Glucose-6-phosphate dehydrogenase

Gene ontology
Molecular function	• glucose-6-phosphate dehydrogenase activity • protein binding • glucose binding • identical protein binding • protein homodimerization activity • NADP binding
Cellular component	• nucleus • cytoplasm • centrosome • microtubule organizing center • cytosol • cytoplasmic side of plasma membrane • membrane • intracellular membrane-bounded organelle • extracellular exosome
Biological process	• cytokine production • carbohydrate metabolic process • glucose metabolic process • pentose-phosphate shunt • transcription initiation from RNA polymerase II promoter • lipid metabolic process • cholesterol biosynthetic process • NADP metabolic process • NADPH regeneration • glutathione metabolic process • pentose-phosphate shunt, oxidative branch • gene expression • negative regulation of protein glutathionylation • response to organic cyclic compound • pentose biosynthetic process • substantia nigra development • response to food • cellular response to oxidative stress • erythrocyte maturation • regulation of neuron apoptotic process • small molecule metabolic process • response to ethanol • ribose phosphate biosynthetic process • glucose 6-phosphate metabolic process • oxidation-reduction process
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr X:
154.53 – 154.55 Mb

Chr X:
74.41 – 74.43 Mb

PubMed search

Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) (EC 1.1.1.49) is a cytosolic enzyme that catalyzes the chemical reaction

D-glucose 6-phosphate + NADP⁺

\rightleftharpoons

6-phospho-D-glucono-1,5-lactone + NADPH + H⁺

This enzyme is in the pentose phosphate pathway (see image), a metabolic pathway that supplies reducing energy to cells (such as erythrocytes) by maintaining the level of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the level of glutathione in these cells that helps protect the red blood cells against oxidative damage. Of greater quantitative importance is the production of NADPH for tissues actively engaged in biosynthesis of fatty acids and/or isoprenoids, such as the liver, mammary glands, adipose tissue, and the adrenal glands. G6PD reduces nicotinamide adenine dinucleotide phosphate (NADP) to NADPH while oxidizing glucose-6-phosphate.^[1]

It is notable in humans when there is a genetic deficiency of G6PD which predisposes to non-immune hemolytic anemia .

Species distribution

G6PD is widely distributed in many species from bacteria to humans. In higher plants, several isoforms of G6PDH have been reported, which are localized in the cytosol, the plastidic stroma, and peroxisomes.^[2] Humans have two isoforms of a single gene coding for G6PD.^[3]

Regulation

Glucose-6-phosphate dehydrogenase is stimulated by its substrate Glucose 6 Phosphate. The usual ratio of NADPH/NADP⁺ in the cytosol of tissues engaged in biosyntheses is about 100/1. Increased utilization of NADPH for fatty acid biosynthesis will dramatically increase the level of NADP⁺, thus stimulating G6PD to produce more NADPH.

G6PD converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of the pentose phosphate pathway.

G6PD is one of a number of glycolytic enzymes activated by the transcription factor Hypoxia-inducible factor 1 (HIF1).^[4]

G6PD is negatively regulated by acetylation on lysine 403 (K403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulates pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes.^[5]

Clinical significance

G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations, have been described with wide ranging levels of enzyme activity and associated clinical symptoms. Two transcript variants encoding different isoforms have been found for this gene.^[6]

Glucose-6-phosphate dehydrogenase deficiency is very common worldwide, and causes acute hemolytic anemia in the presence of simple infection, ingestion of fava beans, or reaction with certain medicines, antibiotics, antipyretics, and antimalarials.^[7]

Cell growth and proliferation are affected by G6PD.^[8] G6PD inhibitors are under investigation to treat cancers and other conditions.^[4] DHEA is a G6PD inhibitor.^[8]

References

↑ Aster J, Kumar V, Robbins SL, Abbas AK, Fausto N, Cotran RS (2010). Robbins and Cotran Pathologic Basis of Disease. Saunders/Elsevier. pp. Kindle Locations 33340–33341. ISBN 1-4160-3121-9.
↑ Corpas FJ, Barroso JB, Sandalio LM, Distefano S, Palma JM, Lupiáñez JA, Del Río LA (Mar 1998). "A dehydrogenase-mediated recycling system of NADPH in plant peroxisomes". The Biochemical Journal 330 (Pt 2): 777–84. doi:10.1042/bj3300777. PMC 1219205. PMID 9480890.
↑ "G6PD glucose-6-phosphate dehydrogenase [ Homo sapiens (human) ]". NCBI. Retrieved 13 December 2015.
1 2 de Lartigue J (2012-06-12). "Cancer Research Moves Beyond the Original Hallmarks of Cancer". OncLive.
↑ Wang YP, Zhou LS, Zhao YZ, Wang SW, Chen LL, Liu LX, Ling ZQ, Hu FJ, Sun YP, Zhang JY, Yang C, Yang Y, Xiong Y, Guan KL, Ye D (Jun 2014). "Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress". The EMBO Journal 33 (12): 1304–20. doi:10.1002/embj.201387224. PMID 24769394.
↑ "Entrez Gene: G6PD glucose-6-phosphate dehydrogenase".
↑ Cappellini MD, Fiorelli G (Jan 2008). "Glucose-6-phosphate dehydrogenase deficiency". Lancet 371 (9606): 64–74. doi:10.1016/S0140-6736(08)60073-2. PMID 18177777.
1 2 Tian WN, Braunstein LD, Pang J, Stuhlmeier KM, Xi QC, Tian X, Stanton RC (Apr 1998). "Importance of glucose-6-phosphate dehydrogenase activity for cell growth". The Journal of Biological Chemistry 273 (17): 10609–17. doi:10.1074/jbc.273.17.10609. PMID 9553122.

External links

PDB gallery

1qki: X-RAY STRUCTURE OF HUMAN GLUCOSE 6-PHOSPHATE DEHYDROGENASE (VARIANT CANTON R459L) COMPLEXED WITH STRUCTURAL NADP+

2bh9: X-RAY STRUCTURE OF A DELETION VARIANT OF HUMAN GLUCOSE 6-PHOSPHATE DEHYDROGENASE COMPLEXED WITH STRUCTURAL AND COENZYME NADP

2bhl: X-RAY STRUCTURE OF HUMAN GLUCOSE-6-PHOSPHATE DEHYDROGENASE (DELETION VARIANT) COMPLEXED WITH GLUCOSE-6-PHOSPHATE

Metabolism: carbohydrate metabolism · pentose phosphate pathway enzymes

oxidative	Glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase Phosphogluconate dehydrogenase

nonoxidative	Phosphopentose isomerase Phosphopentose epimerase Transketolase Transaldolase

Oxidoreductases: alcohol oxidoreductases (EC 1.1)

1.1.1: NAD/NADP acceptor	3-hydroxyacyl-CoA dehydrogenase 3-hydroxybutyryl-CoA dehydrogenase Alcohol dehydrogenase Aldo-keto reductase 1A1 1B1 1B10 1C1 1C3 1C4 7A2 Aldose reductase Beta-Ketoacyl ACP reductase Carbohydrate dehydrogenases Carnitine dehydrogenase D-malate dehydrogenase (decarboxylating) DXP reductoisomerase Glucose-6-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase HMG-CoA reductase IMP dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase L-threonine dehydrogenase L-xylulose reductase Malate dehydrogenase Malate dehydrogenase (decarboxylating) Malate dehydrogenase (NADP+) Malate dehydrogenase (oxaloacetate-decarboxylating) Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) Phosphogluconate dehydrogenase Sorbitol dehydrogenase Hydroxysteroid dehydrogenase: 3 Beta 3-beta-HSD NSDHL 11 Beta HSD11B1 HSD11B2 17 Beta

1.1.2: cytochrome acceptor	D-lactate dehydrogenase (cytochrome) D-lactate dehydrogenase (cytochrome c-553) Mannitol dehydrogenase (cytochrome)

1.1.3: oxygen acceptor	Glucose oxidase L-gulonolactone oxidase Xanthine oxidase

1.1.4: disulfide as acceptor	Vitamin K epoxide reductase Vitamin-K-epoxide reductase (warfarin-insensitive)

1.1.5: quinone/similar acceptor	Malate dehydrogenase (quinone) Quinoprotein glucose dehydrogenase

1.1.99: other acceptors	Choline dehydrogenase L2HGDH

Proteins: enzymes

Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Catalytically perfect enzyme Coenzyme Cofactor Enzyme catalysis Enzyme kinetics Lineweaver–Burk plot Michaelis–Menten kinetics

Regulation	Allosteric regulation Cooperativity Enzyme inhibitor

Classification	EC number Enzyme superfamily Enzyme family List of enzymes

Types	EC1 Oxidoreductases(list) EC2 Transferases(list) EC3 Hydrolases(list) EC4 Lyases(list) EC5 Isomerases(list) EC6 Ligases(list)

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