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

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Abstract

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. 1.8.5.4), 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.

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Abbreviations

AfSQR:

SQR of A. ferroxidans

DFT:

density functional theory

ESM:

Electronic Supporting Material

FAD:

flavin adenine dinucleotide in its oxidized form

FADH− :

flavin adenine dinucleotide in its reduced form

FDSO:

flavin-dependent sulfide oxidase

HED:

(bis)hydroxyethyl disulfide

LMWD:

low-molecular-weight disulfide

MD:

molecular dynamics

PCI:

partial covalent interaction

PCM:

polarizable continuum model

SQR:

sulfide:quinone oxidoreductase

WBI:

Wiberg bond index

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Acknowledgments

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

This research was funded by ANII under grant FCE_3_2016_1_125514.

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  1. Laboratorio de Química Teórica y Computacional, Instituto de Química Biológica, Facultad de Ciencias and Centro de Investigaciones Biomédicas (CEINBIO), Universidad de la República, Iguá 4225, 11400, Montevideo, Uruguay

    Jenner Bonanata & E. Laura Coitiño

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  1. Jenner Bonanata
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Correspondence to Jenner Bonanata or E. Laura Coitiño.

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Bonanata, J., Coitiño, E.L. Understanding the mechanism of H2S oxidation by flavin-dependent sulfide oxidases: a DFT/IEF-PCM study. J Mol Model 25, 308 (2019). https://doi.org/10.1007/s00894-019-4197-y

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