1089/dna.1989.8.733 .
• Van Keuren M, Drabkin H, Hart I, Harker D, Patterson D, Vora S . Regional assignment of human liver-type 6-phosphofructokinase to chromosome 21q22.3 by using somatic cell hybrids and a monoclonal anti-L antibody . Human Genetics . 74 . 1 . 34–40 . September 1986 . 2944814 . 10.1007/bf00278782 . 26346007 .
• Levanon D, Danciger E, Dafni N, Groner Y . Genomic clones of the human liver-type phosphofructokinase . Biochemical and Biophysical Research Communications . 141 . 1 . 374–80 . November 1986 . 2948503 . 10.1016/S0006-291X(86)80379-5 .
• 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 . December 1983 . 6227635 . 437040 . 10.1172/JCI111164 .
• 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 .
• Koster JF, Slee RG, Van Berkel TJ . Isoenzymes of human phosphofructokinase . Clinica Chimica Acta; International Journal of Clinical Chemistry . 103 . 2 . 169–73 . April 1980 . 6445244 . 10.1016/0009-8981(80)90210-7 .
• Vora S, Francke U . Assignment of the human gene for liver-type 6-phosphofructokinase isozyme (PFKL) to chromosome 21 by using somatic cell hybrids and monoclonal anti-L antibody . Proceedings of the National Academy of Sciences of the United States of America . 78 . 6 . 3738–42 . June 1981 . 6455664 . 319647 . 10.1073/pnas.78.6.3738 . 1981PNAS...78.3738V . free .
• Zeitschel U, Bigl M, Eschrich K, Bigl V . Cellular distribution of 6-phosphofructo-1-kinase isoenzymes in rat brain . Journal of Neurochemistry . 67 . 6 . 2573–80 . December 1996 . 8931492 . 10.1046/j.1471-4159.1996.67062573.x . 46068703 .
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides . Nature Biotechnology . 21 . 5 . 566–9 . May 2003 . 12665801 . 10.1038/nbt810 . 23783563 .
• Zhang C, Dowd DR, Staal A, Gu C, Lian JB, van Wijnen AJ, Stein GS, MacDonald PN . Nuclear coactivator-62 kDa/Ski-interacting protein is a nuclear matrix-associated coactivator that may couple vitamin D receptor-mediated transcription and RNA splicing . The Journal of Biological Chemistry . 278 . 37 . 35325–36 . September 2003 . 12840015 . 10.1074/jbc.M305191200 . free.
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . Functional proteomics mapping of a human signaling pathway . Genome Research . 14 . 7 . 1324–32 . July 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ . Immunoaffinity profiling of tyrosine phosphorylation in cancer cells . Nature Biotechnology . 23 . 1 . 94–101 . Jan 2005 . 15592455 . 10.1038/nbt1046 . 7200157 .

Notes and References

1. Web site: Entrez Gene: PFKL phosphofructokinase, liver.
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 . December 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 . December 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 . April 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 . April 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. 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 .
9. Elson A, Bernstein Y, Degani H, Levanon D, Ben-Hur H, Groner Y . Gene dosage and Down's syndrome: metabolic and enzymatic changes in PC12 cells overexpressing transfected human liver-type phosphofructokinase . Somatic Cell and Molecular Genetics . 18 . 2 . 143–61 . March 1992 . 1533471 . 10.1007/bf01233161. 38259672 .