Glucose-6-Phosphate Dehydrogenase::6-Phosphogluconolactonase from the Parasite Giardia lamblia. A Molecular and Biochemical Perspective of a Fused Enzyme
| Autor: | Sergio Enríquez-Flores, Noemí Cárdenas-Rodríguez, Rosa Angélica Castillo-Rodríguez, Fernando Gómez-Chávez, Abigail González-Valdez, Roberto Arreguín-Espinosa, Beatriz Hernández-Ochoa, Saúl Gómez-Manzo, Laura Morales-Luna, Daniel Ortega-Cuellar, Verónica Pérez de la Cruz, Luis Miguel Canseco-Ávila, Víctor Martínez-Rosas |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Microbiology (medical)
congenital hereditary and neonatal diseases and abnormalities QH301-705.5 Metabolite Dehydrogenase Pentose phosphate pathway medicine.disease_cause Microbiology drug target chemistry.chemical_compound Giardia lamblia Virology hemic and lymphatic diseases parasitic diseases medicine Glucose-6-phosphate dehydrogenase Phosphofructokinase 2 Biology (General) fused enzyme 6-phosphogluconolactonase chemistry.chemical_classification glucose 6 phosphate dehydrogenase nutritional and metabolic diseases Enzyme chemistry Biochemistry metabolism |
| Zdroj: | Microorganisms, Vol 9, Iss 1678, p 1678 (2021) Microorganisms Volume 9 Issue 8 |
| ISSN: | 2076-2607 |
| Popis: | Giardia lamblia is a single-celled eukaryotic parasite with a small genome and is considered an early divergent eukaryote. The pentose phosphate pathway (PPP) plays an essential role in the oxidative stress defense of the parasite and the production of ribose-5-phosphate. In this parasite, the glucose-6-phosphate dehydrogenase (G6PD) is fused with the 6-phosphogluconolactonase (6PGL) enzyme, generating the enzyme named G6PD::6PGL that catalyzes the first two steps of the PPP. Here, we report that the G6PD::6PGL is a bifunctional enzyme with two catalytically active sites. We performed the kinetic characterization of both domains in the fused G6PD::6PGL enzyme, as well as the individual cloned G6PD. The results suggest that the catalytic activity of G6PD and 6PGL domains in the G6PD::6PGL enzyme are more efficient than the individual proteins. Additionally, using enzymatic and mass spectrometry assays, we found that the final metabolites of the catalytic reaction of the G6PD::6PGL are 6-phosphoglucono-δ-lactone and 6-phosphogluconate. Finally, we propose the reaction mechanism in which the G6PD domain performs the catalysis, releasing 6-phosphoglucono-δ-lactone to the reaction medium. Then, this metabolite binds to the 6PGL domain catalyzing the hydrolysis reaction and generating 6-phosphogluconate. The structural difference between the G. lamblia fused enzyme G6PD::6PGL with the human G6PD indicate that the G6PD::6PGL is a potential drug target for the rational synthesis of novels anti-Giardia drugs. |
| Databáze: | OpenAIRE |
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