Metabolic target

Hypothermia Reduction of metabolic Target temperature of 32-34°C Bladder temperature Shivering... 

Rowe TC, Weissig V, Lawrence JW. Mitochondrial DNA metabolism targeting drugs. Adv Drug Deliv Rev 2001 49(1-2) 175-187. 

Three major groups of helminths (or worms), the nematodes, trema-todes and cestodes, infect humans. As in all antibiotic regimens, the anthelminthic drugs (Figure 36.1) are aimed at metabolic targets that are present in the parasite but are either absent from or have different characteristics than those of the host. Figure 36.2 illustrates the high incidence of helminthic infections. 

It is now well established that the primary metabolic target of glyphosate is an enzyme of the shikimic acid metabolic pathway, enolpyruvyl shikimate-3-phosphate synthase (2.f ). Via this action, glyphosate blocks the synthesis of the end products of this pathway, notably phenylalanine and tryptophan, but also various subsequent products (Figure 1) ( ,i). It has seemed logical to conclude that the herbicidal effect of glyphosate is a direct result of its effect on the shikimic acid pathway. 

Melarasaprol Energy metabolism Target pathway more important in the parasite T. brucei gambiense... 

However, this does not apply to the special situation when (1) the enzyme is a synthetase which catalyzes the formation of a covalent bond between the metabolite (or antimetabolite) and a second substrate, and (2) the second substrate is available only in a limited amount. In this case, the antimetabolite competes with the metabolite not only for the enzyme but also for the second substrate, with which it will combine covalently to form an inert product. Although this enzyme-mediated reaction of the antimetabolite is reversible by the corresponding metabolite in a competitive manner, due to its potentially crucial metabolic effect, (i.e., the elimination of another, limiting metabolite which is required for the same reaction step of the metabolic pathway), this reaction per se could be responsible for the over-all inhibitory effect of the antimetabolite. That is, in such particular cases, the metabolic target of the inhibitory action of the antimetabolite may be an enzymic reaction step in which it actually plays the role of a substrate. One might think that this type of situation is a rather special and unusual one, as it may be indeed however, it so happens that the first descovered and still important class of classical and semi-classical antimetabolites, the sulfonamides, appears to act in this manner, as indicated by the results of a recent study8 (see Section 3.2.). 

Coprine (10), a cyclopropanone hemiaminal isolated from the edible mushroom Coprims atramentarius, is cleaved by hydrolytic glutaminase enzymes in mammals or bacteria to 1-aminocyclopropanol (11) which is in equilibrium with cyclopropanone and its hydrate 12. This tendency to accumulate as the stabilized hydrate accounts for the eventual toxicity of coprine, which can inactivate one of its metabolic targets, aldehyde dehydrogenase, known to have a kinetically reactive and essential cysteinyl thiolate side chain in its active site. The hydrate, in equilibrium with cyclopropanone, is converted into adduct 13, explaining the observed activity loss. °... 

Rowe PC, Valle D, Brusilow SW (1988) Inborn errors of metabolism in children referred with Reye s syndrome a changing pattern. JAMA 260 3167-3170 Rowe TC, Weissig V, Lawrence JW (2001) Mitochondrial DNA metabolism targeting drugs. Adv... 

Pereira AS, Donato JA, De Nucci G, Implications of the use of semicarbazide as a metabolic target of nitrofurazone contamination in coated products. Food Addit. Contam. 2004 21(l) 63-69. 

It is apparant that parasite adenosine deaminase is a potential metabolic target for the design of new antimalarial chemotherapy. Work is currently under way in our laboratory to more fully understand the action of 2 -deoxycoformycin on the malaria parasite and the possible role of ADA in cellular development and proliferation. 

Pols TW, Noriega LG, Nomura M, Auwerx J, Schoonjans K. The bile acid membrane receptor TGR5 a valuable metabolic target. Dig Dis. 

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