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词条 PFKL
释义

  1. Structure

      Gene    Protein  

  2. Function

  3. Clinical significance

  4. Interactive pathway map

  5. Model organisms

  6. See also

  7. References

  8. Further reading

{{Infobox gene}}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) subunit of 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][1]

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]

Interactive pathway map

{{GlycolysisGluconeogenesis_WP534|highlight=PFKL}}

Model organisms

Model organisms have been used in the study of PFKL function. A conditional knockout mouse line, called Pfkltm1a(EUCOMM)Wtsi[14][15] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[16][17][18]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty six tests were carried out on mutant mice and three significant abnormalities were observed.[12] Few homozygous mutant embryos were identified during gestation, and none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and a hair follicle degeneration phenotype was observed.[12]

See also

  • PFK
  • PFKM
  • PFKP

References

1. ^1 {{cite web | title = Entrez Gene: PFKL phosphofructokinase, liver| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5211| accessdate = }}
2. ^{{cite journal | vauthors = Levanon D, Danciger E, Dafni N, Bernstein Y, Elson A, Moens W, Brandeis M, Groner Y | title = The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK | journal = Dna | volume = 8 | issue = 10 | pages = 733–43 | date = December 1989 | pmid = 2533063 | doi=10.1089/dna.1989.8.733}}
3. ^1 2 3 {{cite journal | vauthors = Vora S, Seaman C, Durham S, Piomelli S | title = Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 1 | pages = 62–6 | date = Jan 1980 | pmid = 6444721 | doi=10.1073/pnas.77.1.62 | pmc=348208}}
4. ^1 {{cite journal | vauthors = Vora S, Davidson M, Seaman C, Miranda AF, Noble NA, Tanaka KR, Frenkel EP, Dimauro S | title = Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency | journal = The Journal of Clinical Investigation | volume = 72 | issue = 6 | pages = 1995–2006 | date = December 1983 | pmid = 6227635 | doi = 10.1172/JCI111164 | pmc=437040}}
5. ^1 {{cite journal | vauthors = Koster JF, Slee RG, Van Berkel TJ | title = Isoenzymes of human phosphofructokinase | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 103 | issue = 2 | pages = 169–73 | date = April 1980 | pmid = 6445244 | doi=10.1016/0009-8981(80)90210-7}}
6. ^1 {{cite journal | vauthors = Musumeci O, Bruno C, Mongini T, Rodolico C, Aguennouz M, Barca E, Amati A, Cassandrini D, Serlenga L, Vita G, Toscano A | title = Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII) | journal = Neuromuscular Disorders | volume = 22 | issue = 4 | pages = 325–30 | date = April 2012 | pmid = 22133655 | doi = 10.1016/j.nmd.2011.10.022 }}
7. ^1 {{cite journal | vauthors = Brüser A, Kirchberger J, Kloos M, Sträter N, Schöneberg T | title = Functional linkage of adenine nucleotide binding sites in mammalian muscle 6-phosphofructokinase | journal = The Journal of Biological Chemistry | volume = 287 | issue = 21 | pages = 17546–53 | date = May 2012 | pmid = 22474333 | doi = 10.1074/jbc.M112.347153 | pmc=3366854}}
8. ^1 {{cite journal | vauthors = Graham DB, Becker CE, Doan A, Goel G, Villablanca EJ, Knights D, Mok A, Ng AC, Doench JG, Root DE, Clish CB, Xavier RJ | title = Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst | journal = Nature Communications | volume = 6 | pages = 7838 | date = 21 July 2015 | pmid = 26194095 | doi = 10.1038/ncomms8838 | pmc=4518307}}
9. ^{{cite journal | vauthors = Elson A, Bernstein Y, Degani H, Levanon D, Ben-Hur H, Groner Y | title = Gene dosage and Down's syndrome: metabolic and enzymatic changes in PC12 cells overexpressing transfected human liver-type phosphofructokinase | journal = Somatic Cell and Molecular Genetics | volume = 18 | issue = 2 | pages = 143–61 | date = March 1992 | pmid = 1533471 | doi=10.1007/bf01233161}}
10. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBCL/salmonella-challenge/ |title=Salmonella infection data for Pfkl |publisher=Wellcome Trust Sanger Institute}}
11. ^{{cite web |url=http://www.sanger.ac.uk/mouseportal/phenotyping/MBCL/citrobacter-challenge/ |title=Citrobacter infection data for Pfkl |publisher=Wellcome Trust Sanger Institute}}
12. ^1 2 3 {{cite journal | doi = 10.1111/j.1755-3768.2010.4142.x | title = The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice | year = 2010 | author = Gerdin AK | journal = Acta Ophthalmologica | volume = 88 | pages = 925–7 }}
13. ^Mouse Resources Portal, Wellcome Trust Sanger Institute.
14. ^{{cite web |url=http://www.knockoutmouse.org/martsearch/search?query=Pfkl |title=International Knockout Mouse Consortium}}
15. ^{{cite web |url=http://www.informatics.jax.org/searchtool/Search.do?query=MGI:4432814 |title=Mouse Genome Informatics}}
16. ^{{cite journal | vauthors = Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A | title = A conditional knockout resource for the genome-wide study of mouse gene function | journal = Nature | volume = 474 | issue = 7351 | pages = 337–42 | date = June 2011 | pmid = 21677750 | pmc = 3572410 | doi = 10.1038/nature10163 }}
17. ^{{cite journal | vauthors = Dolgin E | title = Mouse library set to be knockout | journal = Nature | volume = 474 | issue = 7351 | pages = 262–3 | date = June 2011 | pmid = 21677718 | doi = 10.1038/474262a }}
18. ^{{cite journal | vauthors = Collins FS, Rossant J, Wurst W | title = A mouse for all reasons | journal = Cell | volume = 128 | issue = 1 | pages = 9–13 | date = Jan 2007 | pmid = 17218247 | doi = 10.1016/j.cell.2006.12.018 }}
19. ^{{cite journal | vauthors = van der Weyden L, White JK, Adams DJ, Logan DW | title = The mouse genetics toolkit: revealing function and mechanism | journal = Genome Biology | volume = 12 | issue = 6 | pages = 224 | year = 2011 | pmid = 21722353 | pmc = 3218837 | doi = 10.1186/gb-2011-12-6-224 }}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Kahn A, Meienhofer MC, Cottreau D, Lagrange JL, Dreyfus JC | title = Phosphofructokinase (PFK) isozymes in man. I. Studies of adult human tissues | journal = Human Genetics | volume = 48 | issue = 1 | pages = 93–108 | date = April 1979 | pmid = 156693 | doi = 10.1007/bf00273280 }}
  • {{cite journal | vauthors = Kristensen T, Lopez R, Prydz H | title = An estimate of the sequencing error frequency in the DNA sequence databases | journal = DNA Sequence | volume = 2 | issue = 6 | pages = 343–6 | year = 1992 | pmid = 1446073 | doi = 10.3109/10425179209020815 }}
  • {{cite journal | vauthors = Wang D, Fang H, Cantor CR, Smith CL | title = A contiguous Not I restriction map of band q22.3 of human chromosome 21 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 8 | pages = 3222–6 | date = April 1992 | pmid = 1565613 | pmc = 48838 | doi = 10.1073/pnas.89.8.3222 }}
  • {{cite journal | vauthors = Elson A, Levanon D, Brandeis M, Dafni N, Bernstein Y, Danciger E, Groner Y | title = The structure of the human liver-type phosphofructokinase gene | journal = Genomics | volume = 7 | issue = 1 | pages = 47–56 | date = May 1990 | pmid = 2139864 | doi = 10.1016/0888-7543(90)90517-X }}
  • {{cite journal | vauthors = Levanon D, Danciger E, Dafni N, Bernstein Y, Elson A, Moens W, Brandeis M, Groner Y | title = The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK | journal = Dna | volume = 8 | issue = 10 | pages = 733–43 | date = December 1989 | pmid = 2533063 | doi = 10.1089/dna.1989.8.733 }}
  • {{cite journal | vauthors = Van Keuren M, Drabkin H, Hart I, Harker D, Patterson D, Vora S | title = Regional assignment of human liver-type 6-phosphofructokinase to chromosome 21q22.3 by using somatic cell hybrids and a monoclonal anti-L antibody | journal = Human Genetics | volume = 74 | issue = 1 | pages = 34–40 | date = September 1986 | pmid = 2944814 | doi = 10.1007/bf00278782 }}
  • {{cite journal | vauthors = Levanon D, Danciger E, Dafni N, Groner Y | title = Genomic clones of the human liver-type phosphofructokinase | journal = Biochemical and Biophysical Research Communications | volume = 141 | issue = 1 | pages = 374–80 | date = November 1986 | pmid = 2948503 | doi = 10.1016/S0006-291X(86)80379-5 }}
  • {{cite journal | vauthors = Vora S, Davidson M, Seaman C, Miranda AF, Noble NA, Tanaka KR, Frenkel EP, Dimauro S | title = Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency | journal = The Journal of Clinical Investigation | volume = 72 | issue = 6 | pages = 1995–2006 | date = December 1983 | pmid = 6227635 | pmc = 437040 | doi = 10.1172/JCI111164 }}
  • {{cite journal | vauthors = Vora S, Seaman C, Durham S, Piomelli S | title = Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 1 | pages = 62–6 | date = Jan 1980 | pmid = 6444721 | pmc = 348208 | doi = 10.1073/pnas.77.1.62 }}
  • {{cite journal | vauthors = Koster JF, Slee RG, Van Berkel TJ | title = Isoenzymes of human phosphofructokinase | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 103 | issue = 2 | pages = 169–73 | date = April 1980 | pmid = 6445244 | doi = 10.1016/0009-8981(80)90210-7 }}
  • {{cite journal | vauthors = Vora S, Francke U | title = 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 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 78 | issue = 6 | pages = 3738–42 | date = June 1981 | pmid = 6455664 | pmc = 319647 | doi = 10.1073/pnas.78.6.3738 }}
  • {{cite journal | vauthors = Zeitschel U, Bigl M, Eschrich K, Bigl V | title = Cellular distribution of 6-phosphofructo-1-kinase isoenzymes in rat brain | journal = Journal of Neurochemistry | volume = 67 | issue = 6 | pages = 2573–80 | date = December 1996 | pmid = 8931492 | doi = 10.1046/j.1471-4159.1996.67062573.x }}
  • {{cite journal | vauthors = Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J | title = Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides | journal = Nature Biotechnology | volume = 21 | issue = 5 | pages = 566–9 | date = May 2003 | pmid = 12665801 | doi = 10.1038/nbt810 }}
  • {{cite journal | vauthors = Zhang C, Dowd DR, Staal A, Gu C, Lian JB, van Wijnen AJ, Stein GS, MacDonald PN | title = Nuclear coactivator-62 kDa/Ski-interacting protein is a nuclear matrix-associated coactivator that may couple vitamin D receptor-mediated transcription and RNA splicing | journal = The Journal of Biological Chemistry | volume = 278 | issue = 37 | pages = 35325–36 | date = September 2003 | pmid = 12840015 | doi = 10.1074/jbc.M305191200 }}
  • {{cite journal | vauthors = Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM | title = Functional proteomics mapping of a human signaling pathway | journal = Genome Research | volume = 14 | issue = 7 | pages = 1324–32 | date = July 2004 | pmid = 15231748 | pmc = 442148 | doi = 10.1101/gr.2334104 }}
  • {{cite journal | vauthors = Rush J, Moritz A, Lee KA, Guo A, Goss VL, Spek EJ, Zhang H, Zha XM, Polakiewicz RD, Comb MJ | title = Immunoaffinity profiling of tyrosine phosphorylation in cancer cells | journal = Nature Biotechnology | volume = 23 | issue = 1 | pages = 94–101 | date = Jan 2005 | pmid = 15592455 | doi = 10.1038/nbt1046 }}
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