PFKL

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PFKL
Identifiers
Aliases PFKL, ATP-PFK, PFK-B, PFK-L, phosphofructokinase, liver type
External IDs MGI: 97547 HomoloGene: 55668 GeneCards: 5211
RNA expression pattern
PBB GE PFKL 201102 s at tn.png

PBB GE PFKL 211065 x at tn.png

PBB GE PFKL 214309 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001002021
NM_002626

NM_008826

RefSeq (protein)

NP_001002021.2
NP_002617.3
NP_001002021.2
NP_002617.3

NP_032852.2

Location (UCSC) Chr 21: 44.3 – 44.33 Mb Chr 10: 77.99 – 78.01 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

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[edit]

Gene[edit]

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[edit]

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[edit]

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[edit]

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[edit]

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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GlycolysisGluconeogenesis_WP534 go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to article go to Entrez go to article go to article go to article go to article go to article go to WikiPathways go to article go to Entrez go to article
|{{{bSize}}}px|alt=Glycolysis and Gluconeogenesis edit]]
Glycolysis and Gluconeogenesis edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534". 

Model organisms[edit]

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[edit]

References[edit]

  1. ^ a b "Entrez Gene: PFKL phosphofructokinase, liver". 
  2. ^ 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. PMID 2533063. 
  3. ^ a b c d Vora S, Seaman C, Durham S, Piomelli S (Jan 1980). "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. doi:10.1073/pnas.77.1.62. PMC 348208. PMID 6444721. 
  4. ^ a b Vora S, Davidson M, Seaman C, Miranda AF, Noble NA, Tanaka KR, Frenkel EP, Dimauro S (Dec 1983). "Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency". The Journal of Clinical Investigation 72 (6): 1995–2006. doi:10.1172/JCI111164. PMC 437040. PMID 6227635. 
  5. ^ a b 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. PMID 6445244. 
  6. ^ a b Musumeci 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. PMID 22133655. 
  7. ^ a b Brüser A, Kirchberger J, Kloos M, Sträter N, Schöneberg T (May 2012). "Functional linkage of adenine nucleotide binding sites in mammalian muscle 6-phosphofructokinase". The Journal of Biological Chemistry 287 (21): 17546–53. doi:10.1074/jbc.M112.347153. PMID 22474333. 
  8. ^ a b Graham DB, Becker CE, Doan A, Goel G, Villablanca EJ, Knights D, Mok A, Ng AC, Doench JG, Root DE, Clish CB, Xavier RJ (21 July 2015). "Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst". Nature Communications 6: 7838. doi:10.1038/ncomms8838. PMID 26194095. 
  9. ^ Elson A, Bernstein Y, Degani H, Levanon D, Ben-Hur H, Groner Y (Mar 1992). "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. doi:10.1007/bf01233161. PMID 1533471. 
  10. ^ "Salmonella infection data for Pfkl". Wellcome Trust Sanger Institute. 
  11. ^ "Citrobacter infection data for Pfkl". Wellcome Trust Sanger Institute. 
  12. ^ a b c d Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x. 
  13. ^ Mouse Resources Portal, Wellcome Trust Sanger Institute.
  14. ^ "International Knockout Mouse Consortium". 
  15. ^ "Mouse Genome Informatics". 
  16. ^ 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 (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750. 
  17. ^ Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718. 
  18. ^ Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247. 
  19. ^ van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353. 

Further reading[edit]