Open AccessStructural studies of glucose‐6‐phosphate and NADP + binding to human glucose‐6‐phosphate dehydrogenase
Author(s) -
Gover Sheila,
Kotaka Masayo,
Au Shan W. N.,
Lam Veronica M. S.,
VandeputteRutten Lucy,
Adams Margaret J.
Publication year - 2005
Publication title -
acta crystallographica section d
Language(s) - English
Resource type - Journals
ISSN - 1399-0047
DOI - 10.1107/s0907444905002350
Subject(s) - pentose phosphate pathway , dehydrogenase , glucose 6 phosphate dehydrogenase , tetramer , cofactor , dimer , glucose 6 phosphate , allosteric regulation , nad+ kinase , stereochemistry , binding site , biochemistry , chemistry , enzyme , biology , glycolysis , organic chemistry
Human glucose‐6‐phosphate dehydrogenase (G6PD) is NADP + ‐dependent and catalyses the first and rate‐limiting step of the pentose phosphate shunt. Binary complexes of the human deletion mutant, ΔG6PD, with glucose‐6‐phosphate and NADP + have been crystallized and their structures solved to 2.9 and 2.5 Å, respectively. The structures are compared with the previously determined structure of the Canton variant of human G6PD (G6PD Canton ) in which NADP + is bound at the structural site. Substrate binding in ΔG6PD is shown to be very similar to that described previously in Leuconostoc mesenteroides G6PD. NADP + binding at the coenzyme site is seen to be comparable to NADP + binding in L. mesenteroides G6PD, although some differences arise as a result of sequence changes. The tetramer interface varies slightly among the human G6PD complexes, suggesting flexibility in the predominantly hydrophilic dimer–dimer interactions. In both complexes, Pro172 of the conserved peptide EKP x G is in the cis conformation; it is seen to be crucial for close approach of the substrate and coenzyme during the enzymatic reaction. Structural NADP + binds in a very similar way in the ΔG6PD–NADP + complex and in G6PD Canton , while in the substrate complex the structural NADP + has low occupancy and the C‐terminal tail at the structural NADP + site is disordered. The implications of possible interaction between the structural NADP + and G6P are considered.