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Article Dans Une Revue Molecular Biology and Evolution Année : 2023

Deciphering evolutionary trajectories of lactate dehydrogenases provides new insights into allostery.

Résumé

Abstract Lactate dehydrogenase (LDH, EC.1.1.127) is an important enzyme engaged in the anaerobic metabolism of cells, catalyzing the conversion of pyruvate to lactate and NADH to NAD +. LDH is a relevant enzyme to investigate structure-function relationships. The present work provides the missing link in our understanding of the evolution of LDHs. This allows to explain i) the various evolutionary origins of LDHs in eukaryotic cells and their further diversification, as well as ii) subtle phenotypic modifications with respect to their regulation capacity. We identified a group of cyanobacterial LDHs displaying eukaryotic-like LDH sequence features. The biochemical and structural characterization of Cyanobacterium aponinum LDH, taken as representative, unexpectedly revealed that it displays homotropic and heterotropic activation, typical of an allosteric enzyme, whereas it harbors a long N-terminal extension, a structural feature considered responsible for the lack of allosteric capacity in eukaryotic LDHs. Its crystallographic structure was solved in two different configurations typical of the R-active and T-inactive states encountered in allosteric LDHs. Structural comparisons coupled with our evolutionary analyses helped to identify two amino acid positions that could have had a major role in the attenuation and extinction of the allosteric activation in eukaryotic LDHs rather than the presence of the N-terminal extension. We tested this hypothesis by site-directed mutagenesis. The resulting Cyanobacterium aponinum LDH mutants displayed reduced allosteric capacity mimicking those encountered in plants and human LDHs. This study provides a new evolutionary scenario of LDHs that unifies descriptions of regulatory properties with structural and mutational patterns of these important enzymes.
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Dates et versions

hal-04235286 , version 1 (10-10-2023)

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Adeline Robin, Céline Brochier-Armanet, Quentin Bertrand, Caroline Barette, Eric Girard, et al.. Deciphering evolutionary trajectories of lactate dehydrogenases provides new insights into allostery.. Molecular Biology and Evolution, 2023, msad223, ⟨10.1093/molbev/msad223⟩. ⟨hal-04235286⟩
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