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glutaryl-CoA dehydrogenase (decarboxylating)
glutaryl-CoA dehydrogenase (decarboxylating)
Identifiers
EC no.	1.3.8.6
CAS no.	37255-38-2
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
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NCBI	proteins

GCDH
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1SIQ, 1SIR, 2R0M, 2R0N
Identifiers
Aliases	GCDH, ACAD5, GCD, glutaryl-CoA dehydrogenase, Glutaryl-Coenzyme A dehydrogenase
External IDs	OMIM: 608801; MGI: 104541; HomoloGene: 130; GeneCards: GCDH; OMA:GCDH - orthologs
Gene location (Human)
Chr.	Chromosome 19 (human)
End	12,914,207 bp
Gene location (Mouse)
Chr.	Chromosome 8 (mouse)
End	85,620,550 bp
RNA expression pattern
	Top expressed in
	right lobe of liver; ; apex of heart; ; left ventricle; ; right ovary; ; gastrocnemius muscle; ; left ovary; ; mucosa of transverse colon; ; body of stomach; ; muscle of thigh; ; right adrenal gland;
	Top expressed in
	right kidney; ; human kidney; ; left lobe of liver; ; proximal tubule; ; Ileal epithelium; ; cardiac muscle tissue of left ventricle; ; interventricular septum; ; extraocular muscle; ; choroid plexus of fourth ventricle; ; extensor digitorum longus muscle;
	More reference expression data
	n/a
Gene ontology
Molecular function	oxidoreductase activity, acting on the CH-CH group of donors; acyl-CoA dehydrogenase activity; oxidoreductase activity; glutaryl-CoA dehydrogenase activity; fatty-acyl-CoA binding; flavin adenine dinucleotide binding; glutaryl-CoA hydrolase activity;
Cellular component	mitochondrial matrix; mitochondrion;
Biological process	fatty-acyl-CoA biosynthetic process; tryptophan metabolic process; acyl-CoA metabolic process; fatty acid oxidation; lysine catabolic process; fatty acid beta-oxidation using acyl-CoA dehydrogenase;
	Sources:Amigo / QuickGO
Orthologs
	2639
	270076
	ENSG00000105607
	ENSMUSG00000003809
	Q92947
	Q60759
	NM_000159; NM_013976
	NM_001044744; NM_008097
	NP_000150; NP_039663
	NP_001038209; NP_032123
	Wikidata
View/Edit Human	View/Edit Mouse

Glutaryl-CoA dehydrogenase (GCDH) is an enzyme encoded by the GCDH gene on chromosome 19. The protein belongs to the acyl-CoA dehydrogenase family (ACD). It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and carbon dioxide in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer 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.^[5]

Structure

GCDH is a tetramer with tetrahedral symmetry, 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 domain, a beta-sheet domain in the middle, and another alpha-helical domain at the carboxyl terminus. The flavin adenine dinucleotide (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, 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.^[6] The GCDH gene is mapped onto 19p13.2 and has an exon count of 15.^[7]

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 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.^[8]

Clinical significance

Mutations in the GCDH gene can lead to defects in the enzyme encoded by it which leads to the formation and accumulation of the metabolites 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, acute encephalitis-like crises, spasticity, dystonia, choreoathetosis, ataxia, dyskinesia and seizure and are prevalent one in every 100,000 individuals.^[7] 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 and/or dimers.^[6]

Interactions

GCDH has been seen to interact with:

glutaryl-CoA

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000105607 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000003809 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "GCDH glutaryl-CoA dehydrogenase [ Homo sapiens (human) ]". NCBI. Retrieved 6 August 2015.
^ ^a ^b Fu Z, Wang M, Paschke R, Rao KS, Frerman FE, Kim JJ (August 2004). "Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions". Biochemistry. 43 (30): 9674–84. doi:10.1021/bi049290c. PMID 15274622.
^ ^a ^b Georgiou T, Nicolaidou P, Hadjichristou A, Ioannou R, Dionysiou M, Siama E, Chappa G, Anastasiadou V, Drousiotou A (September 2014). "Molecular analysis of Cypriot patients with Glutaric aciduria type I: identification of two novel mutations". Clinical Biochemistry. 47 (13–14): 1300–5. doi:10.1016/j.clinbiochem.2014.06.017. PMID 24973495.
^ Rao KS, Albro M, Dwyer TM, Frerman FE (December 2006). "Kinetic mechanism of glutaryl-CoA dehydrogenase". Biochemistry. 45 (51): 15853–61. doi:10.1021/bi0609016. PMID 17176108.

External links

Glutaryl-CoA+dehydrogenase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
PDBe-KB provides an overview of all the structure information available in the PDB for Human Glutaryl-CoA dehydrogenase, mitochondrial