The role of the phosphate groups of trinitrophenyl adenosine 5′-triphosphate (TNP-ATP) in allosteric activation of pyruvate carboxylase and the inhibition of acetyl CoA-dependent activation
| Autor: | Chaiyos Sirithanakorn, Sarawut Jitrapakdee, Khanti Rattanapornsompong, Paul V. Attwood |
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| Rok vydání: | 2021 |
| Předmět: |
Allosteric regulation
Biophysics Enzyme Activators chemical and pharmacologic phenomena Biochemistry chemistry.chemical_compound Adenosine Triphosphate Allosteric Regulation Acetyl Coenzyme A medicine Animals Molecular Biology Enzyme Assays Pyruvate Carboxylase chemistry.chemical_classification Molecular Structure Chemistry organic chemicals Acetyl-CoA hemic and immune systems Phosphate Adenosine Adenosine Monophosphate eye diseases Pyruvate carboxylase Adenosine Diphosphate Kinetics Enzyme Liver Carboxylation Phosphorylation Chickens tissues medicine.drug |
| Zdroj: | Archives of Biochemistry and Biophysics. 711:109017 |
| ISSN: | 0003-9861 |
| Popis: | A previous study showed that 2'-3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP) was a weak allosteric activator of Rhizobium etli pyruvate carboxylase (RePC) in the absence of acetyl-CoA. On the other hand, TNP-ATP inhibited the allosteric activation of RePC by acetyl-CoA. Here, we aimed to study the role of triphosphate group of TNP-ATP on its allosteric activation of the enzyme and inhibition of acetyl-CoA-dependent activation of RePC using TNP-ATP and its derivatives, including TNP-ADP, TNP-AMP and TNP-adenosine. The pyruvate carboxylation activity was assayed to determine the effect of reducing the number of phosphate groups in TNP-ATP derivatives on allosteric activation and inhibition of acetyl-CoA activation of RePC and chicken liver pyruvate carboxylase (CLPC). Reducing the number of phosphate groups in TNP-ATP derivatives decreased the activation efficacy for both RePC and CLPC compared to TNP-ATP. The apparent binding affinity and inhibition of activation of the enzymes by acetyl-CoA were also diminished when the number of phosphate groups in the TNP-ATP derivatives was reduced. Whilst TNP-AMP activated RePC, it did not activate CLPC, but it did inhibit acetyl-CoA activation of both RePC and CLPC. Similarly, TNP-adenosine did not activate RePC; however, it did inhibit acetyl-CoA activation using a different mechanism compared to phosphorylated TNP-derivatives. These findings indicate that mechanisms of PC activation and inhibition of acetyl-CoA activation by TNP-ATP and its derivatives are different. This study provides the basis for possible drug development for treatment of metabolic diseases and cancers with aberrant expression of PC. |
| Databáze: | OpenAIRE |
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