Inactivation pathway

Metabolism of 6-MP - Activating and Inactivating Pathways and Their Clinical Relevance... 

Histamine is formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Once formed, histamine is either stored or rapidly inactivated. Very little histamine is excreted unchanged. The major inactivation pathways involve conversion to methylhistamine, methylimidazoleacetic acid, and imidazoleacetic acid. Certain neoplasms (systemic mastocytosis, urticaria pigmentosa, gastric carcinoid, and occasionally myelogenous leukemia) are associated with increased numbers of mast cells or basophils and with increased excretion of histamine and its metabolites. 

In the context of mechanism-based inhibition, kcat does not have the same definition as that commonly used in metabolite formation kinetics kcat is not equivalent to k2 unless k3 greatly exceeds k2 and fc4, which may occur when the inactivation pathway is minor in comparison to the formation of metabolite. 

It should be noted that the mechanism depicted in Scheme 1 is the simplest that is consistent with mechanism-based inhibition. The mechanism for a given inhibitor and enzyme may be considerably more complex due to (a) multiple intermediates [e.g., MIC formation often involves four or more intermediates (29)], (b) detectable metabolite that may be produced from more than one intermediate, and (c) the fact that enzyme-inhibitor complex may produce a metabolite that is mechanistically unrelated to the inactivation pathway. Events such as these will necessitate alternate definitions for Z inact, Kh and r in terms of the microrate constants of the appropriate model. The hyperbolic relationship between rate of inactivation and inhibitor concentration will, however, remain, unless nonhyperbolic kinetics characterize this interaction. Silverman discussed this possibility from the perspective of an allosteric interaction between inhibitor and enzyme (5). Nonhyperbolic kinetics has been observed for the interaction of several drugs with members of the CYPs (30). 

If the inactivated pathway is only one of multiple elimination pathways in the liver, then the predictive model of Eq. (24) becomes... 

Insertion of oxygen atom from Cpd I into the carbon-carbon double bond with formation of epoxide (Scheme Ic) reveals features characteristic for a concerted process, although formation of radical intermediates is possible in many cases. A unified description of this alternative is also provided by the two-state mechanism of catalysis by Cpd I (see the section on Hydroxylation of hydrocarbons). Essentially, the concerted oxygen insertion represents a low-spin reaction surface, whereas the distinct radical intermediate is formed on the high-spin reaction pathway. In the latter case, the carbon radical may attack the nearby heme nitrogen and modify the heme covalently. This reaction is also an important inactivation pathway of cytochromes P450 during oxidative transformations of terminal double and triple bonds. 

The inactivation pathway of ABA is illustrated in Fig. (10) oxidation at C-8 and C-T and subsequent cyclization and reduction, conjugation of the C-1 carboxyl and C-T hydroxyl groups, and photoisomerization of the C-2 double bond. 

Fig. 8 Possible mechanism of the antitussive effect caused by 5 opioid receptor antagonists. Solid arrows indicate activated pathways dotted lines indicate inactivated pathways...

Although aggregation is the predominant means by which proteins become inactivated during refolding, several other inactivation pathways have also been observed. Proteins can be inactivated by thiol-disulfide exchange or alteration of the primary structure by chemical modification of amino acid side chains. In addition, refolded proteins may be inactivate due to the absence of prosthetic groups and metals or because of improper association of the subunits in multimeric proteins (79). 

Finally, to underscore further redundancy as a hallmark of 2-AG inactivation pathways, strong evidence also exists for the direct esterification of this compound into neutral glycerolipids and phospholipids (Di Marzo et al. 1999a). The relevance of these pathways, which were already known when 2-AG was considered a mere intermediate in glyc-erol(phospho)lipid metabolism, to the regulation of the cannabinergic signal still need to be assessed. 

Accounting for half of the oxidizing equivalents based on Ru(tpy) (bpy)O implies that about 50% of the total Ru(IV)0 reacts via a self-inactivation pathway ( x)> which has been demonstrated for polypyridyl oxidants 129). This self-inactivation pathway results from the bimolecular reaction of two oxoruthenium complexes to produce Ru(II) and oxidized polypyridyl ligands, as discussed earlier and shown in Scheme 5. Thus, observations imply that in terms of Scheme 10, kx > k(i > sugar Ru(IV)0. This ordering makes the prediction that a less powerful oxidant will be reduced via the kx and Hq pathways, but not via as long as the rates of the various processes are... 

The last case is the most common one for enzyme inactivation and it is nearly always observed for the killing of microorganisms. The latter is to be explained by the fact that the killing of a microbe will depend on irreversible inactivation of the most unstable of its essential enzymes, and that would be one following the inactivation pathway discussed here, since the other situations imply a smaller k and would therefore imply greater heat stability. 

In contrast to the formation of covalent adducts at flavin or at an amino acid residue by A -cyclopropyl-Af-arylalkylamines and 2-phenylcyclopropylamine, respectively, inactivation of MAO by 1-phenylcyclopropylamine leads to both types of adducts 100). Both inactivation pathways are proposed to originate from an initial one-electron oxidation by flavin to produce a common intermediate, the amine radical cation 33 in Scheme 22 (compounds 33-39). Homolytic cyclopropyl ring opening would lead to the reactive primary alkyl radical 34, which could be captured by the active site radical, either flavin semiquinone or amino acid centered. Subsequent hydrolysis of the imine, pathway (a), forms a... 

---