Metabolism reactions catalyzed

Fig. 10.5 Empath entry for a metabolic reaction catalyzed by HMG-CoA reductase.

Takahashi K, Uejima E, Morisaki T, Takahashi K, Kurokawa N, Azuma J. In vitro inhibitory effects of Kampo medicines on metabolic reactions catalyzed by human liver microsomes. J Clin Pharm Ther 2003 28 319-327. 

Fig. 3. Simple interaction network for the drug clozapine, three P450 enzymes for which clozapine is a substrate, the enzymatic clozapine metabolic reaction catalyzed by the enzymes, and the clozapine metabolite resulting from the reaction. Compound-protein and compound-reaction interactions are shown. Compounds are represented by hexagons, proteins by different solid shapes representing different classes of compound, and enzymatic reactions by rectangles. Edges (interactions) between nodes (network objects) are shown as unidirectional arrows with a mechanism of interaction represented by letters in hexagonal boxes over the arrows (6 binding, Zcatalysis).

The subsequent metabolic reaction catalyzed by dehydroquinate dehydratase presumably also involves a stable carbanion intermediate, judging from the demonstrated formation of a Schiff base during catalysis (526). The likely conformation of the intermediate is that of a skew-boat in which the C-4 and C-5 hydroxyls are di-equitorial (31) (527). 

These chemical effects become important in medicine because living systems operate mostly through the reactions of enzymes, which catalyze all sorts of metabolic reactions but are very sensitive to small changes in their environment. Such sensitivity can lead to preferential absorption of some deleterious isotopes in place of the more normal, beneficial ones. One example in metabolic systems can be found in the incorporation of a radioactive strontium isotope in place of calcium. 

The sensitivity of cellular constituents to environmental extremes places another constraint on the reactions of metabolism. The rate at which cellular reactions proceed is a very important factor in maintenance of the living state. However, the common ways chemists accelerate reactions are not available to cells the temperature cannot be raised, acid or base cannot be added, the pressure cannot be elevated, and concentrations cannot be dramatically increased. Instead, biomolecular catalysts mediate cellular reactions. These catalysts, called enzymes, accelerate the reaction rates many orders of magnitude and, by selecting the substances undergoing reaction, determine the specific reaction taking place. Virtually every metabolic reaction is served by an enzyme whose sole biological purpose is to catalyze its specific reaction (Figure 1.19). 

The net reaction catalyzed by this enzyme depends upon coupling between the two reactions shown in Equations (3.26) and (3.27) to produce the net reaction shown in Equation (3.28) with a net negative AG°. Many other examples of coupled reactions are considered in our discussions of intermediary metabolism (Part III). In addition, many of the complex biochemical systems discussed in the later chapters of this text involve reactions and processes with positive AG° values that are driven forward by coupling to reactions with a negative AG°. ... 

Peroxidases are found in milk and in leukocytes, platelets, and other tissues involved in eicosanoid metabolism (Chapter 23). The prosthetic group is protoheme. In the reaction catalyzed by peroxidase, hydrogen peroxide is reduced at the expense of several substances that will act as electron acceptors, such as ascorbate, quinones, and cytochrome c. The reaction catalyzed by peroxidase is complex, but the overall reaction is as follows ... 

When ketone bodies are being metabolized in extra-hepatic tissues there is an alternative reaction catalyzed by succinyl-CoA-acetoacetate-CoA transferase (thio-phorase)—involving transfer of CoA from succinyl-CoA to acetoacetate, forming acetoacetyl-CoA (Chapter 22). 

The most significant metabolic product of testosterone is DHT, since in many tissues, including prostate, external genitalia, and some areas of the skin, this is the active form of the hormone. The plasma content of DHT in the adult male is about one-tenth that of testosterone, and approximately 400 ig of DHT is produced daily as compared with about 5 mg of testosterone. About 50-100 ig of DHT are secreted by the testes. The rest is produced peripherally from testosterone in a reaction catalyzed by the NADPH-depen-dent 5oi-reductase (Figure 42-6). Testosterone can thus be considered a prohormone, since it is converted into a much more potent compound (dihydrotestosterone) and since most of this conversion occurs outside the testes. Some estradiol is formed from the peripheral aromatization of testosterone, particularly in males. 

In some cases, microorganisms can transform a contaminant, but they are not able to use this compound as a source of energy or carbon. This biotransformation is often called co-metabolism. In co-metabolism, the transformation of the compound is an incidental reaction catalyzed by enzymes, which are involved in the normal microbial metabolism.33 A well-known example of co-metabolism is the degradation of (TCE) by methanotrophic bacteria, a group of bacteria that use methane as their source of carbon and energy. When metabolizing methane, methanotrophs produce the enzyme methane monooxygenase, which catalyzes the oxidation of TCE and other chlorinated aliphatics under aerobic conditions.34 In addition to methane, toluene and phenol have been used as primary substrates to stimulate the aerobic co-metabolism of chlorinated solvents. 

Enzymes catalyze metabolic reactions, the flow of genetic information, the synthesis of molecules that provide biological structure, and help defend us against infections and disease. 

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... 

In contrast to the metabolism of BA and BaP, the 5,6-dihydrodiols formed in the metabolism of DMBA by liver microsomes from untreated, phenobarbital-treated, and 3-methylcholanthrene-treated rats are found to have 5R,6R/5S,6S enantiomer ratios of 11 89, 6 94, and 5 95, respectively (7.49 and Table II). The enantiomeric contents of the dihydrodiols were determined by a CSP-HPLC method (7.43). The 5,6-epoxide formed in the metabolism of DMBA by liver microsomes from 3MC-treated rats was found to contain predominantly (>97%) the 5R,6S-enantiomer which is converted by microsomal epoxide hydrolase-catalyzed hydration predominantly (>95%) at the R-center (C-5 position, see Figure 3) to yield the 5S,6S-dihydrodiol (49). In the metabolism of 12-methyl-BA, the 5S,6S-dihydrodiol was also found to be the major enantiomer formed (50) and this stereoselective reaction is similar to the reactions catalyzed by rat liver microsomes prepared with different enzyme inducers (unpublished results). Labeling studies using molecular oxygen-18 indicate that 5R,68-epoxide is the precursor of the 5S,6S-dihydrodiol formed in the metabolism of 12-methyl-BA (51). 

As a second messenger, DAG is rapidly metabolized under normal conditions, and the predominant route is via phosphorylation to PA, a reaction catalyzed by DAG kinase, for which multiple forms of 64-140 kDa have been identified and characterized. All possess a C-terminal catalytic domain and two or three cysteine-rich repeat sequences. The a, 3 and y forms possess E-F hands and are thus likely to be regulated by changes in the concentration of cytosolic Ca2+. Expression of the mRNA for the a, P, y, C, and 0 forms of DAG kinase appears to be highest in the brain. Once DAG is phosphorylated to PA, this in turn can be converted into PI via CDP-DAG (Fig. 20-2B). 

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. 

---