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-Structure paper
タイトル | Allosteric role of a structural NADP molecule in glucose-6-phosphate dehydrogenase activity. |
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ジャーナル・号・ページ | Proc Natl Acad Sci U S A, Vol. 119, Issue 29, Page e2119695119, Year 2022 |
掲載日 | 2022年7月19日 |
著者 | Xuepeng Wei / Kathryn Kixmoeller / Elana Baltrusaitis / Xiaolu Yang / Ronen Marmorstein / |
PubMed 要旨 | 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 ...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 β-D-glucose 6-phosphate (G6P) and "catalytic" NADP (NADPc), as well as a "structural" NADP (NADPs) located ∼25 Å from the active site, to generate NADPH. While X-ray crystallographic and biochemical studies have revealed a role for NADPs in maintaining the catalytic activity by stabilizing the multimeric G6PD conformation, other potential roles for NADPs 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 NADPc and NADPs 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 NADPs 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. |
リンク | Proc Natl Acad Sci U S A / PubMed:35858355 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.2 - 3.7 Å |
構造データ | EMDB-25224, PDB-7snf: EMDB-25225, PDB-7sng: EMDB-25226, PDB-7snh: EMDB-25227, PDB-7sni: EMDB-26030, PDB-7toe: EMDB-26031, PDB-7tof: EMDB-26428, PDB-7ual: EMDB-26442, PDB-7uc2: |
化合物 | ChemComp-HOH: ChemComp-NAP: ChemComp-BG6: |
由来 |
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キーワード | OXIDOREDUCTASE / dehydrogenase / apo protein / D200N mutant / Glucose-6-phosphate 1-dehydrogenase |