Metabolic pathways scheme

Scherling et al. [12] have thoroughly investigated the biotransformation of nimodipine in rats, dogs, and monkeys, and have proposed the metabolic pathway scheme shown in Figure 1. 

Whatever the true details of the metabolic pathway shown in Scheme 1 might be, there are certain facts which are very secure. Among these are that the nitrosamines are oxidatively dealkylated, that electrophilic intermediates which alkylate proteins and nucleic acids are formed, and that one of the... 

Recently, Voogt et al. [91] have reported on the d5-pathway in steroid metabolism of Asterias rubens. These workers established the existence of the d5-pathway (Scheme 20), analogous to the pathway found in mammals this conclusion was based on the observation that radiolabeled cholesterol (1) was converted to pregnenolone (112), 17a-hydroxypregnenolone (141), and androstenediol (142). Labeled pregnenolone was converted additionally to progesterone (129). Androstenediol (142) was the main metabolite of de-hydroepiandrosterone (143), a reaction catalyzed by 17/i-hydroxysteroid dehydrogenase (17/1-HSD). The metabolic conversion of androstenedione (131) to testosterone (132) is also mediated by 17/J-HSD and is related to... 

Recent work in our laboratories has confirmed the existence of a similar pathway in the oxidation of vindoline in mammals (777). The availability of compounds such as 59 as analytical standards, along with published mass spectral and NMR spectral properties of this compound, served to facilitate identification of metabolites formed in mammalian liver microsome incubations. Two compounds are produced during incubations with mouse liver microsome preparations 17-deacetylvindoline, and the dihydrovindoline ether dimer 59. Both compounds were isolated and completely characterized by spectral comparison to authentic standards. This work emphasizes the prospective value of microbial and enzymatic transformation studies in predicting pathways of metabolism in mammalian systems. This work would also suggest the involvement of cytochrome P-450 enzyme system(s) in the oxidation process. Whether the first steps involve direct introduction of molecular oxygen at position 3 of vindoline or an initial abstraction of electrons, as in Scheme 15, remains unknown. The establishment of a metabolic pathway in mammals, identical to those found in Strep-tomycetes, with copper oxidases and peroxidases again confirms the prospective value of the microbial models of mammalian metabolism concept. 

Figure 6. Simplified scheme of metabolic pathways of cis-chlordane in fish (Route A), desaturation and epoxidation and (Route B), hydroxylations. Both routes are operative in cichlids (as in mammals). Goldfish and bluegills seem to...

In vitro studies on rat liver preparations confirmed the postulated metabolic pathway of nonenzymatic hydrolysis of the oxime 11.69 to the ketone 11.70, followed by enzymatic reduction to 11.71, hydroxylation to diols, and glucuronidation. Clearly, the first step in this metabolic scheme is the nearly quantitative hydrolysis of the oxime to the ketone. 

In the first step of the reductive branch of this metabolic pathway three out of four methyl groups are transferred from methanol to CoM-SH (13) by methyl transferases, with formation of methyl-S-CoM (21) (Scheme 1) [21]. The transformation of 21 and CoB-SH (15) into methane and CoB-S-S-CoM (22) is catalyzed by the methyl-CoM reductase. Again, reductive cleavage of 22 is mediated by the heterodisulfide reductase [22]. The oxidative part involves oxidation of... 

Scheme of microbiological metabolic pathways for biogas production... 

In eukaryotes, such as mammals and fungi, epoxide hydrolases play a key role in the metabolism of xenobiotics, in particular of aromatic systems [30,31 ]. On the other hand, in prokaryotes (e.g. bacteria) these enzymes are essential for the utilization of alkenes as carbon-source. In general, aromatics can be metabolized via two different pathways (Scheme 5) (i) dioxetane formation via dioxyge-... 

Scheme 2. Structures of glucuronide conjugates of andrographolide in human urine and possible metabolic pathways for their production. (Cui et...

Table I summarizes the percentages of sulfadimidine and its metabolites in the plasma of the different species Table II shows the tissue to plasma drug concentration ratios for SDM and its metabolites, while Table III presents the urinary recovery data (for poultry urinary plus faecal recovery). The metabolic pathways observed in various species are summarized in a scheme (Figure 2). Selected data obtained are illustrated in Figures 3-9.

A commonly held belief is that, for an enzyme reaction within a metabolic pathway, a large excess of catalytic capacity relative to a pathway s metabolic flux ensures that a given step is at or near thermodynamic equilibrium. Brooks recently treated the kinetic behavior of reaction schemes one might judge to be at equilibrium, and he showed that individual steps can remain far from equilibrium, even at a high ratio of an enzyme s flux to a pathway s steady-state flux. His calculations indicate that whether a reaction is near equilibrium depends on (a) the overall flux through the enzyme locus and (b) the kinetic parameters of the other enzymes in the pathway. S. P. Brooks (1996) Biochem. Cell Biol. 74, 411. 

A form of regulation in a metabolic pathway in which an end product (or even an intermediate in the pathway) binds to and inhibits an enzyme which catalyzes an earlier reaction in that same pathway. For example, consider the metabolic scheme A B C Din which the steps are respectively catalyzed by the enzymes Ei, E2, and E3. Feedback inhibition would be seen when elevated concentrations of D (or C) inhibited Ei. 

Series first-order processes are especially important in understanding metabolic pathway kinetics. Likewise, one should recognize that unassisted protein folding " is unlikely to be a single-step reaction (say U N), where U represents unfolded protein, and N is the native conformation. At a minimum, realistic schemes for protein folding are apt to occur as a series of isomerizations ... 

For many of the drugs associated with hepatotoxicity, there are examples of structurally related drugs which are latent to bioactivation and toxicity because of the absence of the toxicophore or the existence of alternate metabolic pathways. For example, the hepatotoxicity associated with the use of the anti-Parkinson s agent tolcapone does not occur with the structurally related drug entacapone, despite administration at doses similar to tolcapone (200-1000 mg QD). This disparity may be explained in part by the observation that entacapone does not succumb to the bioactivation reactions of tolcapone in humans (Scheme 15.3) [35]. It is also noteworthy that tolcapone but not entacapone is a potent uncoupler of oxidative... 

Scheme 23.5 Metabolic pathways of lactic acid bacteria leading from pyruvate to a-acetolactate and acetoin and chemical diacetyl formation. ALS a-acetolactate synthase, ALDB a-acetolactate decarboxylase, DDH diacetyl dehydrogenase. (Adapted from [72])...

The metabolic pathway of acetylsalicylic acid is shown in scheme 6. 

Scheme 21 In vitro metabolic pathways of etoricoxib. Trade name Arcoxia (US)...

Scheme 47 Metabolic pathway of metamizol (Weithmann and Alpermann, 1983)...

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