Electron-transferring-flavoprotein dehydrogenase

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Electron-transferring-flavoprotein dehydrogenase
F1.medium.gif
Ribbon diagram of electron-transferring-flavoprotein dehydrogenase with each functional domain differentially colored. Blue band is membrane area.
Identifiers
Symbol ETFD
Alt. symbols ETF-QO
Entrez 2110
HUGO 3483
OMIM 231675
PDB 2GMH (RCSB PDB PDBe PDBj)
RefSeq NM_004453
UniProt Q16134
Other data
Locus Chr. 4 q4q32.1

Electron-transferring-flavoprotein dehydrogenase (ETF dehydrogenase or electron transfer flavoprotein-ubiquinone oxidoreductase, EC 1.5.5.1) is an enzyme that transfers electrons from electron-transferring flavoprotein in the mitochondrial matrix, to the ubiquinone pool in the inner mitochondrial membrane.[1][2] It is part of the electron transport chain. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster.[3] Deficiency in EFT dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency.[4]

Enzyme reaction[edit]

The overall reaction catalyzed by ETF-QO is as follows:[5]

ETF-QO(red) + ubiquinone ↔ ETF-QO(ox) + ubiquinol

Enzymatic activity is usually assayed spectrophotometrically by reaction with octanoyl-CoA as the electron donor and ubiquinone-1 as the electron acceptor. The enzyme can also be assayed via disproportionation of ETF semiquinone. Both reactions are below:[6][7]

Octanoyl-CoA + Q1 ↔ Q1H2 + Oct-2-enoyl-CoA

2 ETF1- ↔ ETFox + ETF2-

Enzyme structure[edit]

ETF-QO consists of one structural domain with three functional domains packed in close proximity: a FAD domain, a 4Fe4S cluster domain, and a UQ-binding domain.[8]

ETF-QO functional domains
ETF-QO Functional Domains

FAD is in an extended conformation and is buried deeply within its functional domain. Multiple hydrogen bonds and a positive helix dipole modulate the redox potential of FAD and can possibly stabilize the anionic semiquinone intermediate. The 4Fe4S cluster is also stabilized by extensive hydrogen bonding around the cluster and its cysteine components. Ubiquinone binding is achieved through a deep hydrophobic binding pocket which is a different mode than other UQ-binding proteins such as succinate-Q oxidoreductase. Although ETF-QO is an integral membrane protein, it does not traverse the entire membrane unlike other UQ-binding proteins.[citation needed]

Enzyme mechanism[edit]

The exact mechanism for the reduction is unknown, although there are two hypothesized pathways. The first pathway is the transferral of electrons from one electron reduced ETF one at a time to the lower potential FAD center. One electron is transferred from the reduced FAD to the iron cluster, resulting in a two electron reduced state with one electron each on the FAD and cluster domains. Then, the bound ubiquinone is reduced to ubiquinol, at least transiently forming the singly reduced semiubiquinone. The second pathway involves the donation of electrons from ETF to the iron cluster, followed by internal transitions between the two electron centers. After equilibration, the rest of the pathway follows as above.[citation needed]

Biological function[edit]

ETQ-QO links the oxidation of fatty acids and some amino acids to oxidative phosphorylation in the mitochondria. Specifically, it catalyzes the transfer of electrons from electron transferring flavoprotein (ETF) to ubiquinone, reducing it to ubiquinol. The entire sequence of transfer reactions is as follows:[citation needed]

Acyl-CoAAcyl-CoA dehydrogenase → ETF → ETF-QO → UQ → Complex III.

Disease relevance[edit]

Deficiency of ETF-QO results in a disorder known as glutaric acidemia type II (also known as MADD for multiple acyl-CoA dehydrogenase deficiency), in which there is an improper buildup of fats and proteins in the body.[9] Complications can involve acidosis or hypoglycemia, with other symptoms such as general weakness, liver enlargement, increased heart failure, and carnitine deficiency. More severe cases involve congenital defects and full metabolic crisis.[10][11][12] Genetically, it is an autosomal recessive disorder, making its occurrence fairly rare. Most affected patients are the result of single point mutations around the FAD ubiquinone interface.[13][14] Milder forms of the disorder have been responsive to riboflavin therapy and are coined riboflavin-responsive MADD (RR-MADD), although due to the varying mutations causing the disease treatment and symptoms can vary considerably.[15][16]

See also[edit]

References[edit]

  1. ^ Ghisla, Sandro; Thorpe, Colin (2004). "Acyl-CoA dehydrogenases. A mechanistic overview". European Journal of Biochemistry 271 (3): 494–508. doi:10.1046/j.1432-1033.2003.03946.x. PMID 14728676. 
  2. ^ He, M.; Rutledge, S.L.; Kelly, D.R.; Palmer, C.A.; Murdoch, G.; Majumder, N.; Nicholls, R.D.; Pei, Z. et al. (2007). "A New Genetic Disorder in Mitochondrial Fatty Acid β-Oxidation: ACAD9 Deficiency". The American Journal of Human Genetics 81 (1): 87–103. doi:10.1086/519219. PMC 1950923. PMID 17564966. 
  3. ^ Watmough, Nicholas J.; Frerman, Frank E. (2010). "The electron transfer flavoprotein: Ubiquinone oxidoreductases". Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797 (12): 1910–1916. doi:10.1016/j.bbabio.2010.10.007. 
  4. ^ Vianey-Liaud, C; Divry, P; Gregersen, N; Mathieu, M (1987). "The inborn errors of mitochondrial fatty acid oxidation". Journal of Inherited Metabolic Disease. 10 Suppl 1: 159–200. PMID 3119938. 
  5. ^ Ramsay, RR; Steenkamp, DJ; Husain, M (1987). "Reactions of electron-transfer flavoprotein and electron-transfer flavoprotein: ubiquinone oxidoreductase". The Biochemical journal 241 (3): 883–92. PMC 1147643. PMID 3593226. 
  6. ^ Beckmann, Joe D.; Frerman, Frank E. (1985). "Reaction of electron-transfer flavoprotein with electron transfer flavoprotein-ubiquinone oxidoreductase". Biochemistry 24 (15): 3922–3925. doi:10.1021/bi00336a017. PMID 2996585. 
  7. ^ Watmough, Nicholas J.; Loehr, James P.; Drake, Steven K.; Frerman, Frank E. (1991). "Tryptophan fluorescence in electron-transfer flavoprotein:ubiquinone oxidoreductase: fluorescence quenching by a brominated pseudosubstrate". Biochemistry 30 (5): 1317–1323. doi:10.1021/bi00219a023. PMID 1991113. 
  8. ^ Zhang, J.; Frerman, F. E.; Kim, J.-J. P. (2006). "Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and electron transfer to the mitochondrial ubiquinone pool". Proceedings of the National Academy of Sciences 103 (44): 16212–16217. doi:10.1073/pnas.0604567103. PMC 1637562. PMID 17050691. 
  9. ^ Frerman, F. E.; Goodman, S. I. (1985). "Deficiency of Electron Transfer Flavoprotein or Electron Transfer Flavoprotein:Ubiquinone Oxidoreductase in Glutaric Acidemia Type II Fibroblasts". Proceedings of the National Academy of Sciences 82 (13): 4517–4520. doi:10.1073/pnas.82.13.4517. 
  10. ^ Galloway, JH; Cartwright, IJ; Bennett, MJ (1987). "Abnormal myocardial lipid composition in an infant with type II glutaric aciduria". Journal of lipid research 28 (3): 279–84. PMID 3572253. 
  11. ^ Singla, Mohit; Guzman, Grace; Griffin, Andrew J.; Bharati, Saroja (2007). "Cardiomyopathy in Multiple Acyl-CoA Dehydrogenase Deficiency". Pediatric Cardiology 29 (2): 446–451. doi:10.1007/s00246-007-9119-6. PMID 17912479. 
  12. ^ Turnbull, DM; Bartlett, K; Eyre, JA; Gardner-Medwin, D; Johnson, MA; Fisher, J; Watmough, NJ (1988). "Lipid storage myopathy due to glutaric aciduria type II: Treatment of a potentially fatal myopathy". Developmental medicine and child neurology 30 (5): 667–72. PMID 3229565. 
  13. ^ Liang, Wen-Chen; Ohkuma, Aya; Hayashi, Yukiko K.; López, Luis Carlos; Hirano, Michio; Nonaka, Ikuya; Noguchi, Satoru; Chen, Liang-Hui et al. (2009). "ETFDH mutations, CoQ10 levels, and respiratory chain activities in patients with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency". Neuromuscular Disorders 19 (3): 212–216. doi:10.1016/j.nmd.2009.01.008. PMID 19249206. 
  14. ^ Goodman, S; Binard, RJ; Woontner, MR; Frerman, FE (2002). "Glutaric acidemia type II: Gene structure and mutations of the electron transfer flavoprotein:ubiquinone oxidoreductase (ETF:QO) gene". Molecular Genetics and Metabolism 77 (1–2): 86–90. doi:10.1016/S1096-7192(02)00138-5. PMID 12359134. 
  15. ^ Olsen, R. K. J.; Olpin, S. E.; Andresen, B. S.; Miedzybrodzka, Z. H.; Pourfarzam, M.; Merinero, B.; Frerman, F. E.; Beresford, M. W. et al. (2007). "ETFDH mutations as a major cause of riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency". Brain 130 (8): 2045–2054. doi:10.1093/brain/awm135. PMID 17584774. 
  16. ^ Rhead, William; Roettger, Vickie; Marshali, Teresa; Amendt, Brad (1993). "Multiple Acyl-Coenzyme A Dehydrogenation Disorder Responsive to Riboflavin: Substrate Oxidation, Flavin Metabolism, and Flavoenzyme Activities in Fibroblasts". Pediatric Research 33 (2): 129–135. doi:10.1203/00006450-199302000-00008. PMID 8433888. 

External links[edit]