Methylglutaconyl-CoA hydratase, mitochondrial

Definition:

Catalyzes the fifth step in the leucine degradation pathway, the reversible hydration of 3-methylglutaconyl-CoA (3-MG-CoA) to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). Can catalyze the reverse reaction but at a much lower rate in vitro. HMG-CoA is then quickly degraded by another enzyme (such as HMG-CoA lyase) to give acetyl-CoA and acetoacetate. Uses other substrates such as (2E)-glutaconyl-CoA efficiently in vitro, and to a lesser extent 3-methylcrotonyl-CoA (3-methyl-(2E)-butenoyl-CoA), crotonyl-CoA ((2E)-butenoyl-CoA) and 3-hydroxybutanoyl-CoA (the missing carboxylate reduces affinity to the active site). Originally it was identified as an RNA-binding protein as it binds to AU-rich elements (AREs) in vitro. AREs direct rapid RNA degradation and mRNA deadenylation. Might have itaconyl-CoA hydratase activity, converting itaconyl-CoA into citramalyl-CoA in the C5-dicarboxylate catabolism pathway. The C5-dicarboxylate catabolism pathway is required to detoxify itaconate, an antimicrobial metabolite and immunomodulator produced by macrophages during certain infections, that can act as a vitamin B12-poisoning metabolite.

References:

[1]. T B Nga Ly, et al. Mutations in the AUH gene cause 3-methylglutaconic aciduria type I. Hum Mutat. 2003 Apr;21(4):401-7. [Content Brief]

[2]. Hongying Shen, et al. The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12. Cell. 2017 Nov 2;171(4):771-782.e11. [Content Brief]

[3]. Lodewijk IJlst, et al. 3-Methylglutaconic aciduria type I is caused by mutations in AUH. Am J Hum Genet. 2002 Dec;71(6):1463-6. [Content Brief]

[4]. K Kurimoto, et al. Crystal structure of human AUH protein, a single-stranded RNA binding homolog of enoyl-CoA hydratase. Structure. 2001 Dec;9(12):1253-63. [Content Brief]

[5]. Matthias Mack, et al. Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism. FEBS J. 2006 May;273(9):2012-22. [Content Brief]

[6]. J Nakagawa, et al. AUH, a gene encoding an AU-specific RNA binding protein with intrinsic enoyl-CoA hydratase activity. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):2051-5. [Content Brief]

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