Kinetic modeling of a crude DERA lysate-catalyzed process in synthesis of statin intermediates

2‐Deoxyribose‐5‐phosphate aldolase from Thermotoga maritima in the synthesis of a statin side‐chain precursor: characterization, modeling and optimization

“…US$20 billion worldwide sales, among which Pfizer's Lipitor (atorvastatin calcium) was the world's top‐selling drug with revenues in excess of US$10 billion per year . Therefore, the preparation of the 2,4,6‐trideoxyhexose has attracted immense effort because of its extremely high market price, and the requirement for high chemical and stereochemical purity at its two chiral centers . Because the chemical synthesis of statins is time‐consuming and consists of a number of synthetic steps that are carried out under very harsh conditions, the use of DERA for the synthesis of the statin side‐chains presents one of the most attractive and promising routes, due to its ability to introduce both stereocenters in a single step …”

“…DERA shows poor resistance to high aldehyde concentrations and low catalytic efficiency towards the sequential aldol addition of unnatural substrates . Thus, large quantities of the enzyme are necessary to obtain industrially useful product yields . This issue can be circumvented by improving its resistance and catalytic activity using a molecular evolution approach, or by applying a cell‐free lysate or a whole‐cell biocatalyst instead of an isolated enzyme or by immobilization on appropriate supports …”

“…In pursuit of finding the most cost‐effective configuration for the lactol synthesis, especially for industrial use, it is of great importance for understanding the mechanisms and kinetics of enzyme systems in detail, which can be achieved by applying mathematical modeling techniques . Although the lack of reports on kinetic data obtained from kinetic models of DERA‐catalyzed reactions is evident, some kinetic studies of related aldolase‐based syntheses can be found . Ručigaj and coworkers (2015) have reported a very complex model for the sequential aldol reaction involving acetyloxyacetaldehyde, acetaldehyde and chloroacetaldehyde as substrates, which was catalyzed by crude DERA‐expressing culture lysate …”

“…Although the lack of reports on kinetic data obtained from kinetic models of DERA‐catalyzed reactions is evident, some kinetic studies of related aldolase‐based syntheses can be found . Ručigaj and coworkers (2015) have reported a very complex model for the sequential aldol reaction involving acetyloxyacetaldehyde, acetaldehyde and chloroacetaldehyde as substrates, which was catalyzed by crude DERA‐expressing culture lysate …”

Recent Progress in the Synthesis of Super-Statins

“…Ručigaj and Krajnc [100] also developed an accurate and efficient kinetic model that described the DERA-lyzate-catalyzed reaction of acetaldehyde 78 with 2-substituted acetaldehydes 79, to provide the corresponding lactols 82. The proposed three-step kinetic model encompassed the formation of intermediate and main products, as well as the side products formed by the parallel undesired reactions.…”