Metabolite-likeness

Additional assays used in early pharmaceutical property profiles usually include plasma protein binding, individual cytochrome P450 assays, stability in the presence of serum, production of metabolites likely to be involved in covalent binding to biomolecules, and interaction with efflux pumps ... 

The examples of threatened metabolites in the tables that follow were selected fi om three main criteria. First, the focus was on endangered organisms that produce unusual secondary metabolites, like microbes, seaweeds, plants, insects, marine invertebrates, and certain vertebrates, in particular the amphibians. Second, particular attention was paid to threatened ecosystems. Third, rarity and... 

Metabolism of TCDD. No metabolites of TCDD have been identified so far. It has recently been reported by Guenthner et al.(20) that TCDD can be metabolized by the mouse liver cytochrome P-U50 system to reactive intermediates, which easily bind covalently to cullular proteins. It is suggested that this extreme reactivity inhibits the formation of normal metabolites like phenols, dihydrodiols, or conjugated products. ... 

Fisher 1998 demonstrates that the more that is learned about the biomarker (half-life, time course in blood or urine, and development of PBPK model) and the exposed population (age, body weight, pharmacoge-netic traits, behavioral factors that affect exposure, and time between exposure and sample measurement), the more refined dose estimates can become. Without such information, a highly transient metabolite like TCE is not a reliable marker of exposure, unless exposure is nearly continuous and uniform. That may not be the case in the general population, so TCE in blood may not be a good biomarker for assessment of general-population exposure, although PBPK models are available to extrapolate from biomarker concentration to external dose in both animals and humans (Clewell et al. 2000). 

There are numerous examples of the inhibition of biosynthesis by fungicides. Some fungicidal secondary metabolites, like cyclohexi-mide and blasticidine, interfere with synthesis of peptide bonds at the ribosomal site (2). Another, kasugamycine, influences aminoacyl-t-RNA/ribosome interactions (3). Finally, another mechanism inhibiting protein biosynthesis is realized on the DNA/RNA- level by the... 

This metabolite like the 7-oxo product mentioned above may also have toxicological consequences. Although chemically quite stable, it may react in vivo with cellular components such as DNA which could lead to profound alterations in cellular processes. 

Antibiotics are microbial metabolites like amino sugars, poly- and oligosaccharides, poly- and olygopeptides etc. with different pharmacological activities. Since the historical discovery of penicillin by Alexander Fleming in 1929, tons of thousands of antibiotics of microbial origin have been isolated and every year new antibiotics are discovered. Some antibiotics produced on a commercial scale have been listed by Perlman 23). The world production of antibiotics has now reached 100000 tons per year. 

Thus, electrons can be directly transferred (DET) to the anode via the cell membrane (a) or via so-called nanowires (b) [vi.vii]. Alternatively, mediated electron transfer (MET) can take place via bacterial electron-shuttling compounds [viii] or reduced secondary metabolites like, e.g., hydrogen, formate, or ethanol [v,ix]. 

Lamellarins were originally extracted from a marine prosobranch mollusk Lamdlaria sp. and subsequently from primitive chordate ascidians (tunicates) [23]. These ascidian species, knovm to produce many bioactive metabolites, likely represent the original producer of lamellarins because these organisms are presumed to be the dietary source of the Lamdlaria mollusks. Lamellarins have been isolated from different tunicates, including recently from the Indian ascidian Didemnum obscurum... 

Precursors. Precursors for this reaction are compounds exhibiting keto-enol tau-tomerism. These compounds are usually secondary metabolites derived from the glycolysis cycle of yeast metabolism during fermentation. Pyruvic acid is one of the main precursor compounds involved in this type of reaction. During yeast fermentation it is decarboxylated to acetaldehyde and then reduced to ethanol. Acetone, ace-toin (3-hydroxybutan-2-one), oxalacetic acid, acetoacetic acid and diacetyl, among others, are also secondary metabolites likely to participate in this kind of condensation reaction with anthocyanins. 

The GT-B fold family includes most prokaryotic enzymes that produce secondary metabolites, like the antibiotics streptomycin, oleandomycin (Fig. 1) and vancomycin, and important bacterial cell wall precursors. It is also predicted to contain the vitally important 0-GlcNAc transferase that modifies many nuclear and cytoplasmic proteins and influences gene transcription. The first glycosyltransferase structure reported in 1994 was for the GT-B fold enzyme, P-glucosyltransferase (BGT) from bacteriophage T4 (22). This enzyme attaches glucose to modified... 

The presence or absence of phosphate ions plays an important role in the expression and accumulation of some secondary products. Zenk et al. (47) have demonstrated a 50% increase in anthraquinone accumulation in cell cultures of Morinda citrofolia when phosphate was increased to a concentration of 5g7h In suspension cultures of Catharanthus roseus, the overall accumulation of secondary metabolites like tryptamine and indole alkaloids has been shown to occur rapidly when cells were shifted to a medium devoid of phosphate (48,49). A study on the uptake of phosphate and its effect on phenylalanine ammonia lyase and the subsequent accumulation of cinnamoyl putrescine in cell suspension cultures of Nicotiana tabacum demonstrated marked sensitivity to phosphate concentration (5DX Enhanced phenylalanine ammonia lyase activity and increased production of cinnamoyl putrescine was induced by subculture onto phosphate-free medium while suppression of these effects and stimulation of growth was observed with phosphate concentrations of 0.02-0.5uM. Interestingly, phenylalanine ammonia lyase activity is stimulated by increasing phosphate concentrations in cell suspension of Catharanthus roseus (51). 

Hypoxia also causes the release of adenosine from cardiac myocytes. Adenosine in a potent dilator of coronary arteries. It has been shown that adenosine activates K xp currents in single coronary artery smooth muscle cells (Dart and Standen, 1993, 1994). Activation of the K xp channel is also involved in the hypoxic vasodilation in the cerebral, renal (Loutzen-hiser and Parker, 1994), skeletal muscle, and cremaster muscle and cheek pouch circulations (see Nelson and Quayle, 1995). Activation of K xp channels in these vascular beds may be a direct consequence of hypoxia on a smooth muscle oxygen sensor, an effect of hypoxia on smooth muscle cell metabolism, or through the release of vasodilator metabolites like adenosine from surrounding tissue, similar to hypoxic coronary vasodilation. 

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