Glutaryl-CoA dehydrogenase (GCDH) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
encoded by the GCDH
gene
In biology, the word gene (from , ; "... Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
on
chromosome 19
Chromosome 19 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 19 spans more than 58.6 million base pairs, the building material of DNA. It is considered the most gene-rich chromosom ...
. The
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respon ...
belongs to the
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 cell (biology), cells. Their action results in the introduction of a :wikt:trans-, tra ...
family (ACD). It catalyzes the
oxidative decarboxylation
Oxidative decarboxylation is a decarboxylation reaction caused by oxidation. Most are accompanied by α- Ketoglutarate α- Decarboxylation caused by dehydrogenation of hydroxyl carboxylic acids such as carbonyl carboxylic acid, malic acid, isocitri ...
of
glutaryl-CoA to
crotonyl-CoA
Crotonyl-coenzyme A is an intermediate in the fermentation of butyric acid, and in the metabolism of lysine and tryptophan. It is important in the metabolism of fatty acids
In chemistry, particularly in biochemistry, a fatty acid is a carboxyl ...
and
carbon dioxide
Carbon dioxide ( chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is t ...
in the degradative pathway of
L-lysine
Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −CO ...
,
L-hydroxylysine, and
L-tryptophan
Tryptophan (symbol Trp or W)
is an α-amino acid that is used in the biosynthesis of proteins. Tryptophan contains an α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with a non-polar aromatic ...
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run c ...
. It uses
electron transfer 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 ...
as its electron acceptor. The enzyme exists 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, ri ...
as a
homotetramer
A tetrameric protein is a protein with a quaternary structure of four subunits (tetrameric). Homotetramers have four identical subunits (such as glutathione S-transferase), and heterotetramers are complexes of different subunits. A tetramer ca ...
of 45-
kD subunits. Mutations in this gene result in the metabolic disorder
glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative
splicing of this gene results in multiple
transcript variants.
Structure
GCDH is a tetramer with
tetrahedral symmetry
150px, A regular tetrahedron, an example of a solid with full tetrahedral symmetry
A regular tetrahedron has 12 rotational (or orientation-preserving) symmetries, and a symmetry order of 24 including transformations that combine a reflection ...
, which allows it to be seen as a
dimer of dimers. Its structure is very similar to other ACDs but the overall
polypeptide fold of the GCDH is made up of three domains: an
alpha-helical bundle amino-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
domain, a
beta-sheet domain in the middle, and another alpha-helical domain at the
carboxyl terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
. The
flavin adenine dinucleotide
Flavin may refer to:
Placename
* Flavin, Aveyron, a commune in southern France
Surname
* Adrian Flavin (born 1979), a professional rugby player
* Christopher Flavin, president of the Worldwatch Institute
* Dan Flavin (1933–1996), a minimali ...
(FAD) is located at the junction between the middle beta-strand and the carboxyl terminal alpha-helix domain of one subunit and the carboxyl-terminal domain of the neighboring subunit. The most distinct difference between GCDH and other ACDs in terms of structure is the carboxyl and amino-terminal regions of the monomer and in the loop between beta-strands 4 and 5 because it is only made up of four residues, whereas other ACDs have much more. The
substrate-binding pocket is filled with a string of three
water molecules
Water () is a polar inorganic compound that is at room temperature a tasteless and odorless liquid, which is nearly colorless apart from an inherent hint of blue. It is by far the most studied chemical compound and is described as the "unive ...
, which gets displaced when the
substrate
Substrate may refer to:
Physical layers
*Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached
** Substrate (locomotion), the surface over which an organism lo ...
binds to the enzyme. The binding pocket is also smaller than some of the other ACD binding pockets because it is responsible for the chain-length specificity of GCDH for alternate substrates.
The GCDH gene is mapped onto 19p13.2 and has an
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 sequenc ...
count of 15.
Function
GCDH is mainly known for the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and carbon dioxide, which is common in the mitochondrial oxidation of lysine, tryptophan, and hydroxylysine. The way it completes this task is through a series of physical, chemical, and electron-transfer steps. It first binds glutaryl-CoA substrate to the oxidized form of the enzyme and abstracts the
alpha-proton of the substrate by the Glu370 catalytic base.
Hydride
In chemistry, a hydride is formally the anion of hydrogen( H−). The term is applied loosely. At one extreme, all compounds containing covalently bound H atoms are called hydrides: water (H2O) is a hydride of oxygen, ammonia is a hydride of ...
is then transferred from the
beta-carbon of the substrate to the N(5) of the FAD, yielding the 2e
−-reduced form of FAD. Thus, this allows for the decarboxylation of glutaconyl-CoA, an enzyme-bound intermediate, by breaking the Cγ-Cδ bond, resulting in formation of a
dienolate anion, a proton, and CO
2. The dienolate intermediate is protonated, resulting in crotonyl-CoA and a release of products from the active site. Finally, the 2e
−-reduced form of FAD is oxidized to two 1e
− steps by an external electron acceptor to complete the turnover.
Clinical significance
Mutations
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, mitosi ...
in the GCDH gene can lead to defects in the enzyme encoded by it which leads to the formation and accumulation of the
metabolites
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 ...
glutaric acid
Glutaric acid is the organic compound with the formula C3H6(COOH)2 . Although the related "linear" dicarboxylic acids adipic and succinic acids are water-soluble only to a few percent at room temperature, the water-solubility of glutaric acid ...
and
3-hydroxyglutaric acid as well as glutarylcarnitine in body fluids, which essentially leads to glutaric aciduria type I, an autosomal recessive metabolic disorder. Symptoms for this disease include:
macrocephaly
Macrocephaly is a condition in which circumference of the human head is abnormally large. It may be pathological or harmless, and can be a familial genetic characteristic. People diagnosed with macrocephaly will receive further medical tests to ...
, acute
encephalitis-like crises,
spasticity
Spasticity () is a feature of altered skeletal muscle performance with a combination of paralysis, increased tendon reflex activity, and hypertonia. It is also colloquially referred to as an unusual "tightness", stiffness, or "pull" of muscles ...
,
dystonia,
choreoathetosis
Choreoathetosis is the occurrence of involuntary movements in a combination of chorea (irregular migrating contractions) and athetosis (twisting and writhing).
It is caused by many different diseases and agents. It is a symptom of several disease ...
,
ataxia
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of t ...
,
dyskinesia
Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Dyskinesia can be anything from a slight tremor o ...
and
seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with l ...
and are prevalent one in every 100,000 individuals.
[ Mutations in the carboxyl-terminal of GCDH have been most identified in patients with glutaric aciduria type I; more specifically, mutations in Ala389Val, Ala389Glu, Thr385Met, Ala377Val, and Ala377Thr all seem to be associated with the disorder because they dissociate to inactive ]monomers
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
...
and/or dimers.[
]
Interactions
GCDH has been seen to interact with:
* glutaryl-CoA
References
External links
*
PDBe-KB
provides an overview of all the structure information available in the PDB for Human Glutaryl-CoA dehydrogenase, mitochondrial
{{Use dmy dates, date=April 2017
EC 1.3.8