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Diversity of chemical mechanisms in thioredoxin catalysis revealed by single-molecule force spectroscopy

Abstract : Thioredoxins (Trxs) are oxidoreductase enzymes, present in all organisms, that catalyze the reduction of disulfide bonds in proteins. By applying a calibrated force to a substrate disulfide, the chemical mechanisms of Trx catalysis can be examined in detail at the single-molecule level. Here we use single-molecule force-clamp spectroscopy to explore the chemical evolution of Trx catalysis by probing the chemistry of eight different Trx enzymes. All Trxs show a characteristic Michaelis-Menten mechanism that is detected when the disulfide bond is stretched at low forces, but at high forces, two different chemical behaviors distinguish bacterial-origin from eukaryotic-origin Trxs. Eukaryotic-origin Trxs reduce disulfide bonds through a single-electron transfer reaction (SET), whereas bacterial-origin Trxs show both nucleophilic substitution (SN2) and SET reactions. A computational analysis of Trx structures identifies the evolution of the binding groove as an important factor controlling the chemistry of Trx catalysis.
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https://hal.inrae.fr/hal-02658468
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Submitted on : Saturday, May 30, 2020 - 12:16:41 PM
Last modification on : Thursday, September 9, 2021 - 9:38:07 AM

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Raul Perez-Jimenez, Jingyuan Li, Pallav Kosuri, Inmaculada Sanchez-Romero, Arun P. Wiita, et al.. Diversity of chemical mechanisms in thioredoxin catalysis revealed by single-molecule force spectroscopy. Nature Structural and Molecular Biology, Nature Publishing Group, 2009, 16 (8), pp.890-898. ⟨10.1038/nsmb.1627⟩. ⟨hal-02658468⟩

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