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Carboxylesterase Inhibitors: Relevance for Pharmaceutical Applications
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carbamate compounds were developed to inhibit almost all members of the serine hydrolase family via covalent modification of serine at the active site (Kathuria et al., 2003; Long et al., 2009; Chang et al., 2013). Carbamates have been identified as potent inhibitors of AchE and these compounds have been widely used for the pest control in several crops, as well as in poultry and domestic animals (Roy et al., 2012; Casida and Durkin, 2013). Recently, several cholinesterase inhibitors containing the carbamate moiety, such as JZL184 and phenethylcymserine, were found to be CES inhibitors (Table 9.11) (Crow et al., 2012; Tsurkan et al., 2013). But all these compounds displayed poor isoform selectivity towards mammalian CES. Strong inhibition of carbamates on CES could be attributed to the very slow hydrolysis rates of the carbamoyl-enzyme intermediate, which was much slower than that of the acetyl-enzyme intermediate (Fig. 9.7) (Scaloni et al., 1994).
Growth Regulating Substances in Mosses
Published in R. N. Chopra, Satish C. Bhatla, Bryophyte Development: Physiology and Biochemistry, 2019
Satish C. Bhatla, Sadhana Dhingra-Babbar
Spectrophotometric demonstration of the enzyme tryptophan synthetase (L-serine hydrolase [adding indole], EC 4.2.1.20) has recently been made from the extracts of protonema of the wild-type and the mutant NAR-2 of F. hygrometrica.98 It is the terminal enzyme in the pathway of tryptophan biosynthesis, and it catalyzes the following three reactions:
Protein-Based Bioscavengers of Organophosphorus Nerve Agents
Published in Brian J. Lukey, James A. Romano, Salem Harry, Chemical Warfare Agents, 2019
Moshe Goldsmith, Yacov Ashani, Tamara. C. Otto, C. Linn Cadieux, David. S. Riddle
BChE (EC 3.1.1.8) is a 574-residue (85 kDa) serine hydrolase that is expressed primarily in human plasma, liver, skin, and leg muscle and is estimated to be ~10-fold more abundant than AChE in human adults (see recent review by Lockridge, 2015). The physiological role of BChE is as yet unknown, but it is generally accepted to have a role in detoxification of neurotoxins that can inactivate AChE and may act to protect it (Masson and Lockridge, 2010). In addition, it was found to be able to substitute for AChE when the latter does not function (Boudinot et al., 2005) and to regulate the hormone ghrelin, which regulates food intake (Chen et al., 2017). BChE is assembled in vivo into soluble, globular tetramers both in plasma and when bound to membranes via an interaction of a four-helix bundle tetramerization domain with a polyproline-rich peptide. The activity of BChE depends on the catalytic triad Ser 198, Glu 325, and His 438 and is inhibited on binding of Ser 198 to an OP (Nicolet et al., 2003). An omega loop connecting residues Asp70 and Trp82 plays an important role in substrate binding in HuBChE.
Species differences in liver microsomal hydrolysis of acyl glucuronide in humans and rats
Published in Xenobiotica, 2022
Hiroyuki Ikuta, Hiroaki Shimada, Kenjiro Sakamoto, Rena Nakamura, Atsushi Kawase, Masahiro Iwaki
The AG deglucuronidation assay was performed using a method adapted from a previous study (Iwamura et al. 2012). Briefly, the incubation mixture consisted of 100 mM Tris-HCl (pH 7.4), with or without 0.3 mg/mL HLM or RLM. To inhibit AG hydrolases, D-SL, a β-glucuronidase inhibitor (Levvy 1952), and/or PMSF, a general serine hydrolase inhibitor (Johnson and Moore 2000), were added to the reaction mixture at final concentrations of 10 and 1 mM, respectively. In a preliminary study, we confirmed that 10 mM D-SL and 1 mM PMSF are sufficient to inhibit β-glucuronidase and esterase-mediated AG hydrolysis in HLM and RLM using DIC-AG (data not shown). The assay was initiated by adding AG to the reaction mixture at a final concentration of 50 μM after 5 min of preincubation at 37°C. In a preliminary study, we confirmed that the rate of AG deglucuronidation is linear up to 100 μM AG. The reaction was terminated by collecting 25 μL of the reaction mixture in 100 μL of 4% phosphoric acid/MeOH at designated 6 time points. The parent drugs released from the respective AGs were then quantified using high-performance liquid chromatography (HPLC). The AG hydrolysis rates were estimated from the formed amount of parent drugs at the respective time points that are within the linear range (5 min for TOL and ZOM, 20 min for LUM and DIC, 60 min for MEF, and 120 min for ETO, respectively). The AG hydrolysis observed in the absence of microsomes (e.g. non-enzymatic AG hydrolysis) subtracted from AG hydrolysis observed in RLM and HLM (e.g. total AG hydrolysis) to estimate enzymatic AG hydrolysis rates in RLM and HLM.
Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome
Published in Ophthalmic Genetics, 2021
Austin D. Igelman, Cristy Ku, Mariana Matioli da Palma, Michalis Georgiou, Elena R. Schiff, Byron L. Lam, Eeva-Marja Sankila, Jeeyun Ahn, Lindsey Pyers, Ajoy Vincent, Juliana Maria Ferraz Sallum, Wadih M. Zein, Jin Kyun Oh, Ramiro S. Maldonado, Joseph Ryu, Stephen H. Tsang, Michael B. Gorin, Andrew R. Webster, Michel Michaelides, Paul Yang, Mark E. Pennesi
Centrosomal protein 78 (CEP78), Centrosomal protein 250 (CEP250), arylsulfatase G (ARSG), and α/β-hydrolase domain containing 12 (ABHD12) have been previously reported as causal for atypical USH (2,4,15–25). CEP78 and CEP250 are ciliary proteins important for the Usher protein network in retinal photoreceptor cells; CEP78 acts in ciliogenesis and CEP250 is expressed on cilia and interacts with CEP78 (4,16–22). Separate from the cilia are ARSG and ABHD12. ARSG encodes a sulfatase enzyme and contains a highly conserved catalytic site (15). Only two variants in ARSG in six patients have been associated with atypical USH in the literature (23,26). ABHD12 encodes a membrane-embedded serine hydrolase that hydrolyzes oxidized phosphatidylserine which is produced in inflammatory conditions and functions as a major lysophosphatidylserine (LPS) lipase in the nervous system (27). Here, we describe the clinical, imaging, and genetic findings in 19 patients in 18 families with bi-allelic variants in CEP78, CEP250, ASRG, and ABHD12 to help characterize these rare conditions.
Non-clinical toxicology evaluation of BIA 10-2474
Published in Critical Reviews in Toxicology, 2021
A. Wallace Hayes, Klaus Weber, Paul Moser, Patrício Soares-da-Silva
In 2016, one subject died and four were hospitalized with neurological symptoms during a clinical trial with the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474. The subject who died, after receiving 50 mg for 5 days, presented evidence of severe brain microhemorrhages and several of the surviving subjects (who received 50 mg for 6 days) also showed evidence of mild to moderate microhemorrhage (Kerbrat et al. 2016). The investigations by the French authorities concluded that it was an unexpected effect of the test item, having ruled out other extraneous causes. Their conclusion was that the accident was likely to have been caused by an unknown off-target effect of BIA 10-2474 (CSST 2016). Despite several studies and the identification of some off-target interactions with other serine hydrolase enzymes (van Esbroeck et al. 2017; Bonifacio, Moser, et al. 2018; Bonifacio et al. 2020), the mechanism responsible for the toxicity remains unproven.