Understanding the mechanism of H2S oxidation by flavin-dependent sulfide oxidases: a DFT/IEF-PCM study
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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. 220.127.116.11), 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.
KeywordsHydrogen 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
partial covalent interaction
polarizable continuum model
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).
This research was funded by ANII under grant FCE_3_2016_1_125514.
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