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http://purl.uniprot.org/citations/10745013http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/10745013http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/10745013http://www.w3.org/2000/01/rdf-schema#comment"

Background

Glucose-6-phosphate dehydrogenase (G6PD) catalyses the first committed step in the pentose phosphate pathway; the generation of NADPH by this enzyme is essential for protection against oxidative stress. The human enzyme is in a dimer<-->tetramer equilibrium and its stability is dependent on NADP(+) concentration. G6PD deficiency results from many different point mutations in the X-linked gene encoding G6PD and is the most common human enzymopathy. Severe deficiency causes chronic non-spherocytic haemolytic anaemia; the usual symptoms are neonatal jaundice, favism and haemolytic anaemia.

Results

We have determined the first crystal structure of a human G6PD (the mutant Canton, Arg459-->Leu) at 3 A resolution. The tetramer is a dimer of dimers. Despite very similar dimer topology, there are two major differences from G6PD of Leuconostoc mesenteroides: a structural NADP(+) molecule, close to the dimer interface but integral to the subunit, is visible in all subunits of the human enzyme; and an intrasubunit disulphide bond tethers the otherwise disordered N-terminal segment. The few dimer-dimer contacts making the tetramer are charge-charge interactions.

Conclusions

The importance of NADP(+) for stability is explained by the structural NADP(+) site, which is not conserved in prokaryotes. The structure shows that point mutations causing severe deficiency predominate close to the structural NADP(+) and the dimer interface, primarily affecting the stability of the molecule. They also indicate that a stable dimer is essential to retain activity in vivo. As there is an absolute requirement for some G6PD activity, residues essential for coenzyme or substrate binding are rarely modified."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.org/dc/terms/identifier"doi:10.1016/s0969-2126(00)00104-0"xsd:string
http://purl.uniprot.org/citations/10745013http://purl.org/dc/terms/identifier"doi:10.1016/s0969-2126(00)00104-0"xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/author"Adams M.J."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/author"Adams M.J."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/author"Au S.W."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/author"Au S.W."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/author"Gover S."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/author"Gover S."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/author"Lam V.M."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/author"Lam V.M."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/date"2000"xsd:gYear
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/date"2000"xsd:gYear
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/name"Structure"xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/name"Structure"xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/pages"293-303"xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/pages"293-303"xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/title"Human glucose-6-phosphate dehydrogenase: the crystal structure reveals a structural NADP(+) molecule and provides insights into enzyme deficiency."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/title"Human glucose-6-phosphate dehydrogenase: the crystal structure reveals a structural NADP(+) molecule and provides insights into enzyme deficiency."xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/volume"8"xsd:string
http://purl.uniprot.org/citations/10745013http://purl.uniprot.org/core/volume"8"xsd:string
http://purl.uniprot.org/citations/10745013http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/10745013
http://purl.uniprot.org/citations/10745013http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/10745013
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