Xenobiotic substrate

Ji X, Tordova M, O Donnell R, Parsons JF, Hayden JB, Gilliland GL, et al. Structnre and function of the xenobiotic substrate-binding site and location of a potential non-substrate-binding site in a class pi glutathione -transferase. Biochemistry 1997 36 9690-702. 

Me(3ner B, Thulke O, Schaffner AR (2003) Arabidopsis glucosyltransferases with activities toward both endogeneous and xenobiotic substrates. Planta 217 138-146... 

Semm albumin is not an enzyme but a transport protein, yet it has demonstrated hydrolytic activity against a variety of xenobiotic substrates. This este-rase-like activity has been known for years, but there is still confusion in the literature regarding its nature and mechanism. Indeed, it was not clear whether this activity is intrinsic to the albumin molecule or results from contamination of albumin preparations by one or more hydrolytic enzymes. More-recent studies with highly purified human serum albumin (HSA) have confirmed that the protein has an intrinsic esterase activity toward several substrates, but that activity due to contaminants and particularly semm cholinesterase is involved... 

There have been sustained efforts in recent years to use the carrier systems of the brush-border membrane of intestinal mucosa to increase absorption of orally administered drugs [29] [30]. One system of particular interest is the intestinal peptide carrier (hPEPTl) whose physiological function is the absorption of di- and tripeptides and whose xenobiotic substrates include /3-lactam antibiotics, renin inhibitors, and angiotensin-converting enzyme (ACE) inhibitors [31]. 

Piperazine fused polycyclic ring systems are unique in terms of structures and properties. Praziquantel 211 is the primary medication for human schistosomiasis, for which it is usually effective in a single dose treatment. As shown in Fig. 10, praziquantel consists of a ketopiperazine fused ring system. A co-crystal of praziquantel and glutathione-5-peroxidase of the helminth Schistosoma japonica was known [63]. Praziquantel binds in a channel joining the two xenobiotic substrate... 

Enzymatic Hydrolysis Reactions of Esters. Xenobiotic compounds containing esters or other acid derivatives in their structures (e.g., amides, carbamates, ureas, etc., see Table 17.3) are often readily hydrolyzed by microorganisms. To understand how enzymatic steps can be used to transform these substances, it is instructive to consider the hydrolases (i.e., enzymes that catalyze hydrolysis reactions) used by organisms to split naturally occurring analogs (e.g., fatty acid esters in lipids or amides in proteins). The same chemical processes, and possibly even some of the same enzymes themselves, are involved in the hydrolysis of xenobiotic substrates. 

Because of the hydrocarbon nature of the methyl group, it generally makes xenobiotic substrates less hydrophilic, which is the opposite of most other conjugation processes. 

Fig. 3.1 Abstraction of substrate properties to common chemical principles is one of the basic concepts of the biosimulation approach (chemical abstraction). From the xenobiotic substrate molecule strategic positions for enzymatic attack are identified, since it is these that represent the reaction profile of a chemical compound in biological systems. The reaction profile determines regio-, chemo-, and stereoselectivity of enzymatic conversions. For these reasons model substrates representing the functionalities...

The enzymatic reaction was carried out in 1.5 mL polypropylene centrifuge tubes containing in a total volume of 250 /nL 125 /nmol 3-/V-morpholinopro-panesulfonate buffer (pH 7.5), 1.25 of /nmol glutathione, xenobiotic substrate (1.25 /nmol of iodomethane, 1.25 /nmol of iodoethane, 0.12 /nmol of methyl parathion, or 1.25 of /nmol dichlorvos), and enzyme. Reactions were initiated by adding the xenobiotic substrate dissolved in 5 /nL of ethanol and terminated after incubation at 30°C by adding 25 /nL of ice-cold 60% perchloric acid. 

Copley S. D. (1998) Microbial dehalogenases enzymes recruited to convert xenobiotic substrates. Curr. Op. Chem. Biol 2, 613-617. 

The glucuronic acid conjugation Is the most versatile of the conjugation reactions In terms of the range of xenobiotic substrates It may accept and Its widespread distribution through species and tissues. The glucuronic acid residue Incorporated Into the conjugate derives from the nucleotide uridine... 

The capacity of the principal metabolic conjugations depends upon the affinities of the transferase enzymes Involved both for the xenobiotic substrate and the endogenous conjugating agent, and upon the availability of the conjugating agent, which may be... 

Miscellaneous reactions and comments. The conjugate of a few xenobiotic substrates have been prepared by procedures other than those described above (Table VIII). 3-Chloroalanlne (L- or DL-) Is... 

Activation of drugs to give toxic products is common. Apart from non-enzymatic activation (e.g., via autoxidation), activation by enzymatic one-electron oxidation or reduction frequently occurs. Several non-specific oxidases and reductases are encountered in mammalian tissues. Enzyme systems that have been studied in detail are peroxidases and microsomal oxidases and reductases. Xanthine oxidase also has received some attention. In many insta .ces the end products of the reaction are critically dependent upon the presence of oxygen in the system. This is because oxygen is an excellent electron acceptor, i.e., it can oxidize donor radicals, forming superoxide in the process. In this way a redox cycle is set up in which the xenobiotic substrate is recovered. The toxic effects of the xenobiotic often can be attributed to the oxidative stress arising from such a cycle. However, it seems that for some substrates, oxidative stress of this kind can be less damaging than anaerobic reduction. Anaerobic reduction can lead to formation of further reduced products with additional toxicity. 

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