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] The tertiary structure of 6PGL employs an α/β hydrolase fold, with active site residues clustered on the loops of the α-helices.

[1] Stability of the tertiary structure of the protein is reinforced through salt bridges between aspartic acid and arginine residues, and from aromatic side-chain stacking interactions.

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.

However, if accumulated, this compound can undergo intramolecular rearrangement to isomerize to the more stable γ-form, which is unable to be hydrolyzed by 6PGL and cannot continue to the non-oxidative phase 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.