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Sci Rep. 2016 Feb 11;6:20629. doi: 10.1038/srep20629.

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

Lassalle L1,2,3, Engilberge S1,2,3, Madern D1,2,3, Vauclare P1,2,3, Franzetti B1,2,3, Girard E1,2,3.

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Univ. Grenoble Alpes, IBS, F-38044 Grenoble, France.
CNRS, IBS, F-38044 Grenoble, France.
CEA, IBS, F-38044 Grenoble, France.


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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