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Biotransformation of Xenobiotics in Living Systems—Metabolism of Drugs: Partnership of Liver and Gut Microflora
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Although the majority of drugs are metabolized by oxidative reactions, reduction reactions are another phase I metabolic reactions that may be also a clinically important pathway of drug metabolism. Reduction reactions may occur on several functional groups such as carbonyl, nitro, hydroxyl, etc., and usually involve the addition of hydrogen to the drug molecule or the removal of oxygen (Table 6.3). These reactions are catalyzed by NADPH-cytochrome P450 reductase resulting in the formation of polar functional groups such as amino and hydroxyl, which may undergo further metabolic reactions. However, it is sometimes difficult to establish whether the reaction proceeds enzymatically or non-enzymatically by interaction with reducing agents. An important role in reduction of xenobiotics belongs to intestinal bacteria that will be discussed in further text (see Section 6.3.2.1).
Molecular Approaches Towards the Synthesis of Biosurfactants
Published in R.Z. Sayyed, Microbial Surfactants, 2022
Vidya Kothari, Arpana Jobanputra
Candida species synthesize Sophorolipids (SLs) which are one of the most common glycolipids (Van Bogaert et al. 2007, Esders et al. 1972). The composition of sophorolipids is sophorose disaccharide glycosidically linked to a hydroxy FA. Several researchers identified, characterized and cloned the genes involved in the biosynthesis of sophorolipids (Bucholtz et al. 1976, Inge et al. 2007, Konishi et al. 2007). Mono-oxygenase enzyme, cytochrome P450 dependant on NADPH (nicotinamide adeninedinucleotide phosphate) is essential for FA conversion. The CPR (cytochrome P450 reductase) gene of Candida bombicola was isolated using degenerate PCR and genomic walking. The CPR gene is composed of 687 amino acids. Heterologous expression in Escherichia coli proved the functionality of the gene. The recombinant protein had NADPH-dependent cytochrome c reducing activity (Hamoen et al. 2003). The genes of cytochrome P450 are diverse and also within the genome of a single organism. The phenomenon responsible for induction and expression of these genes was unknown (Hsieh et al. 2004). Specific glycosyltransferase I lead to the coupling of glycosidic linkage of glucose and FA. Glycosyltranferase II carries out subsequent glycosidic coupling. Both glycosyltransferases have been partially purified (Whiteley et al. 1999, Morita et al. 2007). Like other microorganisms C. bombicola produces glycolipid when grown on alkanes. Cytochrome P450 monooxygenase obtains reducing equivalents from NADPH cytochrome P450 reductase (CPR). The CPR gene of C. bombicola was isolated, sequenced and expressed in E. coli. The recombinant protein shows NADPH-dependent ‘cytochrome c’ reducing activity (Morita et al. 2007, Inoh et al. 2004).
Xenobiotic metabolism and transport in Caenorhabditis elegans
Published in Journal of Toxicology and Environmental Health, Part B, 2021
Jessica H. Hartman, Samuel J. Widmayer, Christina M. Bergemann, Dillon E. King, Katherine S. Morton, Riccardo F. Romersi, Laura E. Jameson, Maxwell C. K. Leung, Erik C. Andersen, Stefan Taubert, Joel N. Meyer
Cytochrome P450 enzymes require a heme cofactor (bound to iron) and a coenzyme (cytochrome P450 reductase) to carry out their reactions (McDonnell and Dang 2013). Unlike humans, C. elegans cannot synthesize heme, and need to scavenge this component from their diet (bacteria) to incorporate it into newly synthesized cytochrome P450 polypeptides (Sinclair and Hamza 2015). C. elegans have a suite of specialized enzymes that deliver environmental heme into the intestine and into other tissues (Chen et al. 2012). Heme availability during xenobiotic challenge might limit the xenobiotic response, but this hypothesis has not been explored experimentally. Cytochrome P450 enzymes also require co-expression of cytochrome P450 reductase, also termed P450 oxidoreductase (POR), which is encoded by emb-8 gene in worms. The emb-8 protein is expressed in highest levels in intestine, neurons, and pharynx and is also expressed in coelomocytes, hypodermis, and germline (essentially the same tissues where P450 enzymes are expressed). Loss of emb-8 produces temperature-sensitive embryonic lethality (Miwa et al. 1980), likely due to its role in embryonic polarization (Rappleye et al. 2003).