7sng
structure of G6PD-WT tetramer
Structural highlights
DiseaseG6PD_HUMAN Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:305900. Deficiency of G6PD is associated with hemolytic anemia in two different situations. First, in areas in which malaria has been endemic, G6PD-deficiency alleles have reached high frequencies (1% to 50%) and deficient individuals, though essentially asymptomatic in the steady state, have a high risk of acute hemolytic attacks. Secondly, sporadic cases of G6PD deficiency occur at a very low frequencies, and they usually present a more severe phenotype. Several types of CNSHA are recognized. Class-I variants are associated with severe NSHA; class-II have an activity <10% of normal; class-III have an activity of 10% to 60% of normal; class-IV have near normal activity.[1] FunctionG6PD_HUMAN Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power. Publication Abstract from PubMedHuman 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. Allosteric role of a structural NADP(+) molecule in glucose-6-phosphate dehydrogenase activity.,Wei X, Kixmoeller K, Baltrusaitis E, Yang X, Marmorstein R Proc Natl Acad Sci U S A. 2022 Jul 19;119(29):e2119695119. doi: , 10.1073/pnas.2119695119. Epub 2022 Jul 12. PMID:35858355[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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