6-phosphogluconolactonase
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Chr. 19 p13.2 | |||||||
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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:[2]
- 6-phospho-D-glucono-1,5-lactone + H2O = 6-phospho-D-gluconate
The tertiary structure of 6PGL employs an
Enzyme Mechanism
6PGL hydrolysis of 6-phosphogluconolactone to 6-phosphogluconic acid has been proposed to proceed via proton transfer to the O5 ring oxygen atom,[4] similar to xylose isomerase[5] and ribose-5-phosphate isomerase.[6] The reaction initiates via attack of a hydroxide ion at the C5 ester. A tetrahedral intermediate forms and elimination of the ester linkage follows, aided by donation of a proton from an active site histidine residue. The specific residue that participates in the proton transfer eluded researchers until 2009, as previous structural studies demonstrated two possible conformations of the substrate in the active site, which position the O5 ring oxygen proximal to either an arginine or a histidine residue.[1] Molecular dynamic simulations were employed to discover that the residue that donates a proton is histidine, and that the arginine residues are only involved in electric stabilization of the negatively charged phosphate group.[4] Electric stabilization of the enzyme-substrate complex also occurs between the product carboxylate and backbone amines of surrounding glycine residues.[4]
Enzyme Structure
6PGL in
Biological Function
6-phosphogluconolactonase catalyzes the conversion of 6-phosphogluconolactone to 6-phosphogluconic acid, both intermediates in the oxidative phase of the pentose phosphate pathway, in which glucose is converted into ribulose 5-phosphate. The oxidative phase of the pentose phosphate pathway releases CO2 and results in the generation of two equivalents of NADPH from NADP+. The final product, ribulose 5-phosphate, is further processed by the organism during the non-oxidative phase of the pentose phosphate pathway to synthesize biomolecules including nucleotides, ATP, and Coenzyme A.[2]
The enzyme that precedes 6PGL in the pentose phosphate pathway,
Disease Relevance
Malarial parasites Plasmodium berghei and Plasmodium falciparum have been shown to express a bi-functional enzyme that exhibits both glucose-6-phosphate dehydrogenase and 6-phosphogluconolactonase activity, enabling it to catalyze the first two steps of the pentose phosphate pathway.[10] This bifunctional enzyme has been identified as a druggable target for malarial parasites,[11] and high-throughput screening of small molecule inhibitors has resulted in the discovery of novel compounds that can potentially be translated into potent antimalarials.[12][13]
References
External links
- 6-phosphogluconolactonase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Collard F, Collet JF, Gerin I, Veiga-da-Cunha M, Van Schaftingen E (October 1999). "Identification of the cDNA encoding human 6-phosphogluconolactonase, the enzyme catalyzing the second step of the pentose phosphate pathway(1)". FEBS Letters. 459 (2): 223–6. S2CID 29302175.
