Metabolism carbamylation reactions

In vivo intermediate in mammals by the detection of two of its derivatives,, the glutathione (GSH) conjugate and its further metabolites formed by an initial carbamylation reaction (W) (see below) and 2-chloroacrolein detected in the microsome-NADPH system and derived from the rearrangement-elimination reaction sequence discussed above (6). Sulfallate also yields 2-chloroacrolein in the microsome-NADPH system, presumably by -CH2 hydroxylation (22) on analogy with the metabolism of EPTC shown previously. 

Carbamylation Reactions. -Alkyl, -benzyl and -chloroallyl thiocarbamates do not readily react with GSH. In contrast, their sulfoxide derivatives ( and 6,) are very effective carbamylating agents for many thiols including GSH (19, ). The GSH conjugates formed vivo via 3 and 6 are quickly cleaved, acetylated and further metabolized as follows (19-21. 23. 24). 

Defects of the enzymes mediating all four reactions of the urea cycle proper have now been established, and there is some evidence of the existence of a fifth enzyme defect, involving carbamyl phosphate synthetase, mediating the initial reaction of the pathway. As the first report of a metabolic disorder involving the urea cycle was only in 1958, it is not surprising that there have been very few reviews of this topic, that of Efron (El) being the most complete to date. 

There are many cholinesterase inhibitors diminishing both AChE and BuChE activities to a comparable extent. However, there are a number of important exceptions the selectivity of some OP and carbamates for BuChE has been described by Aldridge (A4). Carbamates belong to a group of insecticides having a large variation in their effectiveness. They are biologically active because of their structural complementarity to the active surface of AChE and their consequent reaction as substrates with very low turnover numbers (A4, B2). Some carbamates inhibit selectively either AChE or BuChE (Bll, B22). The toxicity of carbamates is dependent on their ability to carbamylate AChE in different tissues and on other factors such as distribution, detoxification, and metabolization. 

Reaction 5 is catalyzed by arginine decarboxylase which has been found in barley (Smith, 1963). Agmatine can be converted to A-carbamoyl putrescine (reaction 6) by agmatine iminohydrolase (E.C. 3.5.3.12). This enzyme has been found in extracts of maize leaves and sunflower (Smith, 1969). The further hydrolysis of A/ -carbamyl putrescine to putrescine (reaction 7) is catalyzed by A-carbamyl putrescine amidohydrolase which has been found in barley leaf extracts (Smith, 1965). The enzyme activities catalyzing reactions 5 and 7 are increased several-fold in K-deficient barley leaves (Smith, 1963, 1965) which correlates well with the high level of putrescine accumulation in K-deficient barley. Further metabolism of putrescine is discussed by Smith, this series, Vol. 7, Chapter 9. 

Another form of spatial organization of metabolism that is often seen in eukaryotes but is less common in bacteria involves enzyme aggregates or multifunctional enzymes. An example is seen in S. cerevisiae where the first two reactions in pyrimidine nucleotide biosynthesis, the synthesis of carbamyl phosphate and the carbamylation of aspartate, are catalyzed by a single bifunctional protein (31). Both reactions are subject to feedback inhibition by UTP, in contrast to the situation inB. subtilis where aspartate transcarbamylase activity is not controlled. It is possible that an evolutionary advantage of the fusion of the genes... 

All transcarbamylation reactions require Cp. as donor of the carbamyl group, i.e. transcarbamylation directly from ureido compounds does not occur. C. p. is probably also the carbamyl donor in the biosynthesis of O- and N-carbamyl derivatives, such as Al-bizziin (see). C.p. is a metabolically active form of ammonia used as the starting material for synthesis of other nitrogenous compounds. 

In preceding sections of this chapter, the important metabolic reactions which yield ammonia have been discussed. Certain of these systems are capable of fixing ammonia (glutamic dehydrogenase, alanine dehydrogenase, L-amino acid oxidase, etc.). The fixation of ammonia in the glutamine synthetase system will be discussed in Chapter 17. The present section will deal with (a) enzymes which fix ammonia to form carbamyl phosphate and (b) enzymes which utilize carbamyl phosphate for the synthesis of arginine (and urea) and pyrimidines. 

The location of the metabolic block appears to be advantageous to cellular economy, sparing energy, and metabolites. The formation of carbamylaspartic acid was essentially an irreversible reaction and inhibition of the sequence at a subsequent step would be considered inefficient since carbamylaspartic acid would be produced whether it were needed or not. It is of further interest that the steps preceding the blocking point, the formation of aspartic acid and carbamyl phosphate, were freely reversible reactions. 

Glutamic acid has appeared as a point of juncture in the network of amino acid metabolism. It is dehydrogenated with NAD to the imino acid and then converted to ketoglutarate. The ammonia liberated is used directly for urea formation (via carbamyl phosphate Section 8 of this chapter). On the one hand, a-ketoglutarate is the universal acceptor of amino groups in transamination reactions on the other hand, as an keto acid it can also be decarboxylated oxidatively. In complete analogy to the oxidative decarboxylation of pyruvate, this reaction leads to acti-... 

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