Ontology type: schema:ScholarlyArticle Open Access: True
2021-07-31
AUTHORSMariel Claudia Gerrard Wheeler, Cintia Lucía Arias, Juliana da Fonseca Rezende e Mello, Nuria Cirauqui Diaz, Carlos Rangel Rodrigues, María Fabiana Drincovich, Alessandra Mendonça Teles de Souza, Clarisa Ester Alvarez
ABSTRACTKey messageNADP-ME2 from Arabidopsis thaliana exhibits a distinctive and complex regulation by fumarate, acting as an activator or an inhibitor according to substrate and effector concentrations. In this work, we used molecular modeling approach and site-directed mutagenesis to characterized the NADP-ME2 structural determinants necessary for allosteric regulation providing new insights for enzyme optimization.AbstractStructure–function studies contribute to deciphering how small modifications in the primary structure could introduce desirable characteristics into enzymes without affecting its overall functioning. Malic enzymes (ME) are ubiquitous and responsible for a wide variety of functions. The availability of a high number of ME crystal structures from different species facilitates comparisons between sequence and structure. Specifically, the structural determinants necessary for fumarate allosteric regulation of ME has been of particular interest. NADP-ME2 from Arabidopsis thaliana exhibits a distinctive and complex regulation by fumarate, acting as an activator or an inhibitor according to substrate and effector concentrations. However, the 3D structure for this enzyme is not yet reported. In this work, we characterized the NADP-ME2 allosteric site by structural modeling, molecular docking, normal mode analysis and mutagenesis. The regulatory site model and its docking analysis suggested that other C4 acids including malate, NADP-ME2 substrate, could also fit into fumarate’s pocket. Besides, a non-conserved cluster of hydrophobic residues in the second sphere of the allosteric site was identified. The substitution of one of those residues, L62, by a less flexible residue as tryptophan, resulted in a complete loss of fumarate activation and a reduction of substrate affinities for the active site. In addition, normal mode analysis indicated that conformational changes leading to the activation could originate in the region surrounding L62, extending through the allosteric site till the active site. Finally, the results in this work contribute to the understanding of structural determinants necessary for allosteric regulation providing new insights for enzyme optimization.Graphic abstract More... »
PAGES37-48
http://scigraph.springernature.com/pub.10.1007/s11103-021-01176-2
DOIhttp://dx.doi.org/10.1007/s11103-021-01176-2
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PUBMEDhttps://www.ncbi.nlm.nih.gov/pubmed/34333694
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