Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
From the six enzyme classes (Faber, 2011; Faber et al., 2015), hydrolases (EC 3) are one of the most versatile enzymes, able to catalyse multiple transformations for synthetic purposes (Bornscheuer and Kazlauskas, 2006). Their selection is usually based on their commercial availability ranging from big chemical enterprises to incipient biotechnological companies, which include in their portfolios a broad number of enzyme variants generally differing in their immobilisation type. From the broad number of hydrolases (amidases, amylases, epoxide hydrolases, esterases, glycosylases, proteases…), lipases have gained special attention due to their possibilities in aqueous medium, organic and also neoteric solvents (Carrea and Riva, 2008; Hernáiz et al., 2010). In addition, the lack of cofactor dependency and ability to work at high substrate concentrations make them attractive biocatalysts for regio-, chemo- and stereoselective processes. The possibility to carry out not only hydrolytic reactions but also synthetic reactions such as acylation, alkoxycarbonylation, aminolysis, ammonolysis, esterification or interesterification among others, have promoted the application of lipases even with industrial purposes (Gotor-Fernández et al., 2006; Ansorge-Schumacher and Thum, 2013; Méndez-Sánchez et al., 2016).
Structure and Function of Human Skin
Marc B. Brown, Adrian C. Williams in The Art and Science of Dermal Formulation Development, 2019
From the above, it is apparent that human skin contains many enzymes – for example, stratum corneum tryptic and chemotryptic proteases – that are required for specific purposes such as desquamation. In addition, the epidermis contains many drug-metabolising enzymes. Histochemical and immunohistochemical methodologies suggest that the majority of these are localised in the viable epidermis, sebaceous glands, and hair follicles. Although present at relatively small quantities in comparison to the liver, they do allow metabolic activity that can effectively reduce the bioavailability of topically applied medicaments; a common misconception is that the skin is an “inert” tissue. Indeed, most Phase 1 (e.g., oxidation, reduction, hydrolysis) and Phase 2 (e.g., methylation, glucuronidation) reactions can occur within the skin, though these tend to be at <10% of the specific activities found in the liver. However, esterases tend to have relatively high activities within skin and, considering that there is a large skin surface area, metabolism of some drugs can be significant in some cases. This metabolic activity can be exploited in the delivery of prodrugs such as steroid esters with the increased lipophilicity afforded by an aliphatic chain improving drug uptake into the tissue where esterases can liberate the free drug within the skin. Microorganisms present on the skin surface, such as Staphylococcus epidermidis may also metabolise topically applied drugs.
Pitfalls and Practical Solutions
Joseph Chamberlain in The Analysis of Drugs in Biological Fluids, 2018
One immediate problem with ester-type drugs is the presence of serum esterases (Chapter 2). If these enzymes are active against the drug the presence of sodium fluoride in the sample tube as an anticoagulant will also inhibit the esterases, as for example in an assay for erythromycin propionate.1368 Adam1369 recommends a fluoride concentration of 5 mg ml 1 for this purpose rather than the usually supplied 1 mg ml−1, when intended as an anticoagulant alone. Brogan et al.1370 have suggested that sodium fluoride is essential in inhibiting the degradation of cocaine in blood samples. Similarly, failure to consider the effects of pseudoesterases has confused research on the metabolism of cocaine in humans.1371,1372
Gold nanoparticles applications: from artificial enzyme till drug delivery
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Kazem Golchin, Jafar Golchin, Shahrooz Ghaderi, Neda Alidadiani, Sajjad Eslamkhah, Masoud Eslamkhah, Soodabeh Davaran, Abolfazl Akbarzadeh
An esterase is a hydrolase enzyme that ruptures esters into an acid and an alcohol in a chemical reaction in water. The reaction is called hydrolysis [40]. According to evidence, the first example of peptide-functionalized GNPs is hydrolytically active against carboxylate esters. The active units are constituted by His-Phe-OH terminating thiols [41,42]. A highly sensitive and selective fluorescent assay for the detection of acetylcholine (ACh) was developed based on enzyme mimics of Au/Ag NPs [43]. This mechanism involved is the following: reacting ACh with acetylcholinesterase (AChE) to form choline that is in turn oxidized by choline oxidase (ChOx) to produce betaine and H2O2, which reacts with Amplex UltraRed (AUR) in the presence of bimetallic NPs catalyst to form a fluorescent product [44].
Stenotrophomonas maltophilia – a low-grade pathogen with numerous virulence factors
Published in Infectious Diseases, 2019
Angelina Trifonova, Tanya Strateva
Esterases are a group of hydrolytic enzymes which in some cases are associated with virulence. This hypothesis was supported by Nicoletti et al. [24]. Their study demonstrated esterase expression in most isolates of S. maltophilia from patients with CF. The putative outer membrane esterase of S. maltophilia К279а is chromosome-encoded and associated with the Smlt3773 gene locus. Based on its DNA sequence, the authors designed a primer pair to detect the presence of an esterase-encoding gene. Some of the S. maltophilia strains did not possess esterase activity despite the presence of an encoding gene. Amplified fragments of the esterase-negative strains were sequenced to establish the cause of this finding. As expected, frameshift mutations forming premature stop codons were found, whereas the analysis of amplicons, obtained from esterase-producing strains, confirmed the presence of wild-type. The results reveal that the esterase-encoding locus is highly conserved. Also, there are highly prevalent, non-functional gene variants among clinical isolates of S. maltophilia from CF patients [24].
Is genetic variability in carboxylesterase-1 and carboxylesterase-2 drug metabolism an important component of personalized medicine?
Published in Xenobiotica, 2020
S. Casey Laizure, Robert B Parker
Esterases are considered promiscuous enzymes with broad substrate specificity (Hatfield et al., 2016). This has been commonly interpreted to mean that carboxylesterase substrate-drugs are susceptible to hydrolysis by multiple esterases. In both the literature and in the FDA-approved labeling information it is common to refer to the metabolism of carboxylesterase-substrate drugs by “esterases” (Entresto-PPI, 2018; Plavix-PPI, 2010; Pradaxa-PPI, 2015) implying that drugs undergoing hydrolysis are susceptible to multiple enzymes. This would greatly diminish the importance of variability in enzyme activity on carboxylesterase-substrate drug disposition such as that due to genetic polymorphisms. If no single enzymatic pathway predominates, then alterations in the activity of a single enzyme would be unlikely to significantly affect drug disposition. However, with few exceptions the evidence shows that for most substrate-drugs hydrolysis occurs predominantly through a single metabolic pathway as illustrated by dimethyl fumarate hydrolysis, which is almost exclusively catalyzed by CES1.
Related Knowledge Centers
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