Glucose-6-phosphate dehydrogenase (G6PD)
Hexose Monophosphate Shunt (Pentose Phosphate Cycle)

Author: Daniele Gianetto
Date: 02/07/2009

Description

DEFINITION

Glucose-6-phosphate dehydrogenase is a cytosolic enzyme in the pentose phosphate pathway, 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. It is notable in humans when there is a genetic deficiency which predisposes to non-immune haemolytic anaemia. In higher plants, several isoforms of G6PDH have been reported, which are localized in the cytosol, the plastidic stroma, and peroxisomes.

DatabaseLink
WikigenesURL
GeneCardsURL
iHOPURL
OMIMURL
Ensembl GeneViewURL

CHEMICAL STRUCTURE AND IMAGES

The mammalian enzyme is a homodimer or a homotetramer with a subunit molecular weight of 54 Kd
Isolation of human glucose-6-pbosphate debydrogenase (G6PD) cDNA clones; primary structure of the protein and unusual 5' non-coding region.1986

A dimer of human G6PD viewed down the twofold axis (see image). In subunit A helices are coloured pink and β strands are blue; in subunit B helices and strands are green and orange, respectively. Secondary structure elements are labelled in subunit A. Structural NADP+ molecules are drawn in dark blue in ball-and-stick mode. The dinucleotide-binding fingerprint and conserved peptide are highlighted in purple. The Cα atoms of some residues discussed in detail in the text are drawn as magenta spheres in subunit B. These are Pro172 (cis/trans conformation), Cys446 (disulphide bridge), Arg459 (mutation site of Canton variant), and Glu206, Lys407, Glu419 and Arg427 (involved in salt bridges at the dimer interface). The N-terminal residues 1–26 are not shown.

A molecular model of human G6PD (Fig. 1A) has been constructed, based on the X-ray crystal structure of the Leuconostoc mesenteroides G6PD. The enzyme is a dimer, each subunit consisting of two domains. The smaller domain is a classic dinucleotide-binding fold which contains the coenzyme binding site. The other larger domain is a β + α fold, with a predominantly antiparallel nine-stranded β-sheet. Human G6PD is in a rapid dimer-tetramer equilibrium although in red cells it has been shown to be displaced to the dimeric state. High pH and ionic strength favours dissociation of the tetramer to dimers, while low values of pH and ionic strength plus divalent cations shift the equilibrium towards tetramers. The smallest functional unit of the human G6PD is the dimer.
Amino acid substitutions at the dimer interface of human glucose-6-phosphate dehydrogenase that increase thermostability and reduce the stabilising effect of NADP

PROTEIN AMINOACIDS PERCENTAGE

SYNTHESIS AND TURNOVER

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.

Cloning, characterization and computational analysis of the 5' regulatory region of ovine glucose 6-phosphate dehydrogenase gene. 2007

Nutrition and gene expression Di Carolyn D. Berdanier, James L. Hargrove

CELLULAR FUNCTIONS

The G6PD enzyme functions in catalyzing the oxidation of glucose-6-phosphate to 6-phosphogluconate, while concomitantly reducing nicotinamide adenine dinucleotide phosphate (NADP+ to NADPH); or, in terms of electron transfer, glucose-6-phosphate loses two electrons to become 6-phosphogluconate and NADP+ gains two electrons to become NADPH. This is the first step in the pentose phosphate pathway. In addition to producing the 5-carbon sugar ribose, G6PD is also responsible for maintaining adequate levels of NADPH inside the cell. NADPH is a required cofactor in many biosynthetic reactions. NADPH is also used to keep glutathione, a tri-peptide, in its reduced form.

REGULATION

The enzyme, glucose-6-phosphate dehydrogenase (G6PDH, EC1.1.1.49), has long been considered and studied as the archetypical X-linked "housekeeping" enzyme that is present in all cells, where it plays the key role in regulating carbon flow through the pentose phosphate pathway. Specifically, the enzyme catalyzes the first reaction in the pathway leading to the production of pentose phosphates and reducing power in the form of NADPH for reductive biosynthesis and maintenance of the redox state of the cell. It was in this latter function that the crucial importance of the enzyme was first appreciated with the description of the human deficiency syndrome. While the gene can be considered to be a constitutively expressed "housekeeping" gene in many tissues, there are several other tissues (liver, adipose, lung, and proliferating cells) wherein modulation of cellular G6PDH activity represents an important component of the integrated response to external stimuli (hormones, growth factors, nutrients, and oxidant stress). In this regard, adaptive regulation of G6PDH has been found to be exerted at transcriptional and posttranscriptional levels.
Glucose-6-phosphate dehydrogenase: a “housekeeping” enzyme subject to tissue specific regulation by hormones, nutrients, and oxidant stress.1994

Papers G6PD and Fibroblasts

Attachments
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3724_fig3.gifdaniele2009-07-02T00:00:00
3725_G6PD_image.jpgdaniele2009-07-02T00:00:00
Fig._1A.jpgdaniele2009-07-02T00:00:00
G6PD.jpegdaniele2009-07-02T00:00:00
G6PD1.docdaniele2009-07-02T00:00:00
G6PD_image.jpgdaniele2009-07-02T00:00:00
G6PD_mechanism.pngdaniele2009-07-02T00:00:00
fig3.gifdaniele2009-07-02T00:00:00
g6pd--600.gifgp2009-10-19T00:00:00
tabella_nutrienti.jpgdaniele2009-07-20T00:00:00
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