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Mathematical modelling of lactone synthesis catalyzed by aldehyde dehydrogenase

Statins, also known as HMG-CoA reductase inhibitors, are cholesterol-lowering medications that are one of the top selling pharmaceutical products nowadays. Even though the chemical route is being employed for the synthesis of statins, it is time-consuming and includes a vast number of steps. Increased commercial demand for enantiomerically pure statins and the need for their simple preparation on the industrial scale has brought much attention onto the enzymatically catalyzed statin synthesis, which presents the most attractive alternative, due to the nature of the enzymes to perform high stereoselective attacks under mild conditions. Once the lactol is enzymatically produced, the desired statin side chain precursor can be obtained by oxidation of the intermediate lactol to lactone.[1, 2] In this work, the oxidation of lactol was catalyzed by aldehyde dehydrogenase (AlDH). The AlDH enzyme belongs to the largest class of oxidoreductases that catalyze biological redox reactions, and which are NAD(P)- dependent enzymes. Since the NAD(P)-dependency is considered as a drawback from the economical point of view, to circumvent the need for NAD+ addition during the reaction, the lactol oxidation catalyzed by NAD-dependent AlDH was coupled with a regeneration system that included NADH oxidase (NOX) (Figure 1). The advantage of the employed enzyme-coupled regeneration system lays in the co-substrate and co-product, which are readily accessible and non- damaging to the applied enzymes: oxygen and water. The kinetics of all reactions were determined using the method of initial rates and were described by Michaelis-Menten kinetic models. The kinetic parameters of the proposed models were estimated by nonlinear regression analysis using simplex or least squares method. Based on the kinetic results, a mathematical model was developed for the lactone synthesis and was validated in a batch reactor. [1] Ručigaj, A. ; Krajnc, M. ; J. Org. Process Res. Dev. 2013, 17, 854-862 [2] Jiao, X.-C. ; Zhang, Y.-J. ; Chen, Q. ; Pan, J. ; Xu, J.-H. ; J. Catal. Sci. Technol., 2016, 6, 7094-7100 Project CARBAZYMES- This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 635595.

lactone ; aldehyde dehydrogenase ; NADH oxidase ; mathematical modeling

Project CARBAZYMES-This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 635595.