New insights into the mechanism of substrates trafficking in Glyoxylate/Hydroxypyruvate reductases

Abstract : Glyoxylate accumulation within cells is highly toxic. In humans, it is associated with hyperoxaluria type 2 (PH2) leading to renal failure. The glyoxylate content within cells is regulated by the NADPH/NADH dependent glyoxylate/hydroxypyruvate reductases (GRHPR). These are highly conserved enzymes with a dual activity as they are able to reduce glyoxylate to glycolate and to convert hydroxypyruvate into D-glycerate. Despite the determination of high-resolution X-ray structures, the substrate recognition mode of this class of enzymes remains unclear. We determined the structure at 2.0 Å resolution of a thermostable GRHPR from Archaea as a ternary complex in the presence of D-glycerate and NADPH. This shows a binding mode conserved between human and archeal enzymes. We also determined the first structure of GRHPR in presence of glyoxylate at 1.40 Å resolution. This revealed the pivotal role of Leu53 and Trp138 in substrate trafficking. These residues act as gatekeepers at the entrance of a tunnel connecting the active site to protein surface. Taken together, these results allowed us to propose a general model for GRHPR mode of action.
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Scientific Reports, Nature Publishing Group, 2016, 6, 〈10.1038/srep20629〉
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http://hal.univ-grenoble-alpes.fr/hal-01280214
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Soumis le : lundi 29 février 2016 - 10:52:08
Dernière modification le : lundi 19 février 2018 - 14:34:03

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Louise Lassalle, Sylvain Engilberge, Dominique Madern, Pierre Vauclare, Bruno Franzetti, et al.. New insights into the mechanism of substrates trafficking in Glyoxylate/Hydroxypyruvate reductases. Scientific Reports, Nature Publishing Group, 2016, 6, 〈10.1038/srep20629〉. 〈hal-01280214〉

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