Metabolic degradation

The final step in the metabolic degradation of uracil is the oxidation of malonic semialdehyde to give malonvl CoA. Propose a mechanism. 

The experiments with (U-l3C)AIRs showed that this nucleoside supplied all of the carbon atoms of pyramine. Because out of 6 carbon atoms of pyramine, only three may come from the imidazole part of AIRs, it can be concluded that the three other carbon atoms come from the ribose part of this nucleoside. In complete agreement with these results, radioactivity from AIRs, labeled mainly with, 4C in its ribose part, was found to incorporate into the three carbon atoms of pyramine, the origin of which was, at the time, unknown. Owing to the minute amount of AIRs supplied (as compared with that of glucose) in both experiments, the incorporation of label from AIRs after metabolic degradation is ruled out. 

The refractory nature of some pollutants, notably, persistent polyhalogenated compounds, has raised problems of bioremediation of contaminated sites (e.g., sediments and dumping sites). There has been interest in the identification, or the production by genetic manipulation, of strains of microorganisms that can metabolically degrade recalcitrant molecules. For example, there are bacterial strains that can reductively dechlorinate PCBs under anaerobic conditions. 

Emphasis is not on compiling a comprehensive review, but rather on problems and potential for research in this area. Allelochemical sources, synthesis, metabolism, degradation, binding in soils, and mode of action are briefly presented and discussed with regard to root-microbe interactions. Data on these areas is accessed with recommendations and suggestions for further investigation. 

In the case of the thiopurines the electrochemical processes do not appear to agree at all with the known biological oxidations. However, again in the case of 6-thiopurine not even a complete picture of the metabolites is available. The electrochemical data indicates that thiopurines are very readily oxidized to disulfides and hence to sulfinic or sulfonic acids. In view of well-known sulfide-disulfide transformations in biological situations (e.g., L-cy-steine to L-cystine), it is not unlikely that part of the metabolic degradation pathway for thiopurines might proceed via reactions of the sulfide moiety. 

Fig. 3 Metabolic degradation pathway suggested for BDE-154 on rats. Adapted from Flakk et al. [50]...

Metabolic degradation rates vary widely between species (Table 19.2). 

Paraquat is used to control aquatic weeds. It also passes into aquatic environments through rain, where it is rapidly accumulated by aquatic organisms, especially fish (Gabryelak and Klekot 1985). Paraquat applied to control aquatic weeds is accumulated by aquatic macrophytes and algae, and it is adsorbed to sediments and suspended materials. Initial applications of 1 to 5 mg/L in the water column are usually not detectable under field conditions after 8 to 27 days (Summers 1980). The half-time persistence of paraquat in water column at normal doses for weed control (i.e., 0.5 to 1.0 mg/L) was 36 h less than 0.01 mg/L was detectable in 2 weeks (Calderbank 1975). In solution, paraquat was subject to photodecomposition and microbial metabolism, degrading to methylamine... 

In the above-mentioned examples, the prediction of CYP-mediated compound interactions is a starting point in any metabolic pathway prediction or enzyme inactivation. This chapter presents an evolution of a standard method [1], widely used in pharmaceutical research in the early-ADMET (absorption, distribution, metabolism, excretion and toxicity) field, which provides information on the biotransformations produced by CYP-mediated substrate interactions. The methodology can be applied automatically to all the cytochromes whose 3 D structure can be modeled or is known, including plants as well as phase II enzymes. It can be used by chemists to detect molecular positions that should be protected to avoid metabolic degradation, or to check the suitability of a new scaffold or prodrug. The fully automated procedure is also a valuable new tool in early-ADMET where metabolite- or mechanism based inhibition (MBI) must be evaluated as early as possible. 

CNTs with different characteristics, which will lead to differences in the mechanism of CNT metabolism, degradation or dissolution, clearance and bioaccumulation. On the other hand, most non-viral gene delivery systems today suffer from both limited levels of gene expression and an unfavourable toxicity profile due to their highly cationic surface character. Therefore, opportunities for CNT-based gene transfer systems are still ample. 

Halogenated aliphatics can be partially or completely degraded under anaerobic conditions through a transformation reaction called reductive de-halogenation. Often a co-metabolic degradation step, reductive dehalogenation... 

In situ models are to evaluate absorption or membrane permeability under the physiologically relevant tissue condition. While the luminal environment can be modulated by the administered solution, the tissue condition is physiologically controlled. The estimated membrane permeability can be, in most cases, assumed to represent the transport across the epithelial cell layer at steady state or quasisteady state. However, one needs to be aware that the involvement of metabolic degradation, which may occur at the cellular surface or within the cytosol, can be a factor leading to biased estimates of membrane permeability and erroneous interpretation of the transport process. Particularly,... 

Most of this chapter (Sect. 5.2) focuses on the chemical reactivity of the lactam bond and its hydrolysis by bacterial enzymes (lactamases), rather than to its metabolic degradation by mammalian enzymes. This is in contradistinction to other chapters of this book, where metabolism in mammals is the focus of discussion. The reason for the attention given here to the chemical reactivity and bacterial degradation of /3-lactams is that these issues have caused more pharmaceutical and clinical problems than metabolic hydrolysis. This also explains why the chemical stability of /3-lactams and their resistance to /3-lactamases have been the subject of countless studies, while the metabolism of these compounds has received less attention. 

Chemical modifications have been carried out in the carbapenem series with a view to reduce the extent of metabolic degradation. The first compound in this series was thienamycin (5.45), which was found to undergo extensive metabolism in rodents and monkeys [121][156] the degree of metabolic degradation, together with its chemical instability, have prevented marketing of this compound. 

In Sect. 6.3, we examined, in some detail, the chemical mechanisms of peptide hydrolysis and showed that, while all are relevant in a pharmaceutical context of production and storage, some are fast enough to shorten the half-life and duration of action of some peptides in the body. However, enzymatic reactions of hydrolysis play a much more important role than non-enzymatic ones in the metabolic degradation of peptides [7] [14][138-141], as discussed in the remainder of this chapter. 

FIGURE 1.2 Possible metabolism (degradation pathway) of protopanaxadiol-type gin-senosides such as ginsenoside Rbi by stomach acidity and by human intestinal bacteria. 

Peptide and protein drugs must be transported without metabolic degradation to the systemic circulation in order to exhibit or exert their pharmacological action. Although active transport of linear peptides and oligopeptides by intestinal oligopeptide transporters has been reported, overall intestinal absorption of peptides is very poor because of metabolic degradation by peptidases. " ... 

Citric acid has three prochiral centres The Krebs cycle is a process involved in the metabolic degradation of carbohydrate (see Section 15.3). It is also called the ciU ic acid cycle, because citric acid was one of the first intermediates identified. Once formed, citric acid is modified by the enzyme aconitase through the intermediate... 

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