Adenylosuccinate synthetase isozymes

Since the two isozymes of adenylosuccinate synthetase differ so markedly, changes in the relative amounts of the two could drastically affect the regulation of the reaction they catalyze, and therefore the direction of purine nucleotide metabolism. Determination of this ratio could be a useful indicator of the relative importance of the biosynthetic and the cyclic aspects of the adenine nucleotide interconversion pathway in different tissues or under different metabolic conditions. 

It appears that adenylosuccinate synthetase is subject to feedback and product inhibition by AMP, adenylosuccinate, GDP, and GMP. The KiS reported for AMP range from 10 to 3000 fx.M for the enzyme from normal cells from various sources 34, 38, 45, 50). The for AMP for adenylosuccinate synthetase from Novikoflf ascites and Walker carcinoma 256 tumors is in the range of 150-190 fiM and are less sensitive to inhibition than the acidic isozyme from rat liver for which the/f i for AMP was 47 /xM 45). In some cases, nucleoside monophosphates such as AMP interact with both nucleotide sites, producing noncompetitive inhibition patterns 38, 45). 

It has been suggested that thyroid hormone (T3) could stimulate the activity of adenylosuccinate synthetase in rat liver 44). Two more recent studies have reported that no such activation was observed (15, 47). The original work was done with an acidic isozyme, while the subsequent work was probably done on the basic isozyme. This study should be repeated using the two purified rat isozymes. 

The regulation of mammalian adenylosuccinate synthetase is complicated. It is dependent on the isozyme content and levels in a given tissue as well as the effects of substrate and product levels. The two isozymes may have different metabolic roles either in AMP biosynthesis and interconversion, or in the functions of the purine nucleotide cycle. Most studies have considered kinetic parameters for the isolated enzyme and in only a few instances has regulation been studied in vivo. Sufficient information is available concerning the regulation of the basic isozyme in muscle to consider that enzyme in detail. Factors controlling the acidic isozyme are less clearly defined. 

Levels of the Isozymes of Adenylosuccinate Synthetase in Rat Liver under Various Nutritional Regimens... 

Matsuda et al. (27) showed that the adenylosuccinate synthetase basic isozyme has a lower Km for aspartate, is more sensitive to inhibition by fructose 1,6-bisphosphate, and less sensitive to inhibition by nucleotides than the acidic isozyme. These properties could indicate that the basic isozyme is regulated coordinately with glycolysis (or gluconeogenesis) as proposed for the operation of the purine nucleotide cycle in skeletal muscle. The enzyme could also be affected by the availability of aspartate, as was found in Ehrlich ascites cells. The increase in basic isozyme activity, under conditions used in this study where the animal must rely on protein for most of its energy, is consistent with the idea that it is involved in the purine nucleotide cycle. This probably is not as an alternative to glutamate dehydrogenase in urea synthesis but is simply in amino acid catabolism. The small... 

DisTMBunoN OF Isozymes of Adenylosuccinate Synthetase in Various Rat Tissues... 

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