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Hydrolytic Enzymes for the Synthesis of Pharmaceuticals
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Sergio González-Granda, Vicente Gotor-Fernández
As mentioned in a previous section, the amidase activity of microorganisms is responsible of the hydrolysis of amides into carboxylic acids, which is a very useful transformation. Alternatively, some microorganisms displayed nitrilases or nitrile hydratase-amidase activities for converting cyano groups in carboxylic acids, representing in some cases an alternative synthetic solution for the production of carboxylic acids. One example is the use of the Rhodococcus rhodochrous SP 361 microorganism from Novozymes, which was able to catalyse the formation of O-protected and unprotected (R)-3-hydroxy-4-cyanobutanoic acids (Scheme 9.18). The results for the desymmetrisation of the dinitriles were highly dependent on the C-2-functionality in terms of activity and selectivity (Kinfe et al., 2009). These compounds are valuable precursors in the synthesis of the blockbuster Atorvastatin, marketed by Pfizer as a calcium salt under the trade name of Lipitor®, drug used as HMG-CoA reductase inhibitor for lowering blood cholesterol preventing cardiovascular diseases. Cyano-converting microorganism for the synthesis of (R)-3-hydroxy-4-cyanobutanoic acid and derivatives through selective nitrile hydrolysis.
B
Published in Caroline Ashley, Aileen Dunleavy, John Cunningham, The Renal Drug Handbook, 2018
Caroline Ashley, Aileen Dunleavy, John Cunningham
Brivaracetam is mainly metabolised by hydrolysis of the amide moiety to form the corresponding carboxylic acid (approximately 60% the elimination), and secondarily by hydroxylation on the propyl side chain (approximately 30% the elimination). The hydrolysis of the amide moiety leading to the carboxylic acid metabolite (34% of the dose in urine) is supported by hepatic and extra-hepatic amidase. The metabolites are inactive.
General toxicology
Published in Timbrell John, Study Toxicology Through Questions, 2017
(a) Azoreductase; (b) amidase; (c) cytochrome P450; (d) glutathione- S-transferase; (e) γ-glutamyltransferase; (f) glycinase; (g) epoxide hydrolase; (h) N acetyltransferase; (i) glucuronosyltransferase; (j) glucuronosyltransferase or sulphotransferase.
Transition state analogue imprinted polymers as artificial amidases for amino acid p-nitroanilides: morphological effects of polymer network on catalytic efficiency
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2018
Divya Mathew, Benny Thomas, K. S. Devaky
Now it is exciting to compare the binding of the mimic to the substrate anilide and to the TSA. Binding to the anilide is evaluated from the Michaelis–Menten constant Km and binding to the TSA can be estimated from the competitive inhibition caused by the added TSA during the catalytic amidolysis (Ki). The influence of the inhibiting template molecule was monitored with amidase MIP C1, prepared in DMSO. Two different inhibitor concentrations were added to the amidolysis media. The velocities were monitored in the same way under the same conditions of amidolysis (1:9 ACN–Tris HCl buffer of pH 7.75 and 45 °C). Evidently, the phosphonate TSA is a very effective inhibitor that binds much better than the substrate S1 by a factor of 33.56 when TSA is present in half the concentration of the substrate PNA [Ki = 0.075 mmol and Km = 2.516 mmol] and by a factor of 66.70 when equal concentration of TSA and substrate are used [Ki = 0.056 mmol and Km = 3.735 mmol]. Since the straight lines intersect in the negative part of the plot the TSA not only bind with the polymer catalyst (C1–TSA), but also with the catalyst–substrate complex (TSA–C1–PNA). Since the exactness of the kinetic evaluation is not high enough, we have not calculated the different inhibitor constants.
Doxorubicin-conjugated D-glucosamine- and folate- bi-functionalised InP/ZnS quantum dots for cancer cells imaging and therapy
Published in Journal of Drug Targeting, 2018
Zahra Ranjbar-Navazi, Morteza Eskandani, Mohammad Johari-Ahar, Ali Nemati, Hamid Akbari, Soudabeh Davaran, Yadollah Omidi
The release profile of doxorubicin was studied using UV-Vis spectrophotometry at the maximum wavelength of 490 nm in PBS buffer (pH = 7.4 and pH = 5, 37 °C) and compared with the calibration curve of doxorubicin. No evident release was observed in the neutral condition (pH = 7.4). Besides, as shown in Figure 7, the drug released in acidic medium (pH = 5.5) was negligible, in large part due to the stable amide bonds between QDs surface carboxylic groups and doxorubicin molecules. In fact, amide bond breaking needs amidase enzyme expressed in cells and many tissues. As a result, physiological conditions were required for doxorubicin release, and accordingly, the cytotoxicity results confirmed the efficient pharmacological effect of doxorubicin-conjugated functionalised QDs indicating the release of doxorubicin due to the enzymatic destruction of amid bounds between drug and QDs in vitro.
Bacteriophage endolysins as a potential weapon to combat Clostridioides difficile infection
Published in Gut Microbes, 2020
Shakhinur Islam Mondal, Lorraine A. Draper, R Paul Ross, Colin Hill
The use of phage therapy in CDI is limited due to the temperate nature of C. difficile bacteriophages (reported to date). In most cases low titers of lysogenic phages have been recovered after induction with mitomycin C. These phages can easily reintegrate into the host genome following the removal of inducers.72 In the case of reported lytic phages, these may also have access the lysogenic life cycle.73,74 Efforts have focused on alternative options and the exploitation of C. difficile phage endolysins have sparked interest as therapeutic alternatives for CDI. Through published articles and online database searches, we identified sequences of putative endolysins from phage/prophage of C. difficile. The majority of these endolysins are amidases and hydrolases and are summarized in Table 2. The catalytic domains include amidase 3 domains, amidase 2 domains, glucosaminidases and NLPC_P60 domains. The sequence homology among the catalytic amidase domains was analyzed. A BLAST search for the sequence of the catalytic amidase domain of CD27L against the amidase containing endolysins obtained from C. difficile phage or prophage sequences was performed. After curation of the sequence cluster to remove duplicates, the sequences of five amidases (CD27L, phyCD, phiCD38, phiCD119 and CD11) were aligned and analyzed using ESPRIPT90 for sequence conservation. Although the sequence identity is low, several conserved residues were found. The conserved four amino acid residues (His 9, Glu 26, His 84, and Glu 144) are coordinating the zinc ion and responsible for catalytic activity (Figure 3a). The three-dimensional structures of major C. difficile endolysins (CD27L, CDG, phiCD211, phiCDHM11 and phiCDMMP01) have been predicted by homology modeling using SWISS MODEL, an online tool (Figure 3b). The potential templates for target endolysins were identified based on the sequence coverage and percentage of identity between the target and template sequence, except for CD27L whose EAD and CBD three-dimensional structure are already available (PDB code 3QAY and 4CU5). Due to the presence of different catalytic groups, the folding patterns are different in amidases, glucosaminidases and NLPC_P60 containing C. difficile endolysins.