Electron-transferring-flavoprotein dehydrogenase
Encyclopedia
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
. 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
. Deficiency in EFT dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency
.
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 also be assayed via disproportionation
of ETF semiquinone. Both reactions are below:
Octanoyl-CoA + Q1 ↔ Q1H2 + Oct-2-enoyl-CoA
2 ETF1- ↔ ETFox + ETF2-
is in an extended conformation and is buried deeply within its functional domain 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.
Acyl-CoA
→ Acyl-CoA dehydrogenase → ETF → ETF-QO → UQ → Complex III.
(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
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. 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
therapy and are coined riboflavin-responsive MADD (RR-MADD), although due to the varying mutations causing the disease treatment and symptoms can vary considerably.
Electron-transferring flavoprotein
An electron transfer flavoprotein is a flavoprotein and functions as a specific electron acceptors for primary dehydrogenases, transferring the electrons to terminal respiratory systems such as electron-transferring-flavoprotein dehydrogenase...
in the mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
, to the ubiquinone
Coenzyme Q
Coenzyme Q10, also known as ubiquinone, ubidecarenone, coenzyme Q, and abbreviated at times to CoQ10 , CoQ, Q10, or Q, is a 1,4-benzoquinone, where Q refers to the quinone chemical group, and 10 refers to the number of isoprenyl chemical subunits in its tail.This oil-soluble, vitamin-like substance...
pool in the inner mitochondrial membrane
Inner mitochondrial membrane
The mitochondrial inner membrane forms internal compartments known as cristae, which allow greater space for the proteins such as cytochromes to function properly and efficiently. The electron transport chain is located on the inner membrane of the mitochondria...
. It is part of the electron transport chain
Electron transport chain
An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster
Iron-sulfur protein
Iron-sulfur proteins are proteins characterized by the presence of iron-sulfur clusters containing sulfide-linked di-, tri-, and tetrairon centers in variable oxidation states...
. Deficiency in EFT dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency
Glutaric acidemia type 2
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...
.
Enzyme Reaction
The overall reaction catalyzed by ETF-QO is as follows:ETF-QO(red) + ubiquinone ↔ ETF-QO(ox) + ubiquinol
Ubiquinol
Ubiquinol is an electron-rich form of coenzyme Q10.The natural ubiquinol form of coenzyme Q10 is 2,3-dimethoxy-5-methyl-6-poly prenyl-1,4-benzoquinol, where the polyprenylated side chain is 9-10 units long in mammals...
Enzymatic activity is usually assayed spectrophotometrically
Spectrophotometry
In chemistry, spectrophotometry is the quantitative measurement of the reflection or transmission properties of a material as a function of wavelength...
by reaction with octanoyl-CoA as the electron donor and ubiquinone-1 as the electron acceptor. The enzyme can also also be assayed via disproportionation
Disproportionation
Disproportionation, also known as dismutation is used to describe a specific type of redox reaction in which a species is simultaneously reduced and oxidized so as to form two different products....
of ETF semiquinone. Both reactions are below:
Octanoyl-CoA + Q1 ↔ Q1H2 + Oct-2-enoyl-CoA
2 ETF1- ↔ ETFox + ETF2-
Enzyme 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. FADFAD
In biochemistry, flavin adenine dinucleotide is a redox cofactor involved in several important reactions in metabolism. FAD can exist in two different redox states, which it converts between by accepting or donating electrons. The molecule consists of a riboflavin moiety bound to the phosphate...
is in an extended conformation and is buried deeply within its functional domain domain. Multiple hydrogen bonds and a positive helix dipole modulate the redox potential of FAD and can possibly stabilize the anionic semiquinone
Semiquinone
Semiquinone is a free radical resulting from the removal of one hydrogen atom with its electron during the process of dehydrogenation of a hydroquinone to quinone or alternatively the addition of a single H atom to a quinone....
intermediate. The 4Fe4S cluster is also stabilized by extensive hydrogen bonding around the cluster and its cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
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.
Enzyme 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.Biological Function
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:Acyl-CoA
Acyl-CoA
Acyl-CoA is a group of coenzymes involved in the metabolism of fatty acids. It is a temporary compound formed when coenzyme A attaches to the end of a long-chain fatty acid inside living cells. The compound undergoes beta oxidation, forming one or more molecules of acetyl-CoA...
→ Acyl-CoA dehydrogenase → ETF → ETF-QO → UQ → Complex III.
Disease Relevance
Deficiency of ETF-QO results in a disorder known as glutaric acidemia type IIGlutaric acidemia type 2
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...
(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
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
or hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
, with other symptoms such as general weakness, liver enlargement, increased heart failure, and carnitine
Carnitine
Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids for the generation of metabolic energy. It is widely...
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
Riboflavin, also known as vitamin B2 or additive E101, is an easily absorbed micronutrient with a key role in maintaining health in humans and animals. It is the central component of the cofactors FAD and FMN, and is therefore required by all flavoproteins. As such, vitamin B2 is required for a...
therapy and are coined riboflavin-responsive MADD (RR-MADD), although due to the varying mutations causing the disease treatment and symptoms can vary considerably.
See also
- Oxidative phosphorylationOxidative phosphorylationOxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
- Electron transport chainElectron transport chainAn electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate...
- Microbial metabolismMicrobial metabolismMicrobial metabolism is the means by which a microbe obtains the energy and nutrients it needs to live and reproduce. Microbes use many different types of metabolic strategies and species can often be differentiated from each other based on metabolic characteristics...
- MetabolismMetabolismMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...