View source for Biology:Methylglutaconyl-CoA hydratase

{{short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''3-Methylglutaconyl-CoA hydratase''', also known as '''MG-CoA hydratase''' and '''AUH''', is an [[Biology:Enzyme|enzyme]] ({{EnzExplorer|4.2.1.18}}) encoded by the ''AUH'' [[Biology:Gene|gene]] on [[Biology:Chromosome 19|chromosome 19]]. It is a member of the [[Biology:Enoyl-CoA hydratase|enoyl-CoA hydratase/isomerase]] superfamily, but it is the only member of that family that is able to bind to [[Biology:RNA|RNA]]. Not only does it bind to RNA, AUH has also been observed to be involved in the metabolic enzymatic activity, making it a dual-role [[Biology:Protein|protein]].<ref name="entrez">{{cite web | title = Entrez Gene: AU RNA binding protein/enoyl-CoA hydratase | url = https://www.ncbi.nlm.nih.gov/gene/549 }}</ref> Mutations of this gene have been found to cause a disease called 3-Methylglutaconic Acuduria Type 1.<ref name="pmid21840233">{{cite journal | vauthors = Mercimek-Mahmutoglu S, Tucker T, Casey B | title = Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion | journal = Molecular Genetics and Metabolism | volume = 104 | issue = 3 | pages = 410–3 | date = Nov 2011 | pmid = 21840233 | doi = 10.1016/j.ymgme.2011.07.021 }}</ref>

== Structure ==
The enzyme AUH has a [[Physics:Molecular mass|molecular mass]] of 32 kDa and the AUH gene consists of 18 exons, is 1.7 [[Biology:Base pair|kb]] long, and is mainly found in kidney, [[Biology:Skeletal muscle|skeletal muscle]], [[Biology:Heart|heart]], [[Biology:Liver|liver]], and [[Biology:Spleen|spleen]] cells. AUH has a similar fold that is found in other members of the enoyl-CoA hydratase/isomerase family; however, it is a hexamer as a [[Chemistry:Dimer|dimer]] of trimers. Also unlike other members of its family, AUH's surface is positively charged in contrast to the negative charge seen on that of other classes. Between the two trimers of the enzyme, wide clefts were seen with a highly positive charge and lysine residues in alpha helix H1. These [[Chemistry:Lysine|lysine]] residues were shown to be the main reason why AUH is able to bind to RNA rather than its counterparts.<ref name="pmid11738050">{{cite journal | vauthors = Kurimoto K, Fukai S, Nureki O, Muto Y, Yokoyama S | title = Crystal structure of human AUH protein, a single-stranded RNA binding homolog of enoyl-CoA hydratase | journal = Structure | volume = 9 | issue = 12 | pages = 1253–63 | date = Dec 2001 | pmid = 11738050 | doi=10.1016/s0969-2126(01)00686-4| doi-access = free }}</ref> Moreover, it has been found that the oligomeric state of AUH depends on whether or not RNA is present. If RNA is near, the AUH will take on an asymmetric shape that loses the 3- and 2-fold crystallographic rotation axes, because of realignment of the internal 3-fold axes of the trimers. Because this enzyme has weak, short-chain [[Biology:Enoyl-CoA hydratase|enoyl-CoA hydratase]] activity, AUH also has a hydrase active-site pocket created by H2A-H3 alpha-helices and the H4A 310 helix of one subunit, and the H8 and H9 alpha-helices of the adjacent subunit within the same trimer. This active-site pocket is not affected by the change in oligomeric state when AUH is in the presence of RNA.<ref name="pmid18831052">{{cite journal | vauthors = Kurimoto K, Kuwasako K, Sandercock AM, Unzai S, Robinson CV, Muto Y, Yokoyama S | title = AU-rich RNA-binding induces changes in the quaternary structure of AUH | journal = Proteins | volume = 75 | issue = 2 | pages = 360–72 | date = May 2009 | pmid = 18831052 | doi = 10.1002/prot.22246 | s2cid = 44523407 }}</ref>

== Function ==
AUH is seen to catalyze the transformation of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl CoA in the [[Chemistry:Leucine|leucine]] [[Biology:Catabolism|catabolism]] pathway. Localized in the mitochondria, AUH is responsible for the fifth step in the leucine degradation pathway and deficiencies in this enzyme's activity leads to a metabolic block in which  3-methylglutaconyl-CoA, accumulates in the [[Biology:Mitochondrial matrix|mitochondrial matrix]]. Also, these [[Chemistry:Organic redox reaction|reductions]] in the enzyme's activity leads to increases in 3-methylglutaric acid and 3-hydroxyisovaleric acid.<ref name="pmid16640564">{{cite journal | vauthors = Mack M, Schniegler-Mattox U, Peters V, Hoffmann GF, Liesert M, Buckel W, Zschocke J | title = Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism | journal = The FEBS Journal | volume = 273 | issue = 9 | pages = 2012–22 | date = May 2006 | pmid = 16640564 | doi = 10.1111/j.1742-4658.2006.05218.x | s2cid = 6261362 | doi-access = free }}</ref>  Another function of AUH is that it binds to an [[Biology:AU-rich element|AU-rich element]] (ARE), containing clusters of the penta-[[Biology:Nucleotide|nucleotide]] AUUUA. AREs have been found in the 3’-untranslated regions of mRNA and they promote mRNA [[Chemistry:Polymer degradation|degradation]]. By binding with ARE, AUH has been suggested to play a role in [[Biology:Neuron|neuron]] survival and transcript stability.<ref name="pmid18831052"/> AUH is also responsible for regulating  mitochondrial protein synthesis and is essential for mitochondrial RNA [[Biology:Metabolism|metabolism]], [[Biology:Biogenesis|biogenesis]], [[Biology:Morphology|morphology]], and function. Decreased levels of AUH also lead to slower cell expansion and [[Biology:Cell growth|cell growth]]. These functions allow AUH to show us that there could be a potential connection between mitochondrial metabolism and gene regulation. Also, reduced or overexprsessed levels of AUH can lead to defects in [[Biology:Translation|mitochondrial translation]], ultimately leading up to changes in mitochondrial morphology, decreased RNA stability, biogenesis, and respiratory function.<ref name="pmid24598254">{{cite journal | vauthors = Richman TR, Davies SM, Shearwood AM, Ermer JA, Scott LH, Hibbs ME, Rackham O, Filipovska A | title = A bifunctional protein regulates mitochondrial protein synthesis | journal = Nucleic Acids Research | volume = 42 | issue = 9 | pages = 5483–94 | date = May 2014 | pmid = 24598254 | doi = 10.1093/nar/gku179 | pmc=4027184}}</ref>
{{Leucine metabolism in humans|align=center}}

== Clinical significance ==
The lack of AUH is most impactful to the human body by causing 3-Methylglutaconic Acuduria Type 1, which is an autosomal recessive disorder of leucine degradation and can range in severity from developmental delay to slowly progressive leukoencephalopathy in adults. Mutations in the ''AUH'' gene has been seen in 10 different sites (5 missense, 3 [[Biology:RNA splicing|splicing]], 1 [[Biology:Deletion (genetics)|single nucleotide deletion]] and 1 single nucleotide duplication) and are present in certain patients who have the disorder. Deletions of exons 1–3 in the gene suggest that these exons are responsible for the biochemical and clinical characteristics of 3-Methylglutaconic Acuduria Type 1.<ref name="pmid21840233"/>  These mutations cause for the deficiency of 3-methylglutaconyl-CoA hydratase which leads to the amalgamation of  3-methylglutaconyl-CoA, 3-methylglutaric acid, and 3-hydroxyisovaleric acid which eventually leads to 3-Methylglutaconic Acuduria Type 1.<ref name="pmid24598254"/>

== Interactions ==

AUH has been seen to interact with:
* ARE <ref name="pmid18831052"/>
* 3-methylglutaconyl-CoA <ref name="pmid16640564"/>

== References ==
{{reflist|33em}}

== External links ==
* {{MeshName|methylglutaconyl-CoA+hydratase}}
* {{EC number|4.2.1.18}}
* {{PDBe-KB2|Q13825|Methylglutaconyl-CoA hydratase, mitochondrial}}

{{Amino acid metabolism enzymes}}
{{Carbon-oxygen lyases}}
{{Enzymes}}

[[Category:EC 4.2.1]]

{{Sourceattribution|Methylglutaconyl-CoA hydratase}}