AUH mutants don't synthesize 3-hydroxy-methylglutaryl-CoA

Stable Identifier
R-HSA-9914271
Type
Reaction [transition]
Species
Homo sapiens
Compartment
mitochondrial matrix
ReviewStatus
5/5
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AUH mutants don't synthesize 3-hydroxy-methylglutaryl-CoA
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The following mutations have been identified in patients with 3-methylglutaconic aciduria, have been shown to have compromised AUH activity in vitro and are classified as either "likely pathological" or "pathological" in ClinVar despite variable clinical presentations:

R197*: causes termination of the protein before E290 that forms part of the catalytic active site; severely compromised enzymatic activity (Iljst et al, 2002; Ly et al, 2003; Duran et al, 1982; Narisawa et al, 1986; Wortmann et al, 2010; Nardecchia et al, 2022).

A240V: compromised enzymatic activity (Ly et al, 2003; Mack et al, 2006; Nardecchia et al, 2022).

G217D: undetectable enzymatic activity in homogenates from patient fibroblasts; predicted to abolish multimerization (Engelke et al, 2006; Wortmann et al, 2010; Nardecchia et al, 2022).

R331*: undetectable enzymatic activity; truncation removes the C-terminal 8 amino acids; based on crystal structure predicted to disrupt active site and subunit interaction (Wortmann et al, 2010; Nardecchia et al, 2022).
Literature References
PubMed ID Title Journal Year
12655555 Mutations in the AUH gene cause 3-methylglutaconic aciduria type I

Ly, TB, Peters, V, Gibson, KM, Liesert, M, Buckel, W, Wilcken, B, Carpenter, K, Ensenauer, R, Hoffmann, GF, Mack, M, Zschocke, J

Hum Mutat 2003
6181239 Inherited 3-methylglutaconic aciduria in two brothers--another defect of leucine metabolism

Duran, M, Beemer, FA, Tibosch, AS, Bruinvis, L, Ketting, D, Wadman, SK

J Pediatr 1982
20855850 3-Methylglutaconic aciduria type I redefined: a syndrome with late-onset leukoencephalopathy

Wortmann, SB, Kremer, BH, Graham, A, Willemsen, MA, Loupatty, FJ, Hogg, SL, Engelke, UF, Kluijtmans, LA, Wanders, RJ, Illsinger, S, Wilcken, B, Cruysberg, JR, Das, AM, Morava, E, Wevers, RA

Neurology 2010
12434311 3-Methylglutaconic aciduria type I is caused by mutations in AUH.

IJlst, L, Loupatty, FJ, Ruiter, JP, Duran, M, Lehnert, W

Am J Hum Genet 2002
16640564 Biochemical characterization of human 3-methylglutaconyl-CoA hydratase and its role in leucine metabolism

Mack, M, Schniegler-Mattox, U, Peters, V, Hoffmann, GF, Liesert, M, Buckel, W, Zschocke, J

FEBS J 2006
16541463 NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism

Engelke, UF, Kremer, B, Kluijtmans, LA, van der Graaf, M, Morava, E, Loupatty, FJ, Wanders, RJ, Moskau, D, Loss, S, van den Bergh, E, Wevers, RA

NMR Biomed 2006
3082934 Deficiency of 3-methylglutaconyl-coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria.

Narisawa, K, Gibson, KM, Sweetman, L, Nyhan, WL, Duran, M, Wadman, SK

J Clin Invest 1986
35457240 3-Methylglutaconic Aciduria Type I Due to AUH Defect: The Case Report of a Diagnostic Odyssey and a Review of the Literature

Nardecchia, F, Caciotti, A, Giovanniello, T, De Leo, S, Ferri, L, Galosi, S, Santagata, S, Torres, B, Bernardini, L, Carducci, C, Morrone, A, Leuzzi, V

Int J Mol Sci 2022
Participants
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Catalyst Activity

methylglutaconyl-CoA hydratase activity of mutant AUH hexamer [mitochondrial matrix]

Physical Entity
mutant AUH hexamer [mitochondrial matrix] (Homo sapiens)
Activity
methylglutaconyl-CoA hydratase activity (GO:0004490)
Normal reaction
beta-methylglutaconyl-CoA + H2O <=> beta-hydroxy-beta-methylglutaryl-CoA (Homo sapiens)
Disease
Cross References
Mondo
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-06-23)
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