Conformational dynamics of tetracenomycin aromatase/cyclase regulate polyketide binding and enzyme aggregation propensity

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dc.creatorVeronica Silva Valadares
dc.creatorLuan Carvalho Martins
dc.creatorErnesto A. Roman
dc.creatorAna Paula Valente
dc.creatorElio Cino
dc.creatorAdolfo Henrique de Moraes Silva
dc.date.accessioned2023-06-28T18:55:26Z
dc.date.accessioned2025-09-09T01:24:10Z
dc.date.available2023-06-28T18:55:26Z
dc.date.issued2021
dc.description.sponsorshipCNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico
dc.description.sponsorshipFAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
dc.description.sponsorshipOutra Agência
dc.identifier.doihttps://doi.org/10.1016/j.bbagen.2021.129949
dc.identifier.issn0304-4165
dc.identifier.urihttps://hdl.handle.net/1843/55506
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofBiochimica et Biophysica Acta - General Subjects
dc.rightsAcesso Restrito
dc.subjectEspectroscopia de fluorescência
dc.subjectBiossíntese
dc.subjectEspectroscopia de ressonância nuclear
dc.subjectAnálise conformacional
dc.subjectDicroismo circular
dc.subjectProteínas - Síntese
dc.subject.otherPolyketide
dc.subject.otherAromatase/cyclase
dc.subject.otherConformational dynamics
dc.subject.otherAggregation
dc.titleConformational dynamics of tetracenomycin aromatase/cyclase regulate polyketide binding and enzyme aggregation propensity
dc.typeArtigo de periódico
local.citation.issue9
local.citation.spage129949
local.citation.volume1865
local.description.resumoBackground: The N-terminal domain of Tetracenomycin aromatase/cyclase (TcmN), an enzyme derived from Streptomyces glaucescens, is involved in polyketide cyclization, aromatization, and folding. Polyketides are a diverse class of secondary metabolites produced by certain groups of bacteria, fungi, and plants with various pharmaceutical applications. Examples include antibiotics, such as tetracycline, and anticancer drugs, such as doxorubicin. Because TcmN is a promising enzyme for in vitro production of polyketides, it is important to identify conditions that enhance its thermal resistance and optimize its function. Methods: TcmN unfolding, stability, and dynamics were evaluated by fluorescence spectroscopy, circular dichroism, nuclear magnetic resonance 15N relaxation experiments, and microsecond molecular dynamics (MD) simulations. Results: TcmN thermal resistance was enhanced at low protein and high salt concentrations, was pH-dependent, and denaturation was irreversible. Conformational dynamics on the μs-ms timescale were detected for residues in the substrate-binding cavity, and two predominant conformers representing opened and closed cavity states were observed in the MD simulations. Conclusion: Based on the results, a mechanism was proposed in which the thermodynamics and kinetics of the TcmN conformational equilibrium modulate enzyme function by favoring ligand binding and avoiding aggregation. General significance: Understanding the principles underlying TcmN stability and dynamics may help in designing mutants with optimal properties for biotechnological applications.
local.identifier.orcidhttps://orcid.org/0000-0002-3344-4084
local.publisher.countryBrasil
local.publisher.departmentICX - DEPARTAMENTO DE QUÍMICA
local.publisher.initialsUFMG
local.url.externahttps://www.sciencedirect.com/science/article/pii/S0304416521001070?via%3Dihub

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