000163037 001__ 163037
000163037 005__ 20251009133841.0
000163037 0247_ $$2doi$$a10.3390/ijms26178266
000163037 0248_ $$2sideral$$a145534
000163037 037__ $$aART-2025-145534
000163037 041__ $$aeng
000163037 100__ $$0(orcid)0000-0001-9962-2157$$aArnedo, María$$uUniversidad de Zaragoza
000163037 245__ $$aLigand–Enzyme Interaction Modeling of Missense Variants Implicated in Mitochondrial HMG-CoA Synthase Deficiency
000163037 260__ $$c2025
000163037 5060_ $$aAccess copy available to the general public$$fUnrestricted
000163037 5203_ $$aHuman mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMG-CoA synthase, mHS) synthase is a key enzyme in ketogenesis and is located mainly in the liver, but also in the colon, skeletal muscle, heart, pancreas, and testes. It is an inner mitochondrial membrane-associated protein. Mutations in the HMGCS2 gene, which encodes this enzyme, lead to “mHS deficiency,” a rare, autosomal recessive, inherited metabolic disorder. To date, about 100 patients with this disorder have been described. The disorder usually appears during the first year of life, often after a period of starvation or an intercurrent illness. A total of 77 different DNA mutations has been described that are considered responsible for mHS deficiency, although the mechanisms leading to loss of function are not fully understood. To study how the different missense variants affect the enzymatic activity of the protein on an atomic scale, we used molecular dynamics computational simulation techniques for variants whose activity could be measured “in vitro.” The study included a total of 46 molecular dynamics trajectories of enzyme–substrate/product interaction simulations, each 500 ns long (23 microseconds total). Currently, the atomic and biophysical effects of the mHS variants on their catalyzed reactions have not been studied in detail experimentally. To our knowledge, molecular dynamics simulations are one of the most promising tools for understanding the molecular basis of the phenotypic consequences of these variants. In the present work, molecular dynamics simulations reliably reproduce most experimental enzyme activity measurements, supporting their future application to the study of new mHS mutations.
000163037 536__ $$9info:eu-repo/grantAgreement/ES/AEI/PID2021-126625OB-I00$$9info:eu-repo/grantAgreement/ES/DGA-FEDER/B32-20R
000163037 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttps://creativecommons.org/licenses/by/4.0/deed.es
000163037 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000163037 700__ $$aRos-Pardo, David
000163037 700__ $$0(orcid)0000-0003-0170-7326$$aPuisac, Beatriz$$uUniversidad de Zaragoza
000163037 700__ $$aLucia-Campos, Cristina$$uUniversidad de Zaragoza
000163037 700__ $$0(orcid)0000-0001-6858-1575$$aGil-Salvador, Marta$$uUniversidad de Zaragoza
000163037 700__ $$0(orcid)0000-0002-4703-6620$$aLatorre-Pellicer, Ana$$uUniversidad de Zaragoza
000163037 700__ $$aMarcos-Alcalde, Íñigo
000163037 700__ $$0(orcid)0000-0003-3203-6254$$aPié, Juan$$uUniversidad de Zaragoza
000163037 700__ $$aGómez-Puertas, Paulino
000163037 7102_ $$11012$$2410$$aUniversidad de Zaragoza$$bDpto. Farmac.Fisiol.y Med.L.F.$$cÁrea Fisiología
000163037 773__ $$g26, 17 (2025), 8266 [20 pp.]$$pInt. j. mol. sci.$$tInternational Journal of Molecular Sciences$$x1661-6596
000163037 8564_ $$s3685616$$uhttps://zaguan.unizar.es/record/163037/files/texto_completo.pdf$$yVersión publicada
000163037 8564_ $$s2688276$$uhttps://zaguan.unizar.es/record/163037/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000163037 909CO $$ooai:zaguan.unizar.es:163037$$particulos$$pdriver
000163037 951__ $$a2025-10-09-13:25:56
000163037 980__ $$aARTICLE