7toe - Revision history

OCA at 08:57, 4 June 2025

2025-06-04T08:57:51Z

← Older revision		Revision as of 08:57, 4 June 2025
Line 15:		Line 15:
	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.		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.

	~~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<ref>PMID:35858355</ref>		, PMID:35858355<ref>PMID:35858355</ref>

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

OCA at 05:54, 5 June 2024

2024-06-05T05:54:58Z

← Older revision		Revision as of 05:54, 5 June 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7toe]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TOE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TOE FirstGlance]. <br>		<table><tr><td colspan='2'>[[7toe]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TOE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TOE FirstGlance]. <br>
	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7toe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7toe OCA], [https://pdbe.org/7toe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7toe RCSB], [https://www.ebi.ac.uk/pdbsum/7toe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7toe ProSAT]</span></td></tr>		</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution\|Resolution]] 3Å</td></tr>
			<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7toe FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7toe OCA], [https://pdbe.org/7toe PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7toe RCSB], [https://www.ebi.ac.uk/pdbsum/7toe PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7toe ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== Disease ==
	[[https://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN]] Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:[https://omim.org/entry/305900 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.<ref>PMID:1611091</ref>		[https://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN] Defects in G6PD are the cause of chronic non-spherocytic hemolytic anemia (CNSHA) [MIM:[https://omim.org/entry/305900 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.<ref>PMID:1611091</ref>
	== Function ==		== Function ==
	[[https://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN]] Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power.		[https://www.uniprot.org/uniprot/G6PD_HUMAN G6PD_HUMAN] Produces pentose sugars for nucleic acid synthesis and main producer of NADPH reducing power.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== 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.		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.

	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<ref>PMID:35858355</ref>		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<ref>PMID:35858355</ref>

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

OCA at 06:55, 14 September 2022

2022-09-14T06:55:23Z

@@ Line 1: / Line 1: @@
-The entry 7toe is ON HOLD
+==Structure of G6PD-WT tetramer with no symmetry imposed==
-Authors: Wei, X., Marmorstein, R.
+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<ref>PMID:35858355</ref>
-Description: Structure of G6PD-WT tetramer with no symmetry imposed
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Wei, X]]
+<div class="pdbe-citations 7toe" style="background-color:#fffaf0;"></div>
-[[Category: Marmorstein, R]]
+== References ==

OCA at 09:07, 16 February 2022

2022-02-16T09:07:43Z

← Older revision		Revision as of 09:07, 16 February 2022
Line 5:		Line 5:
	Authors: Wei, X., Marmorstein, R.		Authors: Wei, X., Marmorstein, R.

	Description: ~~structure~~ of G6PD-WT tetramer with no symmetry imposed		Description: Structure of G6PD-WT tetramer with no symmetry imposed
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Wei, X]]		[[Category: Wei, X]]
	[[Category: Marmorstein, R]]		[[Category: Marmorstein, R]]

OCA: Protected "7toe" [edit=sysop:move=sysop]

2022-02-02T05:38:50Z

Protected "7toe" [edit=sysop:move=sysop]

← Older revision	Revision as of 05:38, 2 February 2022
(No difference)

OCA: New page: '''Unreleased structure''' The entry 7toe is ON HOLD Authors: Wei, X., Marmorstein, R. Description: structure of G6PD-WT tetramer with no symmetry imposed [[Category: Unreleased Struct...

2022-02-02T05:38:49Z

New page: '''Unreleased structure''' The entry 7toe is ON HOLD Authors: Wei, X., Marmorstein, R. Description: structure of G6PD-WT tetramer with no symmetry imposed [[Category: Unreleased Struct...

New page

'''Unreleased structure'''

The entry 7toe is ON HOLD

Authors: Wei, X., Marmorstein, R.

Description: structure of G6PD-WT tetramer with no symmetry imposed
[[Category: Unreleased Structures]]
[[Category: Wei, X]]
[[Category: Marmorstein, R]]