Aminotransferases targets

The liver appeared to be a target organ for hexachloroethane following oral administration. When one dose of 500 mg/kg was administered in an olive oil aqueous emulsion to male sheep, the levels of glutamate dehydrogenase, sorbitol dehydrogenase, ornithine carbamyl transferase, and aspartate aminotransferase in serum increased in the 2-day period after compound administration and then normalized (Fowler 1969b). Hexachloroethane had no effect on bromsulphthalein uptake from the blood by liver cells, but the transfer of this dye to bile was reduced in sheep exposed to doses of 500-1,000 mg/kg/day. 

Among the numerous enzymes that utilize pyridoxal phosphate (PLP) as cofactor, the amino acid racemases, amino acid decarboxylases (e.g., aromatic amino acids, ornithine, glutamic acid), aminotransferases (y-aminobutyrate transaminase), and a-oxamine synthases, have been the main targets in the search for fluorinated mechanism-based inhibitors. Pharmaceutical companies have played a very active role in this promising research (control of the metabolism of amino acids and neuroamines is very important at the physiological level). 

Enzymes containing pyridoxal phosphate are prime targets for suicide inhibition because the chemistry is so naturally suitable. As discussed in Chapter 2, section C2, the pyridoxal ring acts as an electron sink that facilitates the formation of carbanions and also forms part of an extended system of conjugated double bonds. For example, vinyl glycine, CH2=CHCH(NH3+)C02, condenses with the pyridoxal phosphate of aspartate aminotransferase to form a Schiff base, as described in Chapter 2, equation 2.42.19 The a proton may be abstracted (as in equation 2.43) so that the isomerization shown in equation 9.13 readily occurs. 

Hepatic Effects. A single case study reported areas of focal necrosis and cell degeneration in the liver of a worker exposed to an undetermined concentration of hydrazine in air once a week for 6 months (Sotaniemi et al. 1971). Studies of workers exposed to 1,1-dimethylhydrazine have reported changes indicative of a hepatic effect including elevated scrum alanine aminotransferase activity, fatty degeneration, and a positive cephalin flocculation test (Petersen et al. 1970 Shook and Cowart 1957). Although the levels of hydrazine and 1,1-dimethylhydrazine exposure were not determined, these studies indicate qualitatively that tlie liver is a target for both hydrazines. 

Maltnberg LH, Hu WS, Sherman DH. Precursor flux control through targeted chromosomal insertion of the lyseine E-aminotransferase (ku) gene in cephamycin biosynthesis. J Bacteriol 1993 175 6916-6924. 

Of the parasitic diseases the most devastating one is malaria with a worldwide death toll of more than a million people. It is transmitted by the mosquito. To combat this, the life cycle and metabolism of the parasite Plasmodium falciparum is affected through a reduction in the synthesis of xanthurenic acid (92). Xanthurenic acid, required for gametogenesis and fertility of the parasite, is synthesized in the tryptophan degradation pathway through the PLP-dependent enzyme kynurenine aminotransferase. Hence, this enzyme is a target for the development of antimalarial drugs. 

It is necessary to mention that the final effect of hormones on the morphogenetic processes is determined not only by the genetically controlled conditions of the endocrinal system, but also by the genetically controlled ability (competency) of the target-tissue which reacts to the hormone (Shire, 1974). For instance, liver tyrosine aminotransferase (TAT) is an enzyme which is induced by steroids both in vivo and in vitro in cultured cells. Sublines of hepatomas were described in which the level of activity of this enzyme was normal, but which were unable to react to steroid treatment by increasing TAT activity (Levisohn and Thompson,... 

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