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AUH
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1HZD, 2ZQQ, 2ZQR
Identifiers
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
Gene location (Human) Chr. Chromosome 9 (human) Band 9q22.31 Start 91,213,815 bp End 91,361,918 bp
Gene location (Mouse) Chr. Chromosome 13 (mouse) Band 13|13 A5- B1 Start 52,989,155 bp End 53,083,717 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in renal medulla lateral nuclear group of thalamus kidney tubule right ventricle Pons human kidney parotid gland myocardium of left ventricle right adrenal cortex left adrenal cortex Top expressed in facial motor nucleus zygote right ventricle right kidney secondary oocyte interventricular septum proximal tubule myocardium of ventricle muscle of thigh plantaris muscle More reference expression data BioGPS n/a
Gene ontology Molecular function methylglutaconyl-CoA hydratase activity enoyl-CoA hydratase activity catalytic activity lyase activity RNA binding mRNA 3'-UTR binding itaconyl-CoA hydratase activity Cellular component mitochondrial matrix mitochondrion Biological process branched-chain amino acid catabolic process metabolism leucine catabolic process fatty acid beta-oxidation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 549 11992 Ensembl ENSG00000148090 ENSMUSG00000021460 UniProt Q13825 Q9JLZ3 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 Location (UCSC) Chr 9: 91.21 – 91.36 Mb Chr 13: 52.99 – 53.08 Mb PubMed search
Wikidata
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3-Methylglutaconyl-CoA hydratase, also known as MG-CoA hydratase and AUH, is an enzyme (EC 4.2.1.18) 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. Mutations of this gene have been found to cause a disease called 3-Methylglutaconic Acuduria Type 1.

Structure

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. 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.

Function

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. 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. 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.

Leucine metabolism in humans L-Leucine Branched-chain amino acid aminotransferase α-Ketoglutarate Glutamate Glutamate Alanine Pyruvate Muscle: α-Ketoisocaproate (α-KIC) Liver: α-Ketoisocaproate (α-KIC) Branched-chain α-ketoacid dehydrogenase (mitochondria) KIC-dioxygenase (cytosol) Isovaleryl-CoA β-Hydroxy β-methylbutyrate (HMB) Excreted in urine (10–40%) HMB-CoA β-Hydroxy β-methylglutaryl-CoA (HMG-CoA) β-Methylcrotonyl-CoA (MC-CoA) β-Methylglutaconyl-CoA (MG-CoA) CO2 CO2 O2 CO2 H2O CO2 H2O (liver) HMG-CoA lyase Enoyl-CoA hydratase Isovaleryl-CoA dehydrogenase MC-CoA carboxylase MG-CoA hydratase HMG-CoA reductase HMG-CoA  synthase β-Hydroxybutyrate dehydrogenase Mevalonate pathway Thiolase Unknown enzyme β-Hydroxybutyrate Acetoacetyl-CoA Acetyl-CoA Acetoacetate Mevalonate Cholesterol Human metabolic pathway for HMB and isovaleryl-CoA relative to L-leucine. Of the two major pathways, L-leucine is mostly metabolized into isovaleryl-CoA, while only about 5% is metabolized into HMB.

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 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. 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.

Interactions

AUH has been seen to interact with:

• ARE
• 3-methylglutaconyl-CoA

References

1. ^ GRCh38: Ensembl release 89: ENSG00000148090 – Ensembl, May 2017
2. ^ GRCm38: Ensembl release 89: ENSMUSG00000021460 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: AU RNA binding protein/enoyl-CoA hydratase".
6. ^ 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.
7. 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.
8. ^ 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. S2CID 44523407.
9. ^ 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. S2CID 6261362.
10. ^ 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 4027184. PMID 24598254.
11. ^ Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064. PMID 23374455.
12. ^ Zanchi NE, Gerlinger-Romero F, Guimarães-Ferreira L, de Siqueira Filho MA, Felitti V, Lira FS, Seelaender M, Lancha AH (April 2011). "HMB supplementation: clinical and athletic performance-related effects and mechanisms of action". Amino Acids. 40 (4): 1015–1025. doi:10.1007/s00726-010-0678-0. PMID 20607321. S2CID 11120110. 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 that occurs mainly extrahepatically (Block and Buse 1990). Following this enzymatic reaction, may follow one of two pathways. In the first, HMB is produced from 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).
13. ^ Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (2nd ed.). Academic Press. pp. 385–388. ISBN 978-0-12-387784-0. Retrieved 6 June 2016. 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
    Figure 8.57: Metabolism of L-leucine

External links

• methylglutaconyl-CoA+hydratase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• EC 4.2.1.18
• Overview of all the structural information available in the PDB for UniProt: Q13825 (Methylglutaconyl-CoA hydratase, mitochondrial) at the PDBe-KB.

• Biology

• Genes on human chromosome 9
• EC 4.2.1