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| Aliases | AUH, AU RNA binding protein/enoyl-CoA hydratase, Methylglutaconyl-CoA hydratase, AU RNA binding methylglutaconyl-CoA hydratase | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM:600529;MGI:1338011;HomoloGene:1284;GeneCards:AUH;OMA:AUH - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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3-Methylglutaconyl-CoA hydratase, also known asMG-CoA hydratase andAUH, is anenzyme (EC4.2.1.18) encoded by theAUHgene onchromosome 19. It is a member of theenoyl-CoA hydratase/isomerase superfamily, but it is the only member of that family that is able to bind toRNA. Not only does it bind to RNA, AUH has also been observed to be involved in themetabolic enzymatic activity, making it a dual-roleprotein.[5]Mutations of this gene have been found to cause a disease called 3-Methylglutaconic Acuduria Type 1.[6]
The enzyme AUH has amolecular mass of 32kDa and the AUH gene consists of 18exons, is 1.7kb long, and is mainly found inkidney,skeletal muscle,heart,liver, andspleen cells. AUH has a similar fold that is found in other members of the enoyl-CoA hydratase/isomerase family; however, it is ahexamer as adimer oftrimers. 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 inalpha helix H1. Theselysine residues were shown to be the main reason why AUH is able to bind to RNA rather than its counterparts.[7] Moreover, it has been found that theoligomeric 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-foldcrystallographic rotation axes, because of realignment of the internal 3-fold axes of the trimers. Because this enzyme has weak, short-chainenoyl-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.[8]
AUH is seen tocatalyze the transformation of3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl CoA in theleucinecatabolism 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 themitochondrial matrix. Also, thesereductions in the enzyme's activity leads to increases in 3-methylglutaric acid and 3-hydroxyisovaleric acid.[9] Another function of AUH is that it binds to anAU-rich element (ARE), containing clusters of the penta-nucleotide AUUUA. AREs have been found in the 3’-untranslated regions of mRNA and they promote mRNAdegradation. By binding with ARE, AUH has been suggested to play a role inneuron survival andtranscript stability.[8] AUH is also responsible for regulating mitochondrialprotein synthesis and is essential for mitochondrial RNAmetabolism,biogenesis,morphology, and function. Decreased levels of AUH also lead to slower cell expansion andcell 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 inmitochondrial translation, ultimately leading up to changes in mitochondrial morphology, decreased RNA stability, biogenesis, and respiratory function.[10]
 Muscle:α-Ketoisocaproate (α-KIC) Liver:α-Ketoisocaproate (α-KIC) Excreted in urine (10–40%) β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) β-Methylcrotonyl-CoA (MC-CoA) β-Methylglutaconyl-CoA (MG-CoA) MG-CoA hydratase Unknown enzyme  |
The lack of AUH is most impactful to the human body by causing 3-Methylglutaconic Acuduria Type 1, which is anautosomal recessive disorder of leucine degradation and can range in severity from developmental delay to slowly progressiveleukoencephalopathy in adults. Mutations in theAUH gene has been seen in 10 different sites (5missense, 3splicing, 1single nucleotide deletion and 1single 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.[6] 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.[10]
AUH has been seen to interact with:
HMB is a metabolite of the amino acid leucine (Van Koverin and Nissen 1992), an essential amino acid. The first step in HMB metabolism is the reversible transamination of leucine to [α-KIC] that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, [α-KIC] may follow one of two pathways. In the first, HMB is produced from [α-KIC] by the cytosolic enzyme KIC dioxygenase (Sabourin and Bieber 1983). The cytosolic dioxygenase has been characterized extensively and differs from the mitochondrial form in that the dioxygenase enzyme is a cytosolic enzyme, whereas the dehydrogenase enzyme is found exclusively in the mitochondrion (Sabourin and Bieber 1981, 1983). Importantly, this route of HMB formation is direct and completely dependent of liver KIC dioxygenase. Following this pathway, HMB in the cytosol is first converted to cytosolic β-hydroxy-β-methylglutaryl-CoA (HMG-CoA), which can then be directed for cholesterol synthesis (Rudney 1957) (Fig. 1). In fact, numerous biochemical studies have shown that HMB is a precursor of cholesterol (Zabin and Bloch 1951; Nissen et al. 2000).
Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours ... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds
