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The key role of glutamate 172 in the mechanism of type II NADH:quinone oxidoreductase of Staphylococcus aureus.

Sousa FM, Sena FV, Batista AP, Athayde D, Brito JA, Archer M, Oliveira ASF, Soares CM, Catarino T, Pereira MM
Biochim Biophys Acta Bioenerg 1858 823-832 (2017)
Cited: 9 times
EuropePMC logo PMID: 28801048

Abstract

Type II NADH:quinone oxidoreductases (NDH-2s) are membrane bound enzymes that deliver electrons to the respiratory chain by oxidation of NADH and reduction of quinones. In this way, these enzymes also contribute to the regeneration of NAD+, allowing several metabolic pathways to proceed. As for the other members of the two-Dinucleotide Binding Domains Flavoprotein (tDBDF) superfamily, the enzymatic mechanism of NDH-2s is still little explored and elusive. In this work we addressed the role of the conserved glutamate 172 (E172) residue in the enzymatic mechanism of NDH-2 from Staphylococcus aureus. We aimed to test our earlier hypothesis that E172 plays a key role in proton transfer to allow the protonation of the quinone. For this we performed a complete biochemical characterization of the enzyme's variants E172A, E172Q and E172S. Our steady state kinetic measurements show a clear decrease in the overall reaction rate, and our substrate interaction studies indicate the binding of the two substrates is also affected by these mutations. Interestingly our fast kinetic results show quinone reduction is more affected than NADH oxidation. We have also determined the X-ray crystal structure of the E172S mutant (2.55Ǻ) and compared it with the structure of the wild type (2.32Ǻ). Together these results support our hypothesis for E172 being of central importance in the catalytic mechanism of NDH-2, which may be extended to other members of the tDBDF superfamily.

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Articles citing this publication (6)

  1. FAD/NADH Dependent Oxidoreductases: From Different Amino Acid Sequences to Similar Protein Shapes for Playing an Ancient Function. Trisolini L, Gambacorta N, Gorgoglione R, Montaruli M, Laera L, Colella F, Volpicella M, De Grassi A, Pierri CL. J Clin Med 8 E2117 (2019)
  2. Regulation of the mechanism of Type-II NADH: Quinone oxidoreductase from S. aureus. Sena FV, Sousa FM, Oliveira ASF, Soares CM, Catarino T, Pereira MM. Redox Biol 16 209-214 (2018)
  3. The global motion affecting electron transfer in Plasmodium falciparum type II NADH dehydrogenases: a novel non-competitive mechanism for quinoline ketone derivative inhibitors. Xie T, Wu Z, Gu J, Guo R, Yan X, Duan H, Liu X, Liu W, Liang L, Wan H, Luo Y, Tang D, Shi H, Hu J. Phys Chem Chem Phys 21 18105-18118 (2019)
  4. Structural insights into FSP1 catalysis and ferroptosis inhibition. Lv Y, Liang C, Sun Q, Zhu J, Xu H, Li X, Li YY, Wang Q, Yuan H, Chu B, Zhu D. Nat Commun 14 5933 (2023)
  5. Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation. Nakamura T, Mishima E, Yamada N, Mourão ASD, Trümbach D, Doll S, Wanninger J, Lytton E, Sennhenn P, Nishida Xavier da Silva T, Angeli JPF, Sattler M, Proneth B, Conrad M. Nat Struct Mol Biol 30 1806-1815 (2023)
  6. Quinone binding site in a type VI sulfide:quinone oxidoreductase. Miklovics N, Duzs Á, Balogh F, Paragi G, Rákhely G, Tóth A. Appl Microbiol Biotechnol 106 7505-7517 (2022)


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