Methylglutaconyl-CoA hydratase

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AUH
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases AUH, AU RNA binding protein/enoyl-CoA hydratase, Methylglutaconyl-CoA hydratase, AU RNA binding methylglutaconyl-CoA hydratase
External IDs MGI: 1338011 HomoloGene: 1284 GeneCards: AUH
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001306190
NM_001698
NM_001351431
NM_001351432
NM_001351433

NM_016709

RefSeq (protein)

NP_001293119
NP_001689
NP_001338360
NP_001338361
NP_001338362

NP_057918.2
NP_057918

Location (UCSC) Chr 9: 91.21 – 91.36 Mb Chr 13: 52.84 – 52.93 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

3-methylglutaconyl-CoA hydratase (also known as AUH) is an enzyme encoded by the AUH gene on chromosome 19. It is a member of the enoyl-CoA hydratase/isomerase superfamily, but it is the only member of that family that is able to bind to 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 protein.[3] Mutations of this gene have been found to cause a disease called 3-Methylglutaconic Acuduria Type 1.[4]

Structure[edit]

The enzyme AUH has a molecular mass of 32 kDa and the AUH gene consists of 18 exons, is 1.7 kb long, and is mainly found in kidney, skeletal muscle, heart, liver, and 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 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 lysine residues were shown to be the main reason why AUH is able to bind to RNA rather than its counterparts.[5] 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 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.[6]

Function[edit]

AUH is seen to catalyze the transformation of 3-methylglutaconyl-CoA to 3-hydroxy-3-methylglutaryl CoA in the leucine 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 mitochondrial matrix.Also, these reductions in the enzyme’s activity leads to increases in 3-methylglutaric acid and 3-hydroxyisovaleric acid.[7] Another function of AUH is that it binds to an AU-rich element (ARE), containing clusters of the penta-nucleotide AUUUA. AREs have been found in the 3’-untranslated regions of mRNA and they promote mRNA degradation. By binding with ARE, AUH has been suggested to play a role in neuron survival and transcript stability.[6] AUH is also responsible for regulating mitochondrial protein synthesis and is essential for mitochondrial RNA metabolism, biogenesis, morphology, and function. Decreased levels of AUH also lead to slower cell expansion and 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 mitochondrial translation, ultimately leading up to changes in mitochondrial morphology, decreased RNA stability, biogenesis, and respiratory function.[8]

Clinical significance[edit]

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 splicing, 1 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.[4] 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.[8]

Interactions[edit]

AUH has been seen to interact with:

  • ARE [6]
  • 3-methylglutaconyl-CoA [7]

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ "Entrez Gene: AU RNA binding protein/enoyl-CoA hydratase". 
  4. ^ a b Mercimek-Mahmutoglu S, Tucker T, Casey B (Nov 2011). "Phenotypic heterogeneity in two siblings with 3-methylglutaconic aciduria type I caused by a novel intragenic deletion". Molecular Genetics and Metabolism. 104 (3): 410–3. doi:10.1016/j.ymgme.2011.07.021. PMID 21840233. 
  5. ^ Kurimoto K, Fukai S, Nureki O, Muto Y, Yokoyama S (Dec 2001). "Crystal structure of human AUH protein, a single-stranded RNA binding homolog of enoyl-CoA hydratase". Structure. 9 (12): 1253–63. doi:10.1016/s0969-2126(01)00686-4. PMID 11738050. 
  6. ^ a b c Kurimoto K, Kuwasako K, Sandercock AM, Unzai S, Robinson CV, Muto Y, Yokoyama S (May 2009). "AU-rich RNA-binding induces changes in the quaternary structure of AUH". Proteins. 75 (2): 360–72. doi:10.1002/prot.22246. PMID 18831052. 
  7. ^ a b Mack M, Schniegler-Mattox U, Peters V, Hoffmann GF, Liesert M, Buckel W, Zschocke J (May 2006). "Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism". The FEBS Journal. 273 (9): 2012–22. doi:10.1111/j.1742-4658.2006.05218.x. PMID 16640564. 
  8. ^ a b Richman TR, Davies SM, Shearwood AM, Ermer JA, Scott LH, Hibbs ME, Rackham O, Filipovska A (May 2014). "A bifunctional protein regulates mitochondrial protein synthesis". Nucleic Acids Research. 42 (9): 5483–94. doi:10.1093/nar/gku179. PMC 4027184Freely accessible. PMID 24598254. 

External links[edit]