期刊
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
卷 711, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2021.109017
关键词
Pyruvate carboxylase; Allosteric activation; TNP-ATP; TNP-ADP; TNP-AMP; TNP-Adenosine
资金
- Thailand Research Fund [IRN59W0003]
- Science Achievement Scholarship of Thailand (SAST) [IRN59W0003]
This study investigated the effects of the triphosphate group of TNP-ATP and its derivatives on the allosteric activation of the enzyme and inhibition of acetyl-CoA-dependent activation. The findings suggest that reducing the number of phosphate groups in TNP-ATP derivatives decreases their activation efficacy and affects the binding affinity and inhibition of enzyme activation by acetyl-CoA. These results provide insight into potential drug development for metabolic diseases and cancers with abnormal expression of key enzymes.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据