Rational De Novo Design of a Cu-Metalloenzyme for Superoxide Dismutation

Emilie Mathieu (1, 2, 3, 4) , Audrey Tolbert , Karl Koebke (5) , Cédric Tard (6) , Olga Iranzo (7) , James Penner‐hahn , Clotilde Policar (1, 2, 3, 4) , Vincent Pecoraro (5)

1 Département de Chimie - ENS Paris
2 LBM UMR 7203 - Laboratoire des biomolécules
3 PSL - Université Paris Sciences et Lettres
4 SU - Sorbonne Université
5 Department of Chemistry, University of Michigan
6 LCM - Laboratoire de chimie moléculaire
7 ISM2 - Institut des Sciences Moléculaires de Marseille

Superoxide dismutases (SODs) are highly efficient enzymes for superoxide dismutation and the first line of defense against oxidative stress. These metalloproteins contain a redox active metal ion in their active site (Mn, Cu, Fe, Ni) with a tightly controlled reduction potential found in a close range around the optimal value of 0.36 V vs. NHE. Rationally designed proteins with well-defined three-dimensional structures offer new opportunities for obtaining functional SOD mimics. Here we explore four different copper binding scaffolds: H3 (His3), H4 (His4), H2DH (His3Asp with 2 His and 1 Asp in the same plane) and H3D (His3Asp with 3 His in the same plane) using the scaffold of the de novo protein GR3D. EPR and XAS analysis of the resulting copper complexes demonstrates that they are good Cu(II) bound structural mimics of Cu-only SODs. Furthermore, all the complexes exhibit SOD activity, though three orders of magnitude slower than the native enzyme, making them the first de novo copper SOD mimics.

Domaines: Chimie

Emilie Mathieu, Audrey Tolbert, Karl Koebke, Cédric Tard, Olga Iranzo, et al.. Rational De Novo Design of a Cu-Metalloenzyme for Superoxide Dismutation. Chemistry - A European Journal, 2020, 26 (1), pp.249-258. ⟨10.1002/chem.201903808⟩. ⟨hal-02402535⟩