caa a22 4500 467932786 CHVBK 20180406152948.0 cr unu---uuuuu 170328e20060201xx s 000 0 eng 10.1007/s10545-006-0138-x doi (NATIONALLICENCE)springer-10.1007/s10545-006-0138-x A single-residue mutation, G203E, causes 3-hydroxy-3-methylglutaric aciduria by occluding the substrate channel in the 3D structural model of HMG-CoA lyase [Elektronische Daten] [C. Mir, E. Lopez-Viñas, R. Aledo, B. Puisac, C. Rizzo, C. Dionisi-Vici, F. Deodato, J. Pié, P. Gomez-Puertas, F. Hegardt, N. Casals] Summary: 3-Hydroxy-3-methylglutaric aciduria is a rare autosomal recessive genetic disorder that affects ketogenesis and leucine metabolism. The disease is caused by mutations in the gene coding for 3-hydroxy-3-methylglutaryl-coenzyme A lyase (HL). To date 26 different mutations have been described. A (βα)8 TIM barrel structure has been proposed for the protein, and almost all missense mutations identified so far localize in the beta sheets that define the inside cavity. We report an Italian patient who bears homozygously a novel HL mutation, c.608G > A (p. G203E) in beta sheet six. A structural model of the mutated protein suggests that glutamic acid 203 impedes catalysis by blocking the entrance to the inner cavity of the enzyme. Loss of functionality has been confirmed in expression studies in E. coli, which demonstrate that the G203E mutation completely abolishes enzyme activity. Beta sheet six and beta sheet two are the two protein regions that accumulate most missense mutations, indicating their importance in enzyme functionality. A model for the mechanism of enzyme function is proposed. SSIEM and Springer, 2006 Mir C. Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, International University of Catalonia, C/ Josep Trueta s/n, Sant Cugat del Valles, E-08190, Barcelona, Spain aut Lopez-Viñas E. Centre of Molecular Biology "Severo Ochoa” (CSIC-UAM), Cantoblanco, Madrid aut Aledo R. Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, International University of Catalonia, C/ Josep Trueta s/n, Sant Cugat del Valles, E-08190, Barcelona, Spain aut Puisac B. Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, Zaragoza, Spain aut Rizzo C. Divisione di Patologia Metabolica, Ospedale Pediatrico Bambino Gesu, Roma, Italy aut Dionisi-Vici C. Divisione di Patologia Metabolica, Ospedale Pediatrico Bambino Gesu, Roma, Italy aut Deodato F. Divisione di Patologia Metabolica, Ospedale Pediatrico Bambino Gesu, Roma, Italy aut Pié J. Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, Zaragoza, Spain aut Gomez-Puertas P. Centre of Molecular Biology "Severo Ochoa” (CSIC-UAM), Cantoblanco, Madrid aut Hegardt F. Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona, Spain aut Casals N. Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, International University of Catalonia, C/ Josep Trueta s/n, Sant Cugat del Valles, E-08190, Barcelona, Spain aut Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/1(2006-02-01), 64-70 0141-8955 29:1<64 2006 29 10545 https://doi.org/10.1007/s10545-006-0138-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s10545-006-0138-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Mir C. Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, International University of Catalonia, C/ Josep Trueta s/n, Sant Cugat del Valles, E-08190, Barcelona, Spain aut NATIONALLICENCE 700 1- Lopez-Viñas E. Centre of Molecular Biology "Severo Ochoa” (CSIC-UAM), Cantoblanco, Madrid aut NATIONALLICENCE 700 1- Aledo R. Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, International University of Catalonia, C/ Josep Trueta s/n, Sant Cugat del Valles, E-08190, Barcelona, Spain aut NATIONALLICENCE 700 1- Puisac B. Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, Zaragoza, Spain aut NATIONALLICENCE 700 1- Rizzo C. Divisione di Patologia Metabolica, Ospedale Pediatrico Bambino Gesu, Roma, Italy aut NATIONALLICENCE 700 1- Dionisi-Vici C. Divisione di Patologia Metabolica, Ospedale Pediatrico Bambino Gesu, Roma, Italy aut NATIONALLICENCE 700 1- Deodato F. Divisione di Patologia Metabolica, Ospedale Pediatrico Bambino Gesu, Roma, Italy aut NATIONALLICENCE 700 1- Pié J. Department of Pharmacology and Physiology, School of Medicine, University of Zaragoza, Zaragoza, Spain aut NATIONALLICENCE 700 1- Gomez-Puertas P. Centre of Molecular Biology "Severo Ochoa” (CSIC-UAM), Cantoblanco, Madrid aut NATIONALLICENCE 700 1- Hegardt F. Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Barcelona, Spain aut NATIONALLICENCE 700 1- Casals N. Department of Biochemistry and Molecular Biology, Faculty of Health Sciences, International University of Catalonia, C/ Josep Trueta s/n, Sant Cugat del Valles, E-08190, Barcelona, Spain aut NATIONALLICENCE 773 0- Journal of Inherited Metabolic Disease Kluwer Academic Publishers 29/1(2006-02-01), 64-70 0141-8955 29:1<64 2006 29 10545 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer