Structural and mechanistic aspects of S-S bonds in the thioredoxin-like family of proteins

Abstract

Disulfide bonds play a critical role in a variety of structural and mechanistic processes associated with proteins inside the cells and in the extracellular environment. The thioredoxin family of proteins like thioredoxin (Trx), glutaredoxin (Grx) and protein disulfide isomerase, are involved in the formation, transfer or isomerization of disulfide bonds through a characteristic thiol-disulfide exchange reaction. Here, we review the structural and mechanistic determinants behind the thiol-disulfide exchange reactions for the different enzyme types within this family, rationalizing the known experimental data in light of the results from computational studies. The analysis sheds new atomic-level insight into the structural and mechanistic variations that characterize the different enzymes in the family, helping to explain the associated functional diversity. Furthermore, we review here a pattern of stabilization/destabilization of the conserved active-site cysteine residues presented beforehand, which is fully consistent with the observed roles played by the thioredoxin family of enzymes.

A Bioinspired Disulfide/Dithiol Redox Switch in a Rhenium Complex as Proton, H Atom, and Hydride Transfer Reagent

“…FADH 2 acts as a hydride donor in various biochemical processes. For example, it is used as redox reagent by glutathione reductase and thioredoxin reductase, which mediate the glutathione disulfide to glutathione conversion − or thioredoxin reduction, respectively. Synthetic analogues of such hydride donors, for example, Hantzsch esters, have been widely explored in (asymmetric) hydrogenation reactions. − …”

Lipid-derived electrophiles mediate the effects of chemotherapeutic topoisomerase I poisons

“…Conserved cysteine residues located in active sites or situated nearby are a common feature of diverse enzymes (Verma et al, 2016;Rhee and Kil, 2017) where they may serve a direct role via the thiol serving as a nucleophile, which can affect catalysis or allosteric regulation (Sousa et al, 2019). Although the reducing environment of the intracellular milieu generally protects exposed cysteine thiols, structural context, such as hydrogen bonds, can lower the pKa and favor oxidation (Poole, 2015), and reactions with cellular electrophiles can directly inhibit catalysis or trap enzymes in bound states (Vazquez-Torres, 2012).…”

Towards solvent regulated self-activation of N-terminal disulfide bond oxidoreductase-D

“…[14][15][16] At the same time, there are numerous reports for disulfide redox switching reactions achieved using nucleophiles. [17][18][19][20][21][22] The proton transfer reaction is one of the best possible methods for generating such nucleophiles within the protein active site. Here, the amino acid side chains either pair as a proton donor-acceptor duo or associate with solvent molecules.…”