Quantum and Classical Simulations of Orotidine Monophosphate Decarboxylase: Support for a Direct Decarboxylation Mechanism

Biochemistry ◽  
2013 ◽  
Vol 52 (25) ◽  
pp. 4382-4390 ◽  
Author(s):  
Alexandra Vardi-Kilshtain ◽  
Dvir Doron ◽  
Dan Thomas Major
Keyword(s):  
Monophosphate Decarboxylase ◽  
Orotidine Monophosphate Decarboxylase

scholarly journals Substrate distortion in the catalysis of orotidine monophosphate decarboxylase

2014 ◽  
Vol 70 (a1) ◽  
pp. C447-C447
Author(s):  
Masahiro Fujihashi ◽  
Toyokazu Ishida ◽  
Shingo Kuroda ◽  
Kazuya Mito ◽  
Lakshmi Kotra ◽  
...  
Keyword(s):  
Computational Simulation ◽  
Complex Surface ◽  
Pyrimidine Ring ◽  
Wild Type ◽  
Wild Type Enzyme ◽  
Surface Plasmon Resonance Analysis ◽  
Resonance Analysis ◽  
Transition State Stabilization ◽  
Monophosphate Decarboxylase ◽  
Orotidine Monophosphate Decarboxylase

One way for enzymes to affect reactions they catalyze is through transition state stabilization. Another factor to be considered is the contribution of substrate distortion, although it has been thoroughly described for only a few enzymes. We have a longstanding interest in the reaction mechanism of orotidine monophosphate decarboxylase (ODCase) and determined various crystal structures bound with distorted substrates at around 1.5 Å resolution. The enzyme is known as one of the most proficient enzymes, which accelerates the decarboxylation of orotidine 5'-monophosphate (OMP) to form uridine 5'-monophosphate (UMP) by 17 orders of magnitude. One argument against the contribution of substrate distortion to the ODCase reaction is the weak affinity of UMP. The distortions observed so far all appear at the C6-substituent of the pyrimidine ring, which corresponds to the carboxylate of OMP. Since the carboxylate is removed by the reaction, the product UMP should bind more tightly to ODCase than OMP, if the distortion of C6-substituent contributes to the catalysis. In order to investigate this inconsistency, we determined the crystal structure of ODCase with UMP at atomic resolution (1.03 Å). The structure showed an unfavorable interaction between UMP and the catalytic residue K72, an interaction considered to be absent in the OMP complex. Surface plasmon resonance analysis indicated that UMP binds stronger to the K72A mutant than to the wild-type enzyme by 5 orders of magnitude. These analyses invalidate the argument against a contribution of substrate distortion to ODCase catalysis. Finally, we estimated how much the distortion contributes to the catalysis using computational simulation methods. The results indicated that 10-15% decrease of the ΔΔG‡ value is contributed by substrate distortion.

Design of Inhibitors of Orotidine Monophosphate Decarboxylase Using Bioisosteric Replacement and Determination of Inhibition Kinetics

2006 ◽  
Vol 49 (16) ◽  
pp. 4937-4945 ◽  
Author(s):  
Ewa Poduch ◽  
Angelica M. Bello ◽  
Sishi Tang ◽  
Masahiro Fujihashi ◽  
Emil F. Pai ◽  
...  
Keyword(s):  
Inhibition Kinetics ◽  
Bioisosteric Replacement ◽  
Monophosphate Decarboxylase ◽  
Orotidine Monophosphate Decarboxylase

Orotidine Monophosphate Decarboxylase – A Fascinating Workhorse Enzyme with Therapeutic Potential

2015 ◽  
Vol 42 (5) ◽  
pp. 221-234 ◽  
Author(s):  
Masahiro Fujihashi ◽  
Jagjeet S. Mnpotra ◽  
Ram Kumar Mishra ◽  
Emil F. Pai ◽  
Lakshmi P. Kotra
Keyword(s):  
Therapeutic Potential ◽  
Monophosphate Decarboxylase ◽  
Orotidine Monophosphate Decarboxylase
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