000070059 001__ 70059
000070059 005__ 20230706131402.0
000070059 0247_ $$2doi$$a10.3390/ijms19041010
000070059 0248_ $$2sideral$$a105421
000070059 037__ $$aART-2018-105421
000070059 041__ $$aeng
000070059 100__ $$0(orcid)0000-0003-0170-7326$$aPuisac, B.$$uUniversidad de Zaragoza
000070059 245__ $$aHuman mitochondrial HMG-CoA synthase deficiency: Role of enzyme dimerization surface and characterization of three new patients
000070059 260__ $$c2018
000070059 5060_ $$aAccess copy available to the general public$$fUnrestricted
000070059 5203_ $$aMitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (mitochondrial HMG-CoA synthase deficiency or mHS deficiency, OMIM #605911) is an inborn error of metabolism that affects ketone body synthesis. Acute episodes include vomiting, lethargy, hepatomegaly, hypoglycemia and dicarboxylic aciduria. The diagnosis is difficult due to the relatively unspecific clinical and biochemical presentation, and fewer than 30 patients have been described. This work describes three new patients with mHS deficiency and two missense mutations c.334C>T (p.R112W) and c.430G>T (p.V144L) previously not reported. We developed a new method to express and measure the activity of the enzyme and in this work the study is extended to ten new missense variants including those of our patients. Enzymatic assays showed that three of the mutant proteins retained some but seven completely lacked activity. The identification of a patient homozygous for a mutation that retains 70% of enzyme activity opens the door to a new interpretation of the disease by demonstrating that a modest impairment of enzyme function can actually produce symptoms. This is also the first study employing molecular dynamics modelling of the enzyme mutations. We show that the correct maintenance of the dimerization surface is crucial for retaining the structure of the active center and therefore the activity of the enzyme.
000070059 536__ $$9info:eu-repo/grantAgreement/ES/DGA/B20$$9info:eu-repo/grantAgreement/ES/MICINN/IPT2011-0964-900000$$9info:eu-repo/grantAgreement/ES/MICINN/SAF2011-13156-E
000070059 540__ $$9info:eu-repo/semantics/openAccess$$aby$$uhttp://creativecommons.org/licenses/by/3.0/es/
000070059 590__ $$a4.183$$b2018
000070059 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b77 / 294 = 0.262$$c2018$$dQ2$$eT1
000070059 591__ $$aCHEMISTRY, MULTIDISCIPLINARY$$b45 / 172 = 0.262$$c2018$$dQ2$$eT1
000070059 592__ $$a1.312$$b2018
000070059 593__ $$aCatalysis$$c2018$$dQ1
000070059 593__ $$aComputer Science Applications$$c2018$$dQ1
000070059 593__ $$aInorganic Chemistry$$c2018$$dQ1
000070059 593__ $$aSpectroscopy$$c2018$$dQ1
000070059 593__ $$aMolecular Biology$$c2018$$dQ1
000070059 593__ $$aOrganic Chemistry$$c2018$$dQ1
000070059 593__ $$aPhysical and Theoretical Chemistry$$c2018$$dQ1
000070059 593__ $$aMedicine (miscellaneous)$$c2018$$dQ1
000070059 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000070059 700__ $$aMarcos-Alcalde, I.
000070059 700__ $$0(orcid)0000-0001-8457-1377$$aHernández-Marcos, M./Tobajas Morlana, P.
000070059 700__ $$0(orcid)0000-0002-0683-8555$$aLevtova, A.$$uUniversidad de Zaragoza
000070059 700__ $$aSchwahn, B.C.
000070059 700__ $$aDelaet, C.
000070059 700__ $$aLace, B.
000070059 700__ $$aGómez-Puertas, P.
000070059 700__ $$0(orcid)0000-0003-3203-6254$$aPié, J.$$uUniversidad de Zaragoza
000070059 7102_ $$11010$$2770$$aUniversidad de Zaragoza$$bDpto. Pediatría Radiol.Med.Fís$$cÁrea Radiol. y Medicina Física
000070059 7102_ $$11005$$2410$$aUniversidad de Zaragoza$$bDpto. Farmacología y Fisiolog.$$cÁrea Fisiología
000070059 773__ $$g19, 4 (2018), 1010 [12 pp]$$pInt. j. mol. sci.$$tInternational Journal of Molecular Sciences$$x1661-6596
000070059 8564_ $$s330836$$uhttps://zaguan.unizar.es/record/70059/files/texto_completo.pdf$$yVersión publicada
000070059 8564_ $$s108612$$uhttps://zaguan.unizar.es/record/70059/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000070059 909CO $$ooai:zaguan.unizar.es:70059$$particulos$$pdriver
000070059 951__ $$a2023-07-06-12:20:27
000070059 980__ $$aARTICLE