View source for Glutaryl-CoA dehydrogenase

{{Infobox gene}}
{{Infobox enzyme
| name = glutaryl-CoA dehydrogenase (decarboxylating)
| image = 
| image_size = 
| caption = 
| EC_number = 1.3.8.6
| CAS_number = 37255-38-2
| GO_code = 
}}
'''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]], [[hydroxylysine|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-[[Dalton (unit)|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 [[RNA splicing|splicing]] of this gene results in multiple [[Transcription (genetics)|transcript]] variants.<ref name="entrez">{{cite web|title=GCDH glutaryl-CoA dehydrogenase [ Homo sapiens (human) ]|url=https://www.ncbi.nlm.nih.gov/gene/2639|website=NCBI|accessdate=6 August 2015}}</ref>

==Structure==
GCDH is a tetramer with [[tetrahedral symmetry]], which allows it to be seen as a [[Dimer (chemistry)|dimer]] of dimers. Its structure is very similar to other ACDs but the overall [[polypeptide|polypeptide fold]] of the GCDH is made up of three domains: an [[alpha-helical|alpha-helical bundle]] [[amino-terminal]] domain, a [[beta-sheet|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 [[active site|substrate-binding pocket]] is filled with a string of three [[water molecules]], which gets displaced when the [[Substrate (biology)|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.<ref name="pmid15274622">{{cite journal | vauthors = Fu Z, Wang M, Paschke R, Rao KS, Frerman FE, Kim JJ | title = Crystal structures of human glutaryl-CoA dehydrogenase with and without an alternate substrate: structural bases of dehydrogenation and decarboxylation reactions | journal = Biochemistry | volume = 43 | issue = 30 | pages = 9674–84 | date = August 2004 | pmid = 15274622 | doi = 10.1021/bi049290c }}</ref> The GCDH gene is mapped onto 19p13.2 and has an [[exon]] count of 15.<ref name="pmid24973495">{{cite journal | vauthors = Georgiou T, Nicolaidou P, Hadjichristou A, Ioannou R, Dionysiou M, Siama E, Chappa G, Anastasiadou V, Drousiotou A | title = Molecular analysis of Cypriot patients with Glutaric aciduria type I: identification of two novel mutations | journal = Clinical Biochemistry | volume = 47 | issue = 13-14 | pages = 1300–5 | date = September 2014 | pmid = 24973495 | doi = 10.1016/j.clinbiochem.2014.06.017 }}</ref>

== 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 [[proton|alpha-proton]] of the substrate by the Glu370 catalytic base. [[Hydride]] is then transferred from the [[carbon|beta-carbon]] of the substrate to the N(5) of the FAD, yielding the 2e<sup>−</sup>-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 [[anion|dienolate anion]], a proton, and CO<sub>2</sub>. The dienolate intermediate is protonated, resulting in crotonyl-CoA and a release of products from the active site. Finally, the 2e<sup>−</sup>-reduced form of FAD is oxidized to two 1e<sup>−</sup> steps by an external electron acceptor to complete the turnover.<ref name="pmid17176108">{{cite journal | vauthors = Rao KS, Albro M, Dwyer TM, Frerman FE | title = Kinetic mechanism of glutaryl-CoA dehydrogenase | journal = Biochemistry | volume = 45 | issue = 51 | pages = 15853–61 | date = December 2006 | pmid = 17176108 | doi = 10.1021/bi0609016 }}</ref>

==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 [[hydroxyglutaric acid|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|encephalitis-like crises]], [[spasticity]], [[dystonia]], [[choreoathetosis]], [[ataxia]], [[dyskinesia]] and [[seizure]] and are prevalent one in every 100,000 individuals.<ref name="pmid24973495"/> 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.<ref name="pmid15274622"/>

== Interactions ==
GCDH has been seen to interact with:
* [[glutaryl-CoA]]

== References ==
{{Reflist}}

== External links ==
{{Portal|Chemistry|Molecular and Cellular Biology|Biotechnology}}
* {{MeshName|Glutaryl-CoA+dehydrogenase}}

{{Amino acid metabolism enzymes}}
{{CH-CH oxidoreductases}}
{{enzymes}}
{{Use dmy dates|date=April 2017}}

[[Category:EC 1.3.8]]