Metabolite analogues Competitive

The l,25(OH)2D3 receptor of the chick intestine has been extensively characterized by our laboratory and several others, and its biochemical properties reveal many similarities to classical steroid hormone receptors [5,6], The l,25(OH)2D3 receptor is a protein with a molecular mass of approximately 67000 Da when occupied, unoccupied or in the absence of protease inhibitors. The receptor has a high affinity for l,25(OH)2D3 with a Kd in the range of 1-50 x 10 n M. The specificity of the receptor for binding of l,25(OH)2D3 metabolites and analogues, as determined by competitive binding studies, parallels the biological activity of these compounds. 

Antimetabolites are synthetic analogues of normal metabolites and act by competition, i.e. they deceive or defraud bodily processes. 

A. Metabolic activation The antimetabolites (and their subsequent enzymic reaction product(s), respectively) may be utilized as competitive substrate(s) in one (or several consecutive) enzymic reaction(s) along the metabolic pathway of the normal metabolite, but at one stage of the metabolic reaction sequence, the transformed analogue cannot be further utilized as a substrate and, instead, acts as an inhibitor of the enzyme which catalyzes the next reaction step. At this stage, the action of the transformed ( activated ) analogue as an enzyme inhibitor depends on the same general types of structural requirements as outlined in the case of the directly acting enzyme inhibitors (see Section 2.2. ... 

Carvedilol, l-(9H-carbazol-4-yloxy)-3-[[2-(2-metho-xyphenoxy)ethyl]amino]-2-propanol, competitively inhibits 3-receptors (Sponer et al. 1987, Nichols et al. 1989, De Met et al. 1994, Sponer and Feuerstein 1999), blocks ai-receptors (De Mey et al. 1994, Sponer and Feuerstein 1999), and acts as an antioxidant (Yue et al. 1992, 1999, Aruma-NAYAGAM et al. 2001). Hydroxylation of the carba-zol moiety significantly increases the antioxidafive effect. Some metabolites have a ten-times higher oxygen radical-scavenging effect than carvedilol itself (Feuerstein et al. 1993). A hydroxylated analogue of carvedilol affords exceptional antioxidant protection to postischemic rat hearts (Kramer and Weglicki 1996). 

Anfossi, L. et al, Development of a non-competitive immunoassay for monitoring DDT, its metabolites and analogues in water samples. Anal. Chim. Acta, 506, 87,2004. 

Because the competition between the analogue and the natural metabolite is a general feature, the toxicity of the former is influenced by its effects on the assimilation and/or supply of amino acids. In vivo protein synthesis requires the availability of the complete set of amino adds which are picked up from the external medium, and/or are synthesized endogenously. 

Tyrosine hydroxylase Inhibitors - Perhaps the greatest effort is being directed toward studies of the enzyme tyrosine hydroxylase which represents the rate limiting step in catecholamine synthesis. This enzyme catalyzes the conversion of tyrosine to DOPA and Is localized In the particulate fraction of the cell sedimenting at 16,000 x g. Inhibition of this enzyme has been found to be the most effective means of blocking the formation of norepinephrine. Much of the biochemistry of this and other enzymes associated with catecholamines was discussed at the Second Symposium on Catecholamines and published in 1966. Hundreds of compoumds have been examined for anti-tyrosine hydroxylase activity, but only a few exhibited Inhibitor activity vitro, and these were mainly analogues of tyrosine or its catechol metabolites. It has become apparent, however, that there is not always a relationship between vitro and to vivo activity. Of the many compounds thus far tested, two which have shown In vivo activity are a-methyl-1-tyroslne (a-MT) and H44/68 (the methyl ester-HCl of c MT), both acting as competitive antimetabolites of tyrosine. 

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