Phosphogluconate dehydrogenase (decarboxylating)

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phosphogluconate dehydrogenase (decarboxylating)
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Phosphogluconate dehydrogenase dimer, Sheep
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EC no. 1.1.1.44
CAS no. 9073-95-4
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In enzymology, a phosphogluconate dehydrogenase (decarboxylating) (EC 1.1.1.44) is an enzyme that catalyzes the chemical reaction

Contents

6-phospho-D-gluconate + NADP+ D-ribulose 5-phosphate + CO2 + NADPH

Thus, the two substrates of this enzyme are 6-phospho-D-gluconate and NADP+, whereas its 3 products are D-ribulose 5-phosphate, CO2, and NADPH.

This enzyme belongs to the family of oxidoreductases, specifically those acting on the CH-OH group of donor with NAD+ or NADP+ as acceptor. The systematic name of this enzyme class is 6-phospho-D-gluconate:NADP+ 2-oxidoreductase (decarboxylating). Other names in common use include phosphogluconic acid dehydrogenase, 6-phosphogluconic dehydrogenase, 6-phosphogluconic carboxylase, 6-phosphogluconate dehydrogenase (decarboxylating), and 6-phospho-D-gluconate dehydrogenase. This enzyme participates in pentose phosphate pathway. It employs one cofactor, manganese.

Enzyme Structure

The general structure, as well as several critical residues, on 6-phosphogluconate dehydrogenase appear to be well conserved over various species. The enzyme is a dimer, with each subunit containing three domains. The N-terminal coenzyme binding domain contains a Rossmann fold with additional α/β units. The second domain consists of a number of alpha helical structures, and the C-terminal domain consists of a short tail. [1] The tails of the two subunits interact with each other to form a mobile lid on the enzyme's active site. [2]

As of late 2007, 11 structures have been solved for this class of enzymes, with PDB accession codes 1PGJ, 1PGN, 1PGO, 1PGP, 1PGQ, 2IYO, 2IYP, 2IZ0, 2IZ1, 2P4Q, and 2PGD.

Enzyme Mechanism

The conversion of 6-phosphogluconate and NADP to ribulose 5-phosphate, carbon dioxide, and NADPH is believed to follow a sequential mechanism with ordered product release. 6-phosphogluconate is first oxidized to 3-keto-6-phosphogluconate and NADPH is formed and released. Then, the intermediate is decarboxylated, yielding a 1,2-enediol of ribulose 5-phosphate, which tautomerizes to form ribulose 5-phosphate. [3] High levels of NADPH are believed to inhibit the enzyme, while 6-phosphogluconate acts to activate the enzyme. [4]

Biological Function

6-phosphogluconate dehydrogenase is involved in the production of ribulose 5-phosphate, which is used in nucleotide synthesis, and functions in the pentose phosphate pathway as the main generator of cellular NADPH. [5]

Disease Relevance

Since NADPH is required by both thioredoxin reductase and glutathione reductase to reduce oxidized thioredoxin and glutathionine, 6-phosphogluconate dehydrogenase is believed to be involved in protecting cells from oxidative damage. [6] Several studies have linked oxidative stress to diseases such as Alzheimer's disease, [7] [8] as well as cancer, [9] [10] These studies have found phosphogluconate dehydrogenase activity to be up-regulated, both in tumor cells and in relevant cortical regions of Alzheimer's patient brains, [11] most likely as a compensatory reaction to highly oxidative environments.

Recently, phosphogluconate dehydrogenase has been posited as a potential drug target for African sleeping sickness (trypanosomiasis). The pentose phosphate pathway protects the trypanosomes from oxidative stress via the generation of NADPH and provides carbohydrate intermediates used in nucleotide synthesis. [12] Structural differences between mammalian and trypanosome 6-phosphogluconate dehydrogenase have allowed for the development of selective inhibitors of the enzyme. Phosphorylated carbohydrate substrate and transition state analogues, non-carbohydrate substrate analogues and triphenylmethane-based compounds are currently being explored. [13]

Related Research Articles

<span class="mw-page-title-main">Entner–Doudoroff pathway</span> Series of interconnected biochemical reactions

The Entner–Doudoroff pathway is a metabolic pathway that is most notable in Gram-negative bacteria, certain Gram-positive bacteria and archaea. Glucose is the substrate in the ED pathway and through a series of enzyme assisted chemical reactions it is catabolized into pyruvate. Entner and Doudoroff (1952) and MacGee and Doudoroff (1954) first reported the ED pathway in the bacterium Pseudomonas saccharophila. While originally thought to be just an alternative to glycolysis (EMP) and the pentose phosphate pathway (PPP), some studies now suggest that the original role of the EMP may have originally been about anabolism and repurposed over time to catabolism, meaning the ED pathway may be the older pathway. Recent studies have also shown the prevalence of the ED pathway may be more widespread than first predicted with evidence supporting the presence of the pathway in cyanobacteria, ferns, algae, mosses, and plants. Specifically, there is direct evidence that Hordeum vulgare uses the Entner–Doudoroff pathway.

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide phosphate</span> Chemical compound

Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or, in older notation, TPN (triphosphopyridine nucleotide), is a cofactor used in anabolic reactions, such as the Calvin cycle and lipid and nucleic acid syntheses, which require NADPH as a reducing agent ('hydrogen source'). NADPH is the reduced form, whereas NADP+ is the oxidized form. NADP+ is used by all forms of cellular life.

<span class="mw-page-title-main">Calvin cycle</span> Light-independent reactions in photosynthesis

The Calvin cycle, light-independent reactions, bio synthetic phase, dark reactions, or photosynthetic carbon reduction (PCR) cycle of photosynthesis is a series of chemical reactions that convert carbon dioxide and hydrogen-carrier compounds into glucose. The Calvin cycle is present in all photosynthetic eukaryotes and also many photosynthetic bacteria. In plants, these reactions occur in the stroma, the fluid-filled region of a chloroplast outside the thylakoid membranes. These reactions take the products of light-dependent reactions and perform further chemical processes on them. The Calvin cycle uses the chemical energy of ATP and reducing power of NADPH from the light dependent reactions to produce sugars for the plant to use. These substrates are used in a series of reduction-oxidation (redox) reactions to produce sugars in a step-wise process; there is no direct reaction that converts several molecules of CO2 to a sugar. There are three phases to the light-independent reactions, collectively called the Calvin cycle: carboxylation, reduction reactions, and ribulose 1,5-bisphosphate (RuBP) regeneration.

<span class="mw-page-title-main">Pentose phosphate pathway</span> Series of interconnected biochemical reactions

The pentose phosphate pathway is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses as well as ribose 5-phosphate, a precursor for the synthesis of nucleotides. While the pentose phosphate pathway does involve oxidation of glucose, its primary role is anabolic rather than catabolic. The pathway is especially important in red blood cells (erythrocytes). The reactions of the pathway were elucidated in the early 1950s by Bernard Horecker and co-workers.

<span class="mw-page-title-main">Glucose-6-phosphate dehydrogenase</span> Enzyme involved in the production of energy by cells

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

Glyceraldehyde-3-phosphate dehydrogenase (NADP+) (GAPN) is an enzyme that irreversibly catalyzes the oxidation of glyceraldehyde-3-phosphate (GAP) to 3-phosphoglycerate using the reduction of NADP+ to NADPH. GAPN is used in a variant of glycolysis that conserves energy as NADPH rather than as ATP. The NADPH and 3-PG can then be used for synthesis. The most familiar variant of glycolysis uses glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and phosphoglycerate kinase to produce ATP. GAPDH is phosphorylating. GAPN is non-phosphorylating.

<span class="mw-page-title-main">Aldose reductase</span> Enzyme

In enzymology, aldose reductase is an enzyme in humans encoded by the gene AKR1B1. It is an cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides, and primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.

<span class="mw-page-title-main">6-Phosphogluconate dehydrogenase</span> Class of enzymes

6-Phosphogluconate dehydrogenase (6PGD) is an enzyme in the pentose phosphate pathway. It forms ribulose 5-phosphate from 6-phosphogluconate:

<span class="mw-page-title-main">Ribulose 5-phosphate</span> Chemical compound

Ribulose 5-phosphate is one of the end-products of the pentose phosphate pathway. It is also an intermediate in the Calvin cycle.

<span class="mw-page-title-main">6-Phosphogluconic acid</span> Chemical compound

6-Phosphogluconic acid is a phosphorylated sugar acid which appears in the pentose phosphate pathway and the Entner–Doudoroff pathway.

<span class="mw-page-title-main">Ribose 5-phosphate</span> Chemical compound

Ribose 5-phosphate (R5P) is both a product and an intermediate of the pentose phosphate pathway. The last step of the oxidative reactions in the pentose phosphate pathway is the production of ribulose 5-phosphate. Depending on the body's state, ribulose 5-phosphate can reversibly isomerize to ribose 5-phosphate. Ribulose 5-phosphate can alternatively undergo a series of isomerizations as well as transaldolations and transketolations that result in the production of other pentose phosphates as well as fructose 6-phosphate and glyceraldehyde 3-phosphate.

<span class="mw-page-title-main">6-phosphogluconolactonase</span> Cytosolic enzyme

6-Phosphogluconolactonase (EC 3.1.1.31, 6PGL, PGLS, systematic name 6-phospho-D-glucono-1,5-lactone lactonohydrolase) is a cytosolic enzyme found in all organisms that catalyzes the hydrolysis of 6-phosphogluconolactone to 6-phosphogluconic acid in the oxidative phase of the pentose phosphate pathway:

In enzymology, a glycerol-3-phosphate 1-dehydrogenase (NADP+) (EC 1.1.1.177) is an enzyme that catalyzes the chemical reaction

In enzymology, a glyceraldehyde-3-phosphate dehydrogenase (NADP+) (phosphorylating) (EC 1.2.1.13) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Ribose-5-phosphate isomerase</span>

Ribose-5-phosphate isomerase (Rpi) encoded by the RPIA gene is an enzyme that catalyzes the conversion between ribose-5-phosphate (R5P) and ribulose-5-phosphate (Ru5P). It is a member of a larger class of isomerases which catalyze the interconversion of chemical isomers. It plays a vital role in biochemical metabolism in both the pentose phosphate pathway and the Calvin cycle. The systematic name of this enzyme class is D-ribose-5-phosphate aldose-ketose-isomerase.

<span class="mw-page-title-main">2-Dehydro-3-deoxy-phosphogluconate aldolase</span> Class of enzymes

The enzyme 2-dehydro-3-deoxy-phosphogluconate aldolase, commonly known as KDPG aldolase, catalyzes the chemical reaction

<span class="mw-page-title-main">Phosphogluconate dehydratase</span>

The enzyme phosphogluconate dehydratase (EC 4.2.1.12) catalyzes the chemical reaction

<span class="mw-page-title-main">Gluconokinase</span>

In enzymology, a gluconokinase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">6-phosphogluconate dehydrogenase deficiency</span> Medical condition

6-Phosphogluconate dehydrogenase deficiency, or partial deficiency, is an autosomal hereditary disease characterized by abnormally low levels of 6-phosphogluconate dehydrogenase (6PGD), a metabolic enzyme involved in the Pentose phosphate pathway. It is very important in the metabolism of red blood cells (erythrocytes). 6PDG deficiency affects less than 1% of the population, and studies suggest that there may be race variant involved in many of the reported cases. Although it is similar, 6PDG deficiency is not linked to glucose-6-phosphate dehydrogenase (G6PD) deficiency, as they are located on different chromosomes. However, a few people have had both of these metabolic diseases.

<span class="mw-page-title-main">Bernard Horecker</span>

Bernard Leonard (Bernie) Horecker (1914–2010) was an American biochemist known for work on the pentose phosphate pathway, and for cellular regulation in general.

References

  1. ↑ Phillips C, Gover S, Adams MJ (1995). "Structure of 6-phosphogluconate dehydrogenase refined at 2 Å resolution" (PDF). Acta Crystallogr. D. 51 (3): 290–304. Bibcode:1995AcCrD..51..290P. doi:10.1107/S0907444994012229. PMID   15299295.
  2. ↑ He W, Wang Y, Liu W, Zhou CZ (2007). "Crystal structure of Saccharomyces cerevisiae 6-phosphogluconate dehydrogenase Gnd1". BMC Struct. Biol. 7: 38. doi: 10.1186/1472-6807-7-38 . PMC   1919378 . PMID   17570834.
  3. ↑ Chen YY, Ko TP, Chen WH, Lo LP, Lin CH, Wang AH (2010). "Conformational changes associated with cofactor/substrate binding of 6-phosphogluconate dehydrogenase from Escherichia coli and Klebsiella pneumoniae: Implications for enzyme mechanism" (PDF). J. Struct. Biol. 169 (1): 25–35. doi:10.1016/j.jsb.2009.08.006. PMID   19686854.
  4. ↑ Rippa M, Giovannini PP, Barrett MP, Dallocchio F, Hanau S (1998). "6-Phosphogluconate dehydrogenase: the mechanism of action investigated by a comparison of the enzyme from different species". Biochim. Biophys. Acta. 1429 (1): 83–92. doi:10.1016/S0167-4838(98)00222-2. PMID   9920387.
  5. ↑ He W, Wang Y, Liu W, Zhou CZ (2007). "Crystal structure of Saccharomyces cerevisiae 6-phosphogluconate dehydrogenase Gnd1". BMC Struct. Biol. 7: 38. doi: 10.1186/1472-6807-7-38 . PMC   1919378 . PMID   17570834.
  6. ↑ He W, Wang Y, Liu W, Zhou CZ (2007). "Crystal structure of Saccharomyces cerevisiae 6-phosphogluconate dehydrogenase Gnd1". BMC Struct. Biol. 7: 38. doi: 10.1186/1472-6807-7-38 . PMC   1919378 . PMID   17570834.
  7. ↑ Palmer AM (1999). "The activity of the pentose phosphate pathway is increased in response to oxidative stress in Alzheimer's disease". J. Neural Transm. 106 (3–4): 317–328. doi:10.1007/s007020050161. PMID   10392540. S2CID   20352349.
  8. ↑ Martins RN, Harper CG, Stokes GB, Masters CL (1986). "Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer's disease may reflect oxidative stress". J. Neurochem. 46 (4): 1042–1045. doi:10.1111/j.1471-4159.1986.tb00615.x. PMID   3950618. S2CID   337317.
  9. ↑ Toyokuni S, Okamoto K, Yodoi J, Hiai H (1995). "Persistent oxidative stress in cancer". FEBS Lett. 358 (1): 1–3. doi: 10.1016/0014-5793(94)01368-B . PMID   7821417. S2CID   16090349.
  10. ↑ Nerurkar VR, Ishwad CS, Seshadri R, Naik SN, Lalitha VS (1990). "Glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities in normal canine mammary gland and in mammary tumours and their correlation with oestrogen receptors". J. Comp. Pathol. 102 (2): 191–195. doi:10.1016/S0021-9975(08)80124-7. PMID   2324341.
  11. ↑ Palmer AM (1999). "The activity of the pentose phosphate pathway is increased in response to oxidative stress in Alzheimer's disease". J. Neural Transm. 106 (3–4): 317–328. doi:10.1007/s007020050161. PMID   10392540. S2CID   20352349.
  12. ↑ Dardonville C, Rinaldi E, Hanau S, Barrett MP, Brun R, Gilbert IH (2003). "Synthesis and biological evaluation of substrate-based inhibitors of 6-phosphogluconate dehydrogenase as potential drugs against African trypanosomiasis". Bioorg. Med. Chem. 11 (14): 3205–14. doi:10.1016/S0968-0896(03)00191-3. PMID   12818683.
  13. ↑ Hanau S, Rinaldi E, Dallocchio F, Gilbert IH, Dardonville C, Adams MJ, Gover S, Barrett MP (2004). "6-phosphogluconate dehydrogenase: a target for drugs in African trypanosomes". Curr. Med. Chem. 11 (19): 2639–50. doi:10.2174/0929867043364441. PMID   15544466.
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