Selenium in chemistry and biochemistry in comparison to sulfur

Abstract

What makes selenoenzymes--seen from a chemist's view--so special that they cannot be substituted by just more analogous or adapted sulfur proteins? This review compiles and compares physicochemical properties of selenium and sulfur, synthetic routes to selenocysteine (Sec) and its peptides, and comparative studies of relevant thiols and selenols and their (mixed) dichalcogens, required to understand the special role of selenium in selenoproteins on the atomic molecular level. The biochemically most relevant differences are the higher polarizability of Se- and the lower pKa of SeH. The latter has a strikingly different pH-dependence than thiols, with selenols being active at much lower pH. Finally, selected typical enzymatic mechanisms which involve selenocysteine are critically discussed, also in view of the authors' own results.

Redox active motifs in selenoproteins

“…The values derived from both methods were in good agreement but the mass spectrometry method was the more sensitive of the two and allowed us to measure the redox potentials within 1 mV (SI Appendix, Table S2). It is generally believed that the longer selenenylsulfide bond length would reduce the ring strain relative to that of disulfidecontaining rings (15). As expected, the redox potentials of the Sec-containing proteins were lower than those of their Cyscontaining homologs.…”

“…This is a critical aspect of the reactivity of many selenoproteins because reduction of the selenenylsulfide liberates the nucleophilic, and catalytically essential, selenolate (R-Se − ) species. Although it was proposed that the redox potential of selenoproteins might be much lower then their Cyscontaining orthologs (15), only a few Sec-containing proteins have been examined experimentally (24)(25)(26). Herein, we also provide, to our knowledge, the first quantitative comparisons of redox potentials of Sec-containing to all Cys-containing redox motifs in a range of ring sizes.…”

“…It should be noted that the overall features of a selenoprotein are dependent upon both the intrinsic physicochemical features of the Sec residue (5,15), and the interactions of a Sec-containing redox active motif with either substrates or other residues of the active site microenvironment. Context-dependent effects were previously demonstrated with TrxR, where the solely Cys-based motif of the Drosophila enzyme is highly active as part of that enzyme (7,8) but inactive if placed into the mammalian enzyme…”

Crystal Structure and Catalysis of the Selenoprotein Thioredoxin Reductase 1

“…The possibility that Tyr-116 in rat TrxR1 involves hydrogen bond-ing to substrate, as with the corresponding Tyr residue in glutathione reductase, cannot be excluded, but considering that the mutant enzymes showed dual effects with a protection from inactivation by cisplatin and no increase in K m but rather decrease in k cat for Trx, we suggested that the role of Tyr-116 may be to facilitate the selenenylsulfide reduction step. Another issue to be addressed is that we propose the His-472/Glu-477 couple to act as proton acceptors/donators only in the reductive half-reaction, which is not compatible with the "Sec-498/ His-472/Glu-477 swapping triad" as proposed by others on theoretical and thermodynamic modeling grounds (12,40,65). Furthermore, it was found earlier in the nonselenoprotein TrxR1 orthologue of the fruit fly, having a -Ser-Cys-Cys-Ser motif at the C terminus instead of a -Gly-Cys-Sec-Gly motif, that the flanking Ser residues in this motif could activate the Cys residues to approach the reactivity of the mammalian selenoprotein (41), whereas the mammalian enzyme cannot utilize the C-terminal motif derived from the fruit fly enzyme (43).…”

“…We further propose that the His-472 and Glu-477 dyads, argued by others to function together with Sec-498 as a "swapping catalytic triad" (12,40,65), serve the purpose of accepting the two protons needed for activation of the N-terminal FAD/ dithiol motif into two thiolate anions, in two successive steps relayed through His-472. Such reactions would be reminiscent of the function of the corresponding His and Glu residues in glutathione reductase (64).…”