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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 substrates, and the enzyme converts the substrates into different molecules known as products. A ...
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 ba ...
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 chromosome ...
. 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, respo ...
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 cells. Their action results in the introduction of a trans double-bond between C2 ...
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, isocitr ...
of
glutaryl-CoA Glutaryl-coenzyme A is an intermediate in the metabolism of lysine and 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 gr ...
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 and amino acids. Crotonyl-coA and reductases Before a 2007 report by ...
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 transpar ...
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 Alpha_and_beta_carbon , α-amino group, an α-carboxylic acid group, and a side chain indole, making it a polar molecule with ...
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 cell ...
. It uses electron transfer flavoprotein 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, ribo ...
as a
homotetramer A tetrameric protein is a protein with a protein quaternary structure, quaternary structure of four subunits (tetrameric). Homotetramers have four identical Protein subunit, subunits (such as glutathione S-transferase), and heterotetramers are M ...
of 45- kD subunits. Mutations in this gene result in the metabolic disorder
glutaric aciduria type 1 Glutaric acidemia type 1 (GA1) is an inherited disorder in which the body is unable to completely break down the amino acids lysine, hydroxylysine and tryptophan. Excessive levels of their intermediate breakdown products (glutaric acid, glutaryl-C ...
, 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 a ...
, which allows it to be seen as a
dimer Dimer may refer to: * Dimer (chemistry), a chemical structure formed from two similar sub-units ** Protein dimer, a protein quaternary structure ** d-dimer * Dimer model, an item in statistical mechanics, based on ''domino tiling'' * Julius 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 minimalis ...
(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 "univer ...
, which gets displaced when the substrate 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 sequen ...
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 CO2. 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, mi ...
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 is ...
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 Dystonia is a neurological hyperkinetic movement disorder in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal fixed postures. The movements may resemble a tremor. Dystonia is often inten ...
,
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 diseases ...
,
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 ...
,
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 of t ...
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 los ...
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 M ...
and/or dimers.


Interactions

GCDH has been seen to interact with: *
glutaryl-CoA Glutaryl-coenzyme A is an intermediate in the metabolism of lysine and 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 gr ...


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