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Publication Abstract from PubMed

Human glucose-6-phosphate dehydrogenase (G6PD) is the main cellular source of NADPH, and thus plays a key role in maintaining reduced glutathione to protect cells from oxidative stress disorders such as hemolytic anemia. G6PD is a multimeric enzyme that uses the cofactors beta-D-glucose 6-phosphate (G6P) and "catalytic" NADP(+) (NADP(+)c), as well as a "structural" NADP(+) (NADP(+)s) located approximately 25 A from the active site, to generate NADPH. While X-ray crystallographic and biochemical studies have revealed a role for NADP(+)s in maintaining the catalytic activity by stabilizing the multimeric G6PD conformation, other potential roles for NADP(+)s have not been evaluated. Here, we determined the high resolution cryo-electron microscopy structures of human wild-type G6PD in the absence of bound ligands and a catalytic G6PD-D200N mutant bound to NADP(+)c and NADP(+)s in the absence or presence of G6P. A comparison of these structures, together with previously reported structures, reveals that the unliganded human G6PD forms a mixture of dimers and tetramers with similar overall folds, and binding of NADP(+)s induces a structural ordering of a C-terminal extension region and allosterically regulates G6P binding and catalysis. These studies have implications for understanding G6PD deficiencies and for therapy of G6PD-mediated disorders.

, PMID:35858355^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.