PFKL

from Wikipedia, the free encyclopedia
Phosphofructokinase, liver type
other names
  • ATP-PFK
  • PFK-L, PFK-B
Properties of human protein
Mass / length primary structure 780 amino acids, 85018 Da
(isoform 1)
Identifier
Gene name PFKL
External IDs
Enzyme classification
EC, category 2.7.1.11
Orthologue
human House mouse
Entrez 5211 18641
Ensemble ENSG00000141959 ENSMUSG00000020277
UniProt P17858 P12382
Refseq (mRNA) NM_001002021 NM_008826
Refseq (protein) NP_001002021 NP_032852
Gene locus Chr 21: 44.3 - 44.33 Mb Chr 10: 77.99 - 78.01 Mb
PubMed search 5211 18641

The phosphofructokinase, liver type (to German phosphofructokinase type liver, PFKL ) is an enzyme , the liver (L) - subunit of the tetrameric enzyme phosphofructokinase 1 forms and the rate limiting step of the glycolysis catalyzes, namely the conversion of D -Fructose-6- phosphate to D- fructose-1,6-bisphosphate . PFKL is indicated by the same PFKL - gene that in humans to chromosome 21 is, encoded .

structure

gene

The mRNA sequence of PFKL comprises 55 nucleotides on the 5 ' and 515 nucleotides on the 3' non-coding regions and 2337 nucleotides in the coding region, which encode 779 amino acids . This coding region shows only a 68% similarity between PFKL and the muscular PFK .

protein

The 80  kDa protein is one of three types of subunits that make up the five tetrameric PFK isozymes. The liver PFK (PFK-5) contains only PFKL, while the erythrocyte PFK contains five isozymes, which are composed of different combinations of PFKL and the second subunit type, PFKM. The subunits evolved from a common prokaryotic ancestor through gene duplication and mutation events . In general, the N -terminus of the subunits carries out their catalytic activity, while the C -terminus contains allosteric ligand binding sites .

function

The PFKL gene codes for one of three protein subunits of the PFK, which are expressed and combined in a tissue-specific manner to form the tetrameric PFK. As a PFK subunit, PFKL is involved in the catalysis of the phosphorylation of fructose-6-phosphate to fructose-1,6-bisphosphate. This irreversible reaction is the most important rate-limiting step in glycolysis. It has been shown that a knock-down of PFKL impairs glycolysis and promotes metabolism via the pentose phosphate pathway . In addition, PFKL regulates the NADPH oxidase activity via the pentose phosphate pathway depending on the NADPH concentration.

PFKL has also been detected in leukocytes , kidneys and brain.

Clinical significance

Because erythrocyte PFK consists of both PFKL and PFKM, this heterogeneous composition has been associated with the differing PFK activity and organ involvement observed in some hereditary PFK deficiencies in which myopathy , hemolysis, or both occur can, as with glycogen storage disease type VII, also known as Tarui disease.

The overexpression of PFKL was charged with red blood cells and fibroblasts of Down syndrome brought and biochemical changes of PFK in conjunction to improve their glycolytic function. In addition, the PFKL gene is shown on the triple region of chromosome 21 responsible for Down's syndrome, which indicates that this gene has also appeared in triplicate.

Animal model

Model organisms were used to investigate the PFKL function . A conditional knockout mouse line called Pfkl tm1a (EUCOMM) Wtsi was developed as part of the International Knockout Mouse Consortium program.

Male and female animals were subjected to standardized phenotypic screening to determine the effects of the deletion . Twenty-six tests were carried out on mutant mice and three significant abnormalities were observed. Few homozygous mutant embryos were identified during gestation and none survived to weaning . The remainder of the tests were performed on heterozygous mutant adult mice and a phenotype of hair follicle degeneration was observed.

Individual evidence

  1. ↑ Mara Dierssen, Rafa de la Torre: Down Syndrome: From Understanding the Neurobiology to Therapy . tape 197 . Elsevier, 2012, ISBN 978-0-444-54299-1 , pp. 184 ( limited preview in Google Book search).
  2. ↑ D. Levanon, E. Danciger, N. Dafni, Y. Bernstein, A. Elson, W. Moens, M. Brandeis, Y. Groner: The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK. In: DNA. Volume 8, number 10, December 1989, pp. 733-743, doi : 10.1089 / dna.1989.8.733 , PMID 2533063 .
  3. ^ A b c S. Vora, C. Seaman, S. Durham, S. Piomelli: Isozymes of human phosphofructokinase: identification and subunit structural characterization of a new system. In: Proceedings of the National Academy of Sciences . Volume 77, number 1, January 1980, pp. 62-66, doi : 10.1073 / pnas.77.1.62 , PMID 6444721 , PMC 348208 (free full text).
  4. ^ A b S. Vora, M. Davidson, C. Seaman, AF Miranda, NA Noble, KR Tanaka, EP Frenkel, S. Dimauro: Heterogeneity of the molecular lesions in inherited phosphofructokinase deficiency. In: The Journal of clinical investigation. Volume 72, number 6, December 1983, pp. 1995-2006, doi : 10.1172 / JCI111164 , PMID 6227635 , PMC 437040 (free full text).
  5. ↑ A. Brüser, J. Kirchberger, M. Kloos, N. Sträter, T. Schöneberg: Functional linkage of adenine nucleotide binding sites in mammalian muscle 6-phosphofructokinase. In: Journal of Biological Chemistry . Volume 287, Number 21, May 2012, pp. 17546–17553, doi : 10.1074 / jbc.M112.347153 , PMID 22474333 , PMC 3366854 (free full text).
  6. ^ O. Musumeci, C. Bruno, T. Mongini, C. Rodolico, M. Aguennouz, E. Barca, A. Amati, D. Cassandrini, L. Serlenga, G. Vita, A. Toscano: Clinical features and new molecular findings in muscle phosphofructokinase deficiency (GSD type VII). In: Neuromuscular disorders: NMD. Volume 22, Number 4, April 2012, pp. 325-330, doi : 10.1016 / j.nmd.2011.10.022 , PMID 22133655 .
  7. ^ DB Graham, CE Becker, A. Doan, G. Goel, EJ Villablanca, D. Knights, A. Mok, AC Ng, JG Doench, DE Root, CB Clish, RJ Xavier: Functional genomics identifies negative regulatory nodes controlling phagocyte oxidative burst. In: Nature Communications . Volume 6, July 2015, p. 7838, doi : 10.1038 / ncomms8838 , PMID 26194095 , PMC 4518307 (free full text).
  8. ↑ JF Koster, RG Slee, TJ Van Berkel: Isoenzymes of human phosphofructokinase. In: Clinica Chimica Acta. Volume 103, Number 2, April 1980, pp. 169-173, doi : 10.1016 / 0009-8981 (80) 90210-7 , PMID 6445244 .
  9. ↑ A. Elson, Y. Bernstein, H. Degani, D. Levanon, H. Ben-Hur, Y. Groner: Gene dosage and Down's syndrome: metabolic and enzymatic changes in PC12 cells overexpressing transfected human liver-type phosphofructokinase. In: Somatic cell and molecular genetics. Volume 18, Number 2, March 1992, pp. 143-161, doi : 10.1007 / bf01233161 , PMID 1533471 .
  10. ↑ Genes: Pfkl. In: mousephenotype.org. International Mouse Phenotyping Consortium, accessed November 2, 2019 .
  11. ↑ PFKL TM1A (EUCOMM) Wtsi . In: informatics.jax.org. Mouse Genome Informatics , accessed November 2, 2019 .
  12. ^ WC Skarnes, B. Rosen, AP West, M. Koutsourakis, W. Bushell, V. Iyer, AO Mujica, M. Thomas, J. Harrow, T. Cox, D. Jackson, J. Severin, P. Biggs, J. Fu, M. Nefedov, PJ de Jong, AF Stewart, A. Bradley: A conditional knockout resource for the genome-wide study of mouse gene function. In: Nature . Volume 474, number 7351, June 2011, pp. 337-342, doi : 10.1038 / nature10163 , PMID 21677750 , PMC 3572410 (free full text).
  13. ^ E. Dolgin: Mouse library set to be knockout. In: Nature . Volume 474, Number 7351, June 2011, pp. 262-263, doi : 10.1038 / 474262a , PMID 21677718 .
  14. ↑ a b c A. K. Gerdin: The Sanger Mouse Genetics Program: high throughput characterization of knockout mice. In: Acta Ophthalmologica . Volume 88, September 2010, pp. 925-927, doi : 10.1111 / j.1755-3768.2010.4142.x .
  15. ↑ L. van der Weyden, JK White, DJ Adams, DW Logan: The mouse genetics toolkit: revealing function and mechanism. In: Genome biology. Volume 12, number 6, June 2011, p. 224, doi : 10.1186 / gb-2011-12-6-224 , PMID 21722353 , PMC 3218837 (free full text) (review).