Using a Recombinant Metagenomic Lipase for Enantiomeric Separation of Pharmaceutically Important Drug Intermediates
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Enzymes are natural catalysts that facilitate the majority of the reactions occurring in biological systems. Use of natural catalysts (enzymes) for chemical processes is referred to as “white biotechnology” (Giovanni, 2003; Walsh, 2001). Natural catalysts are required in small amounts compared with chemical catalysts and can replace relatively dangerous chemicals and save resources (Jaeger, 2004; Patel, 2003; Panke et al., 2004). Currently, the biotechnological potential of hydrolytic enzymes is of special interest. Among these, lipases provide new and innovative biotechnological solutions, which in turn increase efficiency and productivity for manufacturers. They are a familiar valuable biocatalyst in food, pharmaceutical, detergent, and chemical industries. Lipase-catalyzed reactions have received much attention in recent years, as they successfully catalyze interesterification, acidolysis, esterification, alcoholysis, and aminolysis in addition to its hydrolytic activity on triglycerides (Guncheva et al., 2011; Kourist et al., 2010).
Structural Organization of the Liver
Robert G. Meeks, Steadman D. Harrison, Richard J. Bull in Hepatotoxicology, 2020
Lysosomes are defined as organelles specialized for intracellular digestion. They contain a wide variety of hydrolytic enzymes called acid hydrolases because they operate best at an acidic pH (about 5). Although it is simple to define lysosomes conceptually, it is difficult to identify them morphologically because they are highly pleomorphic. Lysosomal content may be homogeneous or heterogeneous and may include dense pigments, myelin figures, or partially digested organelles (Figure 20). Their positive identification in electron micrographs requires that the organelle be bound by a single membrane and show a positive histochemical reaction for acid phosphatase, a representative acid hydrolase (Bainton, 1981; deDuve, 1969, 1975; Novikoff et al., 1956; Novikoff, 1973). In addition, histochemistry has identified a region of SER and Golgi complex rich in acid phosphatase (Novikoff and Yam, 1978). It is thought that lysosomal enzymes synthesized in the RER and transported to the SER are subsequently transferred to the Golgi complex, where the enzymes are modified and packaged as lysosomes (Hasilik, 1980). The aforementioned group of acid-phosphatase-rich organelles (the Golgi complex, ER and lysosomes) has been called GERL (Novikoff and Yam, 1978).
Valproate
Stanley R. Resor, Henn Kutt in The Medical Treatment of Epilepsy, 2020
Compared to VPA, valpromide offers two minor advantages, but presents one major disadvantage. VPA plasma levels derived from valpromide tend to fluctuate less than those derived from the free acid or sodium salt (95), and valpromide appears to be more effective than VPA in the prevention of febrile seizures (96), however, because it is a potent inhibitor of liver microsomal epoxide hydrolase (at least 100 times as potent as VPA itself) (97), in patients taking CBZ it dramatically increases the levels of CBZ-epoxide (average increase > 300%; range 100 to >800%), causing symptoms such as dizziness and confusion in some patients (98) and possibly increasing the risk of fetal malformations (99). However, interactions associated with valpromide may not be limited just to patients taking CBZ. Inhibition of epoxide hydrolase may have broader implications because the enzyme is important for the detoxification of reactive epoxide metabolites of drugs and environmental pollutants which can be cytotoxic, mutagenic, and carcinogenic (100).
Biotherapeutic effect of cell-penetrating peptides against microbial agents: a review
Published in Tissue Barriers, 2022
Idris Zubairu Sadiq, Aliyu Muhammad, Sanusi Bello Mada, Bashiru Ibrahim, Umar Aliyu Umar
Protein-derived peptides are peptides that are often derived from proteins, which may originate from natural sources such as plants, animals, or microorganisms (bacteria, yeast, and fungi). These protein-derived peptides are usually obtained from enzyme hydrolysis, fermentation, or digestion.19 Hydrolytic enzymes are commonly used to digest these proteins from a variety of sources, after which the bioactivity of the entire crude extract is assessed, followed by a series of activity-guided purification and identification to determine the most appropriate sequence.15,20 A peptide generated from the prion protein with a hydrophobic sequence was demonstrated to have powerful antiprion effects in prion-infected cells by reducing the pathogenic scrapie isoform crucial for prion pathogenicity.21 A research utilized both an in silico and an experimental technique to find protein-derived CPPs by extracting arginine-rich peptide segments from SwissProt proteins and analyzing their cell-penetrating capabilities.22 A study revealed multiple unique human-protein-derived CPPs employing a combination of in silico and experimental methods. Twenty of the sixty peptides tested were found to be functional, with the neurturin peptide performing best across the peptides screened.23
Peroxisome proliferator-activated receptor-gamma (PPARγ) and its immunomodulation function: current understanding and future therapeutic implications
Published in Expert Review of Clinical Pharmacology, 2022
Carlos Antonio Trindade da Silva, Juliana Trindade Clemente-Napimoga, Henrique Ballassini Abdalla, Rosanna Tarkany Basting, Marcelo Henrique Napimoga
Interestingly, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have advantageous effects, exerting their biological effects by activating PPARγ [79]. The activation of PPARγ appears to have anti-atherogenic effects through inhibiting endothelial adhesion molecule expression. Notably, EPA, but not DHA, increased the expression of CYP2J2 in a dose and time-dependent manner in human umbilical vein endothelial cells. The pretreatment with a PPARγ antagonist, GW9662, inhibits EPA-induced CYP2J2 expression [67]. In a recent study, the 15d-PGJ2 revealed that the soluble epoxide hydrolase (sEH) is covalently modified by 15d-PGJ2. This interaction inhibits its hydrolase activity mediated by its covalent adduction to the hydrolase [80]. In agreement, 15d-PGJ2 co-localizes with the sEH enzyme in various cell types, such as astrocytes, macrophages, and small arteries. In this regard, it is possible to speculate that enhanced 15d-PGJ2 levels may imply a more significant inhibition of sEH, which in turn would augment the bioavailability of EETs, EDPs, and other epoxy-fatty acids with anti-inflammatory and analgesic properties, and therefore PPARγ. This synergistic mechanism could contribute to a resolution of the inflammation [81]. Although their low stability and fast degradation is a limitation of bioactive lipids usage, it compensates for their potent analgesic effects mediated by PPARγ, encouraging the development of new strategies for drug delivery.
Metabolism and disposition of lesinurad, a uric acid reabsorption inhibitor, in humans
Published in Xenobiotica, 2019
Vishal Shah, Chun Yang, Zancong Shen, Bradley M. Kerr, Kathy Tieu, David M. Wilson, Jesse Hall, Michael Gillen, Caroline A. Lee
Metabolite M4 was detected following incubation in HLM but not in CYP2C9 recombinant enzyme (Figure 8). In contrast, metabolite M3c was detected following incubation in CYP2C9 recombinant enzyme but not in HLM (Figures 7 and 8). The formation of M3c was mediated by CYP2C9 and further hydrolyzed to M4. Several hydrolytic enzymes such as mEH, butyrylcholinesterase, esterase, carboxypeptidase, and leukotriene hydrolase were assessed. The hydrolysis of M3c to M4 was mediated by mEH (Figure 9). The chemical inhibition study with sulfaphenazole demonstrated that M4 formation was inhibited by 97%. The overall contribution of CYP2C9, the fraction metabolized (fm) by this isoform, was determined to be ∼50% based on human excreta data following the human [14C]lesinurad study. The metabolites M3, M3b, M4, M5 were M5b were summed up based amount excreted in urine and feces based on % of dose to determine the fraction metabolized by CYP2C9 (fm,CYP2C9) as shown in Table 5.
Related Knowledge Centers
- Biochemistry
- Catalysis
- Enzyme
- Esterase
- Lipase
- Phosphatase
- Protease
- Lipid
- Glycoside Hydrolase
- Purine Nucleoside Phosphorylase