Metabolism other pathways

Protein kinase B is a serine-threonine kinase, also known as Akt. One of the signal transduction pathways from protein kinase B (Akt) leads to the effects of insulin on glucose metabolism. Other pathways, long associated with Akt, result in the phosphorylation of a host of other proteins that affect cell growth, cell cycle entry, and cell survival. In general, phosphorylation of these proteins by Akt inhibits their action and promotes cell survival. 

Certain of the central pathways of intermediary metabolism, such as the citric acid cycle, and many metabolites of other pathways have dual purposes—they serve in both catabolism and anabolism. This dual nature is reflected in the designation of such pathways as amphibolic rather than solely catabolic or anabolic. In any event, in contrast to catabolism—which converges to the common intermediate, acetyl-CoA—the pathways of anabolism diverge from a small group of simple metabolic intermediates to yield a spectacular variety of cellular constituents. 

The 4-phosphopantetheine group of CoA is also utilized (for essentially the same purposes) in acyl carrier proteins (ACPs) involved in fatty acid biosynthesis (see Chapter 25). In acyl carrier proteins, the 4-phosphopantetheine is covalently linked to a serine hydroxyl group. Pantothenic acid is an essential factor for the metabolism of fat, protein, and carbohydrates in the tricarboxylic acid cycle and other pathways. In view of its universal importance in metabolism, it is surprising that pantothenic acid deficiencies are not a more serious problem in humans, but this vitamin is abundant in almost all foods, so that deficiencies are rarely observed. 

The Pentose Phosphate Pathway Other Pathways of Hexose Metabolism... 

THE PENTOSE PHOSPHATE PATHWAY OTHER PATHWAYS OF HEXOSE METABOLISM / 165... 

The present data give us no indication of what the other pathways of DMN metabolism might be. Other pathways, including denitrosation and reduction of the NO group to the unsymmetrical hydrazine have been reported (27). 

The herbicide alachlor (4.146, Fig. 4.7) also displayed species-dependent toxicity, since it induced nasal tumors in rats but not in mice. Its metabolic scheme in rats and mice (Fig. 4.7) shows that alachlor can be transformed into 2,6-diethylaniline (4.149) by two different pathways, one of which proceeds via formation of 4.147. The other pathway implies glutathione (GSH) conjugation, followed by /3-lyase-mediated liberation of the thiol, followed by S-methylation to produce the methylsulfide 4.148. The two secondary amides 4.147 and 4.148 were hydrolyzed by microsomal arylamidases, but alachlor itself was not a substrate for this enzyme. The hydrolytic product 2,6-diethylaniline (4.149) was oxidized in nasal tissues to the electrophilic quinonimine metabolite 4.150, which can bind covalently to proteins. Aryl-... 

The in vivo metabolism of nitrovasodilators, as exemplified above, can result from a number of pathways and mechanisms. The obvious pathways that come to mind first are enzymatic and nonenzymatic hydrolysis. As discussed below, the former pathway does not appear to occur, while the latter should play a limited role in vivo. The two other pathways to be discussed are hemoprotein-catalyzed and thiol-mediated reductive denitrations. 

Thiol elimination to create a C=C bond is also seen in the metabolism of spironolactone (11.101, Fig. 11.13) [131]. This diuretic drug undergoes a number of metabolic reactions in humans, one of which is ready hydrolysis at the thioester bond to yield deacetyl-spironolactone (see Chapt. 7). This reaction is in competition with other pathways such as lactone hydrolysis, S-oxygenation, and dethioacetylation. The latter reaction is the one of interest here, since the elimination of CH3CO-SH transforms the C(5)-C(6) bond into a C=C bond to produce the active metabolite canrenone (11.102, Fig. 

Some inhibitors for this pathway, often described in the literature, do not directly affect the clathrin pathway but rather affect features involved with other pathways. For example, the acidification of endosomes is employed by the other types of endocytosis as well—therefore, these inhibitors are less specific and are described in the section Intracellular Trafficking The same occurs with dynamin dependence or metabolic activity (section Metabolic Activity ). 

Empath is a Cabinet database of metabolic pathways that models a metabolic pathway chart. It initially models the Boehringer Mannheim wall chart [35] but other pathway layouts are possible. It currently includes 1462 steps (metabolic reactions). The Empath database consists of more than 8000 live objects. Every object has an exact geometric location, that is, x, y coordinate, which is optionally indicated by visible hotspots. The chart is clickable everywhere and the image recenters itself around the selected point. The current object is the one closest to the center of the image and is identified by a bull s eye. A summary of the object is given (e.g., its structure, EC number, SMILES, reaction stoichiometry, etc.). Empath provides navigational features such as zoom in/out, wider, thinner, taller and shorter. 

From activated isoprene, the metabolic pathway leads via dimerization to activated geraniol (1 = 2) and then to activated farnesol = 3). At this point, the pathway divides into two. Further extension of farnesol leads to chains with increasing numbers of isoprene units—e.g., phytol (1 = 4), dolichol (1 = 14-24), and rubber = 700-5000). The other pathway involves a head-to-head linkage between two farnesol residues, giving rise to squalene (1 = 6), which, in turn, is converted to cholesterol (1 = 6) and the other steroids. 

Modulation by ligands. An important variable that regulates flow through a metabolic pathway is precursor availability (metabolite A in the case shown here). The availability of precursor A increases along with the activity of the metabolic pathways that form A (3) and it decreases with increasing activity of other pathways that also consume A (4). Transport from one cell compartment to another can also restrict the availability of A. 

Hypericum has been found to also interact with drugs metabolized via other pathways. For example, it decreases serum levels of digoxin, which is metabolized via the P-glycoprotein drug transporter, and reduces levels of theophylline and warfarin, which are metabolized via CYP1A2 and CYP2C9 pathways, respectively. It is possible that St. John s wort might also induce those enzymes via the steroid X receptor (Wentworth et ah, 2000). 

Cytochromes P450 form a very large group of heme enzymes that catalyze the hydroxylation of a variety of substrates. They are important in drug metabolism, in cholesterol and steroid hormone biosynthesis, and in numerous other pathways. They have been found to participate in reactions other than hydroxyla-tions. 

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