Metabolite analogues

Scheme 1 Examples of precursor-directed biosynthesis (PDB) of fungal metabolite analogues...

Similarly, the experiments of Matolcsy et al. (1974a 1974b 1975), in which several metabolite analogues of mevalonic acid and homomevalonic acid have been tested for anti-juvenile action, were unsuccessful. Support for the rationale that these metabolite analogues would block the formation of juvenile hormone at the mevalonate level was provided by the successful inhibition of cholesterol biosynthesis by mevalonate analogues in humans. Yet, a fluorinated mevalonate analogue, 4-fluoromethyl-4-hydroxy-tetrahydro-2H-pyran-2-one (FMev, 72) was found to act as a potent inhibitor of JH biosynthesis by Quistad and co-workers... 

Other vertebrate hormones are dealt with under metabolite analogues (Sections 9.1 and 9.4.2), and steric factors (Sections 12.2 and 12.4). 

Other metabolite analogues of proven value in prophylaxis and therapy... 

Curiously enough, a metabolite analogue may be treated as a metabolite by one species and as an antagonist by a related species. For example, dethiobiotin... 

Many of these antagonisms present a picture that is the inorganic equivalent of the metabolite analogues discussed in Chapter 9. 

Tipper and Strominger (1965), by comparing molecular models of penicillin and D-alanyl-D-alanine claimed that the former could effectively function as a metabolite analogue of the latter. Thus the N to N" distances in these molecules, shown as projections of molecular models in (13.7) and (13.8), are identical, namely 3.3 A. Also the N" to C distances are similar in both models, namely 2.5 A. From N to C is 5.4 A in the penicillins and 5.7 A in alanyl-alanine, distances which are not identical but still quite similar. The D-con-figuration of the penicillin is maintained by the sulfur atom in conjunction with the carbon atom that is common to both rings. [Epimerization at the 6-position, see (13.4), causes loss of all antibacterial activity.] The most reactive bond in the penicillin molecule (the j8-lactam bond) corresponds in position to the peptide bond joining the two D-alanine residues. However, there are discrepancies the... 

There are some kinds of drug action where the structure itself plays an outstanding part, namely in the use of metabolite analogues. In many other kinds of action, a physical property is its main source, and this property could be provided by many kinds of structure. 

Excellent prophylaxis, and even cure, of the disease can be obtained with the following drugs mixed with the food (a) sulphonamides, especially sulfaquinoxaline, (b) amprolium (9.27), a metabolite analogue of thiamine, or (c) nitrofurazone (4.25). 

Enzymes, their substrates and other metabolites. 289 Metabolite analogues definition, derivation, and mode of action. 295 History of metabolite antagonism prior to 1940. 302 The folic acid antagonists. 303... 

Metabolite analogues definition, derivation, and mode of action... 

Those metabolites (substrates or coenzymes) that are present in only small amounts in a cell or tissue can be antagonized by substances known as metabolite analogues. The molecules of each such analogue have a region which is similar to that region of the metabolite which makes contact with... 

Antagonistic metabolite analogues have been found for almost every known vitamin. For example, when the thiazole portion of thiamine (2.1) is replaced by a similarly substituted pyridine ring, the product ( pyrithia-mine ) produces characteristic symptoms of thiamine-deficiency in mice (Woolley, 1950) [see Section 9.4 for a commercially successful thiamine antagonist (9.24)]. 

Desoxypyridoxine [(9.3)3 R = --CH3] produces signs of vitamin deficiency in man, chicks, and rats, rapidly reversed by the vitamin [ (9.3)5 R = -CH20H] (Mueller and Vilter, 1950). For most of the vitamins, several antagonists are known. Metabolite analogues have also been found for aminoacids, purines, pyrimidines, some hormones, and the participating acids of the Krebs cycle. 

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