Enzymatic pathways

Metabolism. MetaboHsm of histamine occurs via two principal enzymatic pathways (Fig. 1). Most (50 to 70%) histamine is metabolized to /V-methylhistamine by A/-methyltransferase, and some is metabolized further by monoamine oxidase to /V-methy1imidazo1eacetic acid and excreted in the urine. The remaining 30 to 40% of histamine is metabolized to imidazoleacetic acid by diamine oxidase, also called histaminase. Only 2 to 3% of histamine is excreted unchanged in the urine. 

Nifurtimox, a nitrofuran, is a prodrug that is reduced to unstable nitroanion radicals, which react to produce highly toxic oxygen metabolites, such as superoxide and peroxide. Oxidative stress subsequently kills the parasite, which seems to lack effective enzymatic pathways to detoxify oxygen metabolites. 

D-Camitine 14 L-Carnitine Thyroid inhibitor Multi-enzymatic pathway Agrobacterium sp. Single-stage fermentation of four processes [7]... 

An enzymatic pathway for indole degradation was found in A. niger, inducible by the substrate within a 5-h period during growth. Among the enzymes found, anthranilate hydroxylase, N-formylanthranilate deformylase, 2,3-dihydroxybenzoate decarboxylase, and catechol dioxygenase were isolated, and their activities were demonstrated in a cell-free system [342],... 

Despite intense study of the chemical reactivity of the inorganic NO donor SNP with a number of electrophiles and nucleophiles (in particular thiols), the mechanism of NO release from this drug also remains incompletely understood. In biological systems, both enzymatic and non-enzymatic pathways appear to be involved [28]. Nitric oxide release is thought to be preceded by a one-electron reduction step followed by release of cyanide, and an inner-sphere charge transfer reaction between the ni-trosonium ion (NO+) and the ferrous iron (Fe2+). Upon addition of SNP to tissues, formation of iron nitrosyl complexes, which are in equilibrium with S-nitrosothiols, has been observed. A membrane-bound enzyme may be involved in the generation of NO from SNP in vascular tissue [35], but the exact nature of this reducing activity is unknown. 

Cocaine-mediated hepatotoxicity has been associated with the conversion of cocaine to norcocaine and further oxidation products. The enzymes involved in in vitro hepatic oxidative N-demethylation of cocaine (192) were investigated (237), and two different enzymatic pathways appear to be important in the formation of the hepatotoxic metabolite. Cytochrome P-450 monooxygenases accomplish the direct N-demethylation of cocaine to norcocaine (194) as confirmed by induction and inhibition studies (Scheme 42). The second pathway for cocaine N-demethylation involves formation of cocaine /V-oxide (193) as an intermediate and two enzymes. A flavin-containing monooxygenase is first thought to convert cocaine to cocaine /V-oxide, followed by cytochrome P-450-... 

Genetic polymorphism may result in poor metabolizers (i.e., individuals who have only a limited or no capacity to metabolize a given chemical via a specific enzymatic pathway), and extensive metabolizers (i.e., individuals who have a sufficient capacity to metabolize a given chemical via a specific enzymatic pathway) and individuals of a particular group may therefore respond differently to exposure to chemicals. 

It is clear that, as understanding of the underlying principles of both iminium ion and enamine catalysis improves, the trae power of these cascade sequences will be fully exploited. It can be expected that introduction of subsequent independent catalytic cycles will add to the complexity and applicabihty of these processes and provide highly regulated cascades that mimic the power of enzymatic pathways. 

The KEGG (Kyoto Encyclopedia of Genes and Genomes) LIGAND database provides chemical structures for around 12 000 chemical compounds and drugs with biological information around 2000 compounds are annotated to enzymatic pathways. 

MefaboZ/sm/Excref/on- Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. In adult EMs, mean half-life is 5.2 hours. In PMs, mean half-life is 21.6 hours. 

The kallikrein-kinin system is an enzymatic pathway giving rise to two predominant vasoactive peptides, kallidin and bradykinin. Kallikrein, the enzyme responsible for the formation of these peptides, exists in plasma and tissues. However, circulating levels of the end products, kalhdin and bradykinin, are quite low because the kalhkrein enzymes are present largely in inactive forms. In addition, the short half-life of these peptides (15 seconds) also contributes to low plasma levels. In general, the kinins produce relaxation of vascular smooth muscle and vasodilation. Bradykinin causes... 

The eicosanoids, so called because of their derivation from a 20-carbon unsaturated fatty acid, arachidonic acid (eicosatetraenoic acid), are obtained from membrane phospholipids and synthesized de novo at the time of cellular stimulation. Arachidonic acid is cleaved from membrane-bound phosphatidylcholine by the enzyme phospholipase A2. Alternatively, arachidonic acid may be derived by the sequential actions of phospholipase C and diacylglyceryl lipase. Arachidonic acid can then follow either of two enzymatic pathways that result in the production of inflammatory mediators. The pathway initiated by cyclooxygenase (COX) produces prostaglandins the lipoxygenase pathway generates leukotrienes (Fig. 36.2). 

Intracellular messenger substances can be formed and degraded again in specific enzyme reactions. Via enzymatic pathways, large amoimts of messenger substances can be rapidly created and inactivated again. 

In some cell types (including cardiac muscle cells, pancreatic cells), another second messenger", the cyclic ADP-ribose (Fig. 6.8), is involved in opening the ryanodin receptors (Lee et al., 1994). The cADP-ribose is formed from NAD by an enzymatic pathway with the help of an ADP-ribosyl cyclase. 

In contrast to fresh muscle, meat has low levels of NAD (Madhavi and Carpenter, 1993). Thus, NAD-dependent enzymatic pathways for NOMb formation ate relatively unimportant in meat curing. In commercial practice, nitrite is reduced to NO by nonenzymatic means, including use of reductants such as ascorbate and erythorbate. Although meat has sufficient reducing ability to obtain a slow conversion of nitrite to NO, ascorbate or its isomer, erythorbate, is commonly added to curing brines or sausage emulsions to obtain faster NO production and thus a more rapid development of cured meat color. Care must be taken... 

Calcium Multiple physiologic actions through regulation of multiple enzymatic pathways Strontium suppresses bone resorption and increases bone formation, calcium and phosphate required for bone mineralization Osteoporosis, osteomalacia, deficiencies in calcium or phosphate Ectopic calcification... 

Two types of enzymatic pathways, the so-called phase I and phase II pathways, are generally implicated in drug biotransformation. Phase I pathways correspond to functionalization processes, whereas phase II correspond to biosynthetic or conjugative processes. Phase I functionalization processes include oxidation, reduction, hydrolysis, hydration, and isomerization reactions. 

In general, man is able to carry out all the metabolic transformations found in other mammals and does not show any particular differences in the presence or absence of an enzymatic pathway. 

As a result, pathways are available in many microoganisms for processing di-hydroxybenzene derivatives. Such continued breakdown proceeds via enzymatic pathways which open the ring between the two hydroxyl substituents (ortho cleavage) or adjacent to them (meta cleavage). The resulting chain compounds are... 

The role that the malo-lactic reaction—the decarboxylation of malic acid—plays in the overall physiology of the cell, and the enzymatic pathway of the reaction are two questions which have plagued enologists since the discovery of the reaction. Morenzoni (71) has described this discovery by Ochoa and coworkers (72, 73, 74), and he has related how their early representation of the reaction led to some confusion. We are now convinced, from studies by Radler and coworkers (75, 76) with partly purified enzymes from Lactobacillus and Leuconostoc, that the reaction is catalyzed by an inducible malate carboxy lyase with NAD (nicotinamide adenine dinucleotide) and Mn2+ as cofactors ... 

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