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QM/MM reveals the sequence of substrate binding during OPRT action
N N Subrahmanyeswara Rao1, Parag A Deshpande1
1Quantum and Molecular Engineering Laboratory, Department of Chemical Engineering, Indian Institute of Technology Kharagpur, Kharagpur 721302, India.
Computational Biology and Chemistry
|March 14, 2018
Summary
Computational studies revealed the binding mechanism of orotate phosphoribosyltransferase (OPRT). The enzyme sequentially binds orotic acid (OA) and the magnesium-activated phosphoribosyl pyrophosphate (Mg-PRPP) complex for optimal activity.
Area of Science:
- Biochemistry
- Computational Chemistry
- Enzymology
Background:
- Orotate phosphoribosyltransferase (OPRT) catalyzes a key step in pyrimidine biosynthesis.
- Understanding the OPRT reaction mechanism is crucial for drug development targeting this enzyme.
Purpose of the Study:
- To computationally investigate the substrate binding pathways of orotate phosphoribosyltransferase (OPRT).
- To elucidate the role of Mg2+ ions in the OPRT enzymatic reaction.
Main Methods:
- Quantum mechanics/molecular mechanics (QM/MM) framework was employed.
- Computational modeling of the enzymatic reaction involving phosphoribosyl pyrophosphate (PRPP) and orotic acid (OA).
- Analysis of four proposed binding pathways for substrates and Mg2+ ions.
Main Results:
- The Mg2+-PRPP complex demonstrated significant stabilization, identifying it as the true substrate.
- Pathways involving initial PRPP-OPRT complex formation or PRPP migration were energetically unfavorable.
- Sequential binding of OA followed by the Mg2+-PRPP complex to OPRT was found to be the most energetically favorable pathway.
Conclusions:
- The study confirms a sequential binding mechanism for OPRT: orotic acid (OA) binds first, followed by the Mg2+-activated phosphoribosyl pyrophosphate (Mg-PRPP) complex.
- This detailed mechanistic insight provides a foundation for designing OPRT inhibitors.
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