PFKM

from Wikipedia, the free encyclopedia
Muscle phosphofructokinase
other names
  • ATP-PFK, PFKA
  • GSD7, PFKX
  • PFK-1, PFK1, PPP1R122

Existing structural data : 4OMT

Properties of human protein
Mass / length primary structure 780 amino acids, 85183 Da
(isoform 1)
Identifier
Gene name PFKM
External IDs
Enzyme classification
EC, category 2.7.1.11
Orthologue
human House mouse
Entrez 5213 18642
Ensemble ENSG00000152556 ENSMUSG00000033065
UniProt P08237 P47857
Refseq (mRNA) NM_000289 NM_001163487
Refseq (protein) NP_000280 NP_001156959
Gene locus Chr 12: 48.11 - 48.15 Mb Chr 15: 98.09 - 98.13 Mb
PubMed search 5213 18642

The muscle-phosphofructokinase (English: phosphofructokinase, muscle type , PFKM ) is an enzyme , the muscle (M) - 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 . PFKM is the same PFKM - gene that in humans to chromosome 12 is, encoded .

A lack of PFKM in the muscles causes an abnormal accumulation of glucose-6-phosphate and fructose-6-phosphate and can lead to Tarui disease .

structure

gene

The PFKM gene is located on chromosome 12. The coding region in PFKM is only 68% similar to that of the liver- type PFKL.

protein

The 85  kDa protein is one of three types of subunits that make up the five tetrameric PFK isozymes. The muscle isozyme of ( PFK1 ) consists exclusively of PFKM. The liver PFK (PFK-5) only contains the second subunit type, PFKL, while the erythrocyte PFK contains five isozymes, which are composed of various combinations of PFKM and PFKL. These subunits evolved from a common prokaryotic ancestor through gene duplication and mutation events . In general, the N -terminus of the subunits exerts their catalytic activity, while the C -terminus contains allosteric ligand binding sites .

function

The PFKM 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, PFKM 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.

Although the PFKM subunit is primarily incorporated into muscle and erythrocyte PFK, PFKM is also expressed in the heart, brain, and testes.

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. It has been shown that mutations in the PFKM gene cause Tarui disease due to homozygosity for catalytically inactive M subunits. It has been confirmed that PFKM is implicated in muscle PFK deficiency with early onset hyperuricemia .

Although PFKM drives glycolysis, its overexpression has been linked to type 2 diabetes and insulin resistance in skeletal muscle . One possible explanation suggests that the overexpression is supposed to compensate for the allosteric inhibition of PFK1 through excessive oxidation of free fatty acids and the accumulation of citrate and acetyl-CoA .

Individual evidence

  1. ^ Donald Voet, Judith G. Voet, Charlotte W. Pratt: Textbook of Biochemistry . 3. Edition. John Wiley & Sons, 2019, ISBN 978-3-527-82123-5 , pp. 644 ( limited preview in Google Book search).
  2. ↑ phosphofructokinase, muscle (human)
  3. ↑ 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 .
  4. ↑ a b c d 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).
  5. ↑ a b c d 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).
  6. ↑ 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 .
  7. ↑ 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).
  8. ^ 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 .
  9. ↑ A. Kahn, MC Meienhofer, D. Cottreau, JL Lagrange, JC Dreyfus: Phosphofructokinase (PFK) isozymes in man. I. Studies of adult human tissues. In: Human Genetics. Volume 48, Number 1, April 1979, pp. 93-108, doi : 10.1007 / bf00273280 , PMID 156693 .
  10. ↑ a b S. Keildson, J. Fadista, C. Ladenvall, Hedman, T. Elgzyri, KS Small, E. Grundberg, AC Nica, D. Glass, JB Richards, A. Barrett, J. Nisbet, HF Zheng, T Rönn, K. Ström, KF Eriksson, I. Prokopenko, TD Spector, ET Dermitzakis, P. Deloukas, MI McCarthy, J. Rung, L. Groop, PW Franks, CM Lindgren, O. Han: Expression of phosphofructokinase in skeletal muscle is influenced by genetic variation and associated with insulin sensitivity. In: Diabetes. Volume 63, number 3, March 2014, pp. 1154–1165, doi : 10.2337 / db13-1301 , PMID 24306210 , PMC 3931395 (free full text).