Understanding the mechanism of H2S oxidation by flavin-dependent sulfide oxidases: a DFT/IEF-PCM study

  • Jenner BonanataEmail author
  • E. Laura CoitiñoEmail author
Original Paper
Part of the following topical collections:
  1. QUITEL 2018 (44th Congress of Theoretical Chemists of Latin Expression)


In the last years, H2S has been recognized as a signaling molecule in mammals, which can synthesize and catabolize (by oxidation) such species. The latter process is accelerated by a sulfide:quinone oxidoreductase (SQR, E.C., a flavin-dependent sulfide oxidase (FDSO). FDSOs catalyze electron transfer from H2S to an acceptor in catalytic cycles involving two phases: (I) reduction of FAD by H2S (SH) and (II) electron transfer from FADH to the electron acceptor. The first step of FAD reduction consists on the reaction of SH with a catalytic disulfide at the active site of the enzyme, to yield a thiolate and a persulfide in the protein. This step is ca. 106 times faster than the analogous reaction with low-molecular-weight disulfides (LMWDs) and the causes of such extraordinary acceleration remain unknown. Using the IEF-PCM(ε ≈ 10)/M06-2X-D3/6-31+G(d,p) level of theory, we have modeled the reaction of SH with a disulfide as located in a representative model of the active site extracted from a prokaryotic SQR, assessing the effects of partial covalent interactions (PCIs) between the leaving sulfur atom and flavin ring on the activation Gibbs free-energy barrier at 298 K (G298K). To also evaluate the importance of entropic penalties on the first step, we have modeled at the same level of theory the reaction of (bis)hydroxyethyl disulfide in aqueous solution, a LMWD for which experimental data is available. Our results show that PCIs between the leaving sulfur atom and the flavin group only have a minor effect (G298K reduced by 1.6 kcal mol−1) while compensating entropic penalties could have a much larger effect (up to 8.3 kcal mol−1). Finally, we also present here a first model of some of further steps in the phase I of the catalytic cycle as in mammalian FDSOs, providing some light about their detailed mechanism.

Graphical abstract



Hydrogen sulfide Flavoenzyme Sulfide oxidase Sulfide:quinone oxidoreductase Partial covalent interactions Entropic effects 



SQR of A. ferroxidans


density functional theory


Electronic Supporting Material


flavin adenine dinucleotide in its oxidized form


flavin adenine dinucleotide in its reduced form


flavin-dependent sulfide oxidase


(bis)hydroxyethyl disulfide


low-molecular-weight disulfide


molecular dynamics


partial covalent interaction


polarizable continuum model


sulfide:quinone oxidoreductase


Wiberg bond index



The authors want to thank Prof. Beatriz Álvarez (Universidad de la República, Uruguay) for pointing-out the interest of addressing SQR mechanisms by computational modeling. JB and ELC are active members of the National System of Researchers (SNI-ANII, Uruguay) and of the Program of Development of the Basic Sciences (PEDECIBA).

Funding information

This research was funded by ANII under grant FCE_3_2016_1_125514.

Supplementary material

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Laboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias and Centro de Investigaciones Biomédicas (CEINBIO)Universidad de la RepúblicaMontevideoUruguay

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