Structural (betaalpha) 8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase
Casals Farré, Núria
Elias-Jones, Alun C.
Cresto, Juan C.
Chamoles, Nestor A.
Abdenur, Jose E.
Hegardt, Fausto G.
This study describes three novel homozygous missense mutations (S75R, S201Y, and D204N) in the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase gene, which caused 3-hydroxy-3-methylglutaric aciduria in patients from Germany, England, and Argentina. Expression studies in Escherichia coli show that S75R and S201Y substitutions completely abolished the HMG-CoA lyase activity, whereas D204N reduced catalytic efficiency to 6.6% of the wild type. We also propose a three-dimensional model for human HMG-CoA lyase containing a (βα)8 (TIM) barrel structure. The model is supported by the similarity with analogous TIM barrel structures of functionally related proteins, by the localization of catalytic amino acids at the active site, and by the coincidence between the shape of the substrate (HMG-CoA) and the predicted inner cavity. The three novel mutations explain the lack of HMG-CoA lyase activity on the basis of the proposed structure: in S75R and S201Y because the new amino acid residues occlude the substrate cavity, and in D204N because the mutation alters the electrochemical environment of the active site. We also report the localization of all missense mutations reported to date and show that these mutations are located in the β-sheets around the substrate cavity.
61 - Medicina
American Society for Biochemistry and Molecular Biology
Is part of
Journal of Biological Chemistry
Casals Farré, Núria; Gómez-Puertas, Paulino; Pié, Juan [et al.]. Structural (betaalpha) 8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. Journal of Biological Chemistry, 2003, 278(31), p. 29016-29023. Disponible en: <https://www.jbc.org/content/278/31/29016>. Fecha de acceso: 26 may. 2020. DOI: 10.1074/jbc.M304276200.
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© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.