Electron-transferring-flavoprotein dehydrogenase (''ETF dehydrogenase'' or ''electron transfer flavoprotein-ubiquinone oxidoreductase'', ) is an enzyme that transfers electrons from

electron-transferring flavoprotein An electron transfer flavoprotein (ETF) or electron transfer flavoprotein complex (CETF) is a flavoprotein located on the matrix face of the inner mitochondrial membrane and functions as a specific electron acceptor for primary dehydrogenases, tra ...

in the

mitochondrial matrix In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribo ...

, to the

ubiquinone Coenzyme Q, also known as ubiquinone and marketed as CoQ10, is a coenzyme family that is ubiquitous in animals and most bacteria (hence the name ubiquinone). In humans, the most common form is coenzyme Q10 or ubiquinone-10. It is a 1,4-benzoq ...

pool in the

inner mitochondrial membrane The inner mitochondrial membrane (IMM) is the mitochondrial membrane which separates the mitochondrial matrix from the intermembrane space. Structure The structure of the inner mitochondrial membrane is extensively folded and compartmentalized. T ...

. It is part of the

electron transport chain An electron transport chain (ETC) is a series of protein complexes and other molecules that transfer electrons from electron donors to electron acceptors via redox reactions (both reduction and oxidation occurring simultaneously) and couples th ...

. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster. In humans, it is encoded by the

ETFDH Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ''ETFDH'' gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron tran ...

gene. Deficiency in ETF dehydrogenase causes the human

genetic disease A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

multiple acyl-CoA dehydrogenase deficiency Glutaric acidemia type 2 is an autosomal recessive metabolic disorder that is characterised by defects in the ability of the body to use proteins and fats for energy. Incompletely processed proteins and fats can build up, leading to a dangerous c ...

Function

ETQ-QO links the oxidation of

fatty acids In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...

and some

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

to oxidative phosphorylation in the mitochondria. Specifically, it catalyzes the transfer of electrons from

electron transferring flavoprotein An electron transfer flavoprotein (ETF) or electron transfer flavoprotein complex (CETF) is a flavoprotein located on the matrix face of the inner mitochondrial membrane and functions as a specific electron acceptor for primary dehydrogenases, tra ...

(ETF) to ubiquinone, reducing it to ubiquinol. The entire sequence of transfer reactions is as follows:

Acyl-CoA Acyl-CoA is a group of coenzymes that metabolize fatty acids. Acyl-CoA's are susceptible to beta oxidation, forming, ultimately, acetyl-CoA. The acetyl-CoA enters the citric acid cycle, eventually forming several equivalents of ATP. In this way ...

→

Acyl-CoA dehydrogenase Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 ...

→ ETF → ETF-QO → UQ →

Complex III Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...

Catalyzed reaction

The overall reaction catalyzed by ETF-QO is as follows: ETF-QO(red) + ubiquinone ↔ ETF-QO(ox) +

ubiquinol A ubiquinol is an electron-rich (reduced) form of coenzyme Q (ubiquinone). The term most often refers to ubiquinol-10, with a 10-unit tail most commonly found in humans. The natural ubiquinol form of coenzyme Q is 2,3-dimethoxy-5-methyl-6-poly p ...

Enzymatic activity is usually assayed spectrophotometrically by reaction with

octanoyl-CoA Octanoyl-coenzyme A is the endpoint of beta oxidation in peroxisomes. It is produced alongside acetyl-CoA and transferred to the mitochondria to be further oxidized into acetyl-CoA. See also *Caprylic acid Caprylic acid (), also known under ...

as the electron donor and ubiquinone-1 as the electron acceptor. The enzyme can also be assayed via

disproportionation In chemistry, disproportionation, sometimes called dismutation, is a redox reaction in which one compound of intermediate oxidation state converts to two compounds, one of higher and one of lower oxidation states. More generally, the term can b ...

of ETF semiquinone. Both reactions are below: Octanoyl-CoA + Q₁ ↔ Q₁H₂ + Oct-2-enoyl-CoA 2 ETF_1- ↔ ETF_ox + ETF_2-

Structure

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.

FAD A fad or trend is any form of collective behavior that develops within a culture, a generation or social group in which a group of people enthusiastically follow an impulse for a short period. Fads are objects or behaviors that achieve short- ...

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 Semiquinone (or ubisemiquinone) is a free radical resulting from the removal of one hydrogen atom with its electron during the process of dehydrogenation of a hydroquinone, such as hydroquinone itself or catechol, to a quinone or alternatively the ...

intermediate. The 4Fe4S cluster is also stabilized by extensive hydrogen bonding around the cluster and its

cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...

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.

Mechanism

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.

Clinical significance

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. Complications can involve

acidosis Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma. The term ''acidemia'' describes t ...

hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...

, with other symptoms such as general weakness, liver enlargement, increased heart failure, and

carnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids into mitochondria to be oxidized for energy production, an ...

deficiency. More severe cases involve congenital defects and full metabolic crisis. 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. Milder forms of the disorder have been responsive to

riboflavin Riboflavin, also known as vitamin B2, is a vitamin found in food and sold as a dietary supplement. It is essential to the formation of two major coenzymes, flavin mononucleotide and flavin adenine dinucleotide. These coenzymes are involved in ...

therapy and are coined riboflavin-responsive MADD (RR-MADD), although due to the varying mutations causing the disease treatment and symptoms can vary considerably.

References

External links

ENZYME entry on EC 1.5.5.1BRENDA entry on EC 1.5.5.1
* {{Portal, Biology Cellular respiration Metabolism EC 1.5.5