Kinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibition

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dc.contributor.authorTeixeira, Olívia
dc.contributor.authorMartins, Ingrid Bernardes Santana [UNESP]
dc.contributor.authorFroes, Thamires Quadros
dc.contributor.authorde Araujo, Alexandre Suman [UNESP]
dc.contributor.authorNonato, Maria Cristina
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionUniversidade Federal do Rio de Janeiro (UFRJ)
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.date.accessioned2023-07-29T13:54:31Z
dc.date.available2023-07-29T13:54:31Z
dc.date.issued2023-07-01
dc.description.abstractTuberculosis (TB) is a leading cause of death worldwide. TB represents a serious public health threat, and it is characterized by high transmission rates, prevalence in impoverished regions, and high co-infection rates with HIV. Moreover, the serious side effects of long-term treatment that decrease patient adherence, and the emergence of multi-resistant strains of Mycobacterium tuberculosis, the causing agent of TBs, pose several challenges for its eradication. The search for a new TB treatment is necessary and urgent. Dihydroorotate dehydrogenase (DHODH) is responsible for the stereospecific oxidation of (S)-dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. DHODH has been considered an attractive target against infectious diseases. As a first step towards exploiting DHODH as a drug target against TB, we performed a full kinetic characterization of both bacterial MtDHODH and its human ortholog (HsDHDOH) using both substrates coenzyme Q0 (Q0) and vitamin K3 (K3). MtDHODH follows a ping-pong mechanism of catalysis and shares similar catalytic parameters with the human enzyme. Serendipitously, Q0 was found to inhibit MtDHODH (KI (Q0) = 138 ± 31 μM). To the best of our knowledge, Q0 is the first non-orotate like dihydroorotate-competitive inhibitor for class 2 DHODHs ever described. Molecular dynamics simulations along with in silico solvent mapping allowed us to successfully probe protein flexibility and correlate it with the druggability of binding sites. Together, our results provide the starting point for the design of a new generation of potent and selective inhibitors against MtDHODH.en
dc.description.affiliationLaboratório de Cristalografia de Proteínas Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo, SP
dc.description.affiliationCenter for the Research and Advancement in Fragments and molecular Targets (CRAFT) Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo, SP
dc.description.affiliationInstituto de Biofísica Carlos Chagas Filho Universidade Federal do Rio de Janeiro, RJ
dc.description.affiliationInstituto de Biociências Letras e Ciências Exatas Departamento de Física UNESP, SP
dc.description.affiliationUnespInstituto de Biociências Letras e Ciências Exatas Departamento de Física UNESP, SP
dc.description.sponsorshipCentro Nacional de Processamento de Alto Desempenho em São Paulo
dc.description.sponsorshipUniversidade Estadual Paulista
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ)
dc.description.sponsorshipIdFAPESP: 2019/25532-1
dc.description.sponsorshipIdFAPESP: 2020/16316-0
dc.description.sponsorshipIdCNPq: 409272/2021-3
dc.description.sponsorshipIdCAPES: 88887.643249/2021-00
dc.identifierhttp://dx.doi.org/10.1016/j.bbagen.2023.130378
dc.identifier.citationBiochimica et Biophysica Acta - General Subjects, v. 1867, n. 7, 2023.
dc.identifier.doi10.1016/j.bbagen.2023.130378
dc.identifier.issn1872-8006
dc.identifier.issn0304-4165
dc.identifier.scopus2-s2.0-85159115113
dc.identifier.urihttp://hdl.handle.net/11449/248818
dc.language.isoeng
dc.relation.ispartofBiochimica et Biophysica Acta - General Subjects
dc.sourceScopus
dc.subjectEnzyme kinetics
dc.subjectHomology modeling
dc.subjectIn silico solvent mapping
dc.subjectInhibition
dc.subjectMolecular dynamics simulation
dc.titleKinetic and structural studies of Mycobacterium tuberculosis dihydroorotate dehydrogenase reveal new insights into class 2 DHODH inhibitionen
dc.typeArtigo

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