Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an
enzyme
An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''ETFDH''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. This gene encodes a component of the
electron-transfer system in
mitochondria
A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...
and is essential for
electron transfer
Electron transfer (ET) occurs when an electron relocates from an atom, ion, or molecule, to another such chemical entity. ET describes the mechanism by which electrons are transferred in redox reactions.
Electrochemical processes are ET reactio ...
from a number of mitochondrial
flavin-containing
dehydrogenase
A dehydrogenase is an enzyme belonging to the group of oxidoreductases that oxidizes a substrate by reducing an electron acceptor, usually NAD+/NADP+ or a flavin coenzyme such as FAD or FMN. Like all catalysts, they catalyze reverse as well as ...
s to the main respiratory chain.
Function
Electron-transferring-flavoprotein dehydrogenase 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 ...
accepts electrons from
electron-transfer flavoprotein which is located in the
mitochondrial matrix
In the mitochondrion, the matrix is the space within the inner membrane. It can also be referred as the mitochondrial fluid. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitoc ...
and
reduces ubiquinone
Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring Cofactor (biochemistry), biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, ...
in the mitochondrial membrane. Deficiency in electron-transferring-flavoprotein dehydrogenase have been demonstrated in some patients with
type II glutaric aciduria.
Structure
The ''ETFDH'' gene is located on the q arm of
chromosome 4
Chromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 190 million base pairs (the building material of DNA) and represents between 6 and 6.5 percent of the to ...
in position 32.1 and has 13
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
s spanning 36,613 base pairs.
The protein is
synthesized as a 67-kDa
precursor which is
targeted to mitochondria and processed in a single step to a 64-kDa mature form located in the mitochondrial membrane.
This 64-kDA mature form is a monomer
integrated into the mitochondrial inner membrane, containing a
4Fe-4S cluster and 1 molecule of
FAD
A fad, trend, or craze 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 time period.
Fads are objects or behaviors tha ...
.
Function
This enzyme, along with electron transfer flavoprotein (ETF), is required for electron transfer from more than 9 mitochondrial flavin-containing dehydrogenases to the main respiratory chains.
It accepts electrons from ETF and reduces ubiquinone.
Clinical Significance
Mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in the ''ETFDH'' can cause glutaric aciduria 2C (GA2C), an
autosomal recessively inherited disorder of
fatty acid
In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an ...
,
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
, and
choline
Choline is a cation with the chemical formula . Choline forms various Salt (chemistry), salts, such as choline chloride and choline bitartrate. An essential nutrient for animals, it is a structural component of phospholipids and cell membrane ...
metabolism. It is characterized by multiple
acyl-CoA dehydrogenase deficiencies resulting in large excretion not only of
glutaric acid, but also of
lactic,
ethylmalonic,
butyric,
isobutyric,
2-methyl-butyric, and
isovaleric acid
Isovaleric acid, also known as 3-methylbutanoic acid or β-methylbutyric acid, is a branched-chain alkyl carboxylic acid with the chemical formula (CH3)2CHCH2CO2H. It is classified as a short-chain fatty acid. Like other low-molecular-weight car ...
s.
A c.250G>A (p.Ala84Thr) mutation, the most common mutation in the ''ETFDH'' gene, causes increased production of
reactive oxygen species
In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...
(ROS) and shortened
neurite
A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture ...
s in cells
expressing this mutant compared to
wild type
The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, " ...
cells.
Suberic acid
Suberic acid, also octanedioic acid, is a dicarboxylic acid
In organic chemistry, a dicarboxylic acid is an organic compound containing two carboxyl groups (). The general molecular formula for dicarboxylic acids can be written as , where R ca ...
, an accumulated
intermediate metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
in dehydrogenase deficiency, can significantly impair neurite outgrowth in
NSC34 cells. This shortening of neurites can be restored by
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 ...
,
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 from the cytosol into mitochondria to be oxidized for f ...
, or
Coenzyme Q10
Coenzyme Q10 (CoQ10 ), also known as ubiquinone, is a naturally occurring biochemical cofactor (coenzyme) and an antioxidant produced by the human body. It can also be obtained from dietary sources, such as meat, fish, seed oils, vegetables, ...
supplements.
Interactions
The encoded protein
interacts with
MYH7B,
LINC00174,
LINC00574,
Homeobox protein goosecoid-2,
AIRE,
OTX1
Homeobox protein OTX1 is a protein that in humans is encoded by the ''OTX1'' gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is tra ...
,
Keratin-associated protein 13-2,
Keratin-associated protein 11-1,
TRIM69,
Zinc finger protein 581, and
COX6B1.
References
Further reading
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