C-Terminal end and aminoacid Lys48 in HMG-CoA lyase are involved in substrate binding and enzyme activity
| Autor: | Eduardo López-Viñas, Gabriel Santpere, Fausto G. Hegardt, Paulino Gómez-Puertas, Sebastián Menao, Juan Pié, Adriana Y. Sierra, Patricia Carrasco, Josep Clotet, Esther Gratacós, Núria Casals, Beatriz Puisac |
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| Rok vydání: | 2007 |
| Předmět: |
Models
Molecular Stereochemistry Endocrinology Diabetes and Metabolism Molecular Sequence Data Biochemistry Protein Structure Secondary chemistry.chemical_compound Endocrinology Ribose TIM barrel Escherichia coli Genetics medicine Humans Moiety Amino Acid Sequence Molecular Biology Conserved Sequence chemistry.chemical_classification biology Oxo-Acid-Lyases Substrate (chemistry) Lyase Adenosine Recombinant Proteins Enzyme assay Enzyme chemistry Mutation biology.protein Acyl Coenzyme A Protein Binding medicine.drug |
| Zdroj: | Molecular Genetics and Metabolism. 91:120-127 |
| ISSN: | 1096-7192 |
| Popis: | 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase adopts a (betaalpha)(8) TIM barrel structure with an additional beta9, alpha11 and alpha12 helices. Location of HMG part of the substrate has been suggested but the binding mode for the CoA moiety remains to be resolved. As mutation F305 fs(-2), which involves the last 21 residues of the protein, and mutation K48N caused 3-hydroxy-3-methylglutaric aciduria in two patients, we examined the role of the C-terminal end and Lys(48) in enzyme activity. Expression studies of various C-terminal-end-deleted and K48N-mutated proteins revealed that residues 311-313 (localized in the loop between alpha11 and alpha12 helices) and Lys(48) are essential for enzyme activity. An in silico docking model locating HMG-CoA on the surface of the enzyme implicates Asn(311) and Lys(313) in substrate binding by establishing multiple polar contacts with phosphate and ribose groups of adenosine, and Lys(48) by contacting the carboxyl group of the panthotenic acid moiety. |
| Databáze: | OpenAIRE |
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