Adenylosuccinate synthetase levels

Although tumour growth inhibition by 6-mercaptopurine has been attributed to the inhibition of the conversion of inosinic acid to adenylic acid [309, 310, 312], probably at the first step, this conversion by cell-free extracts from the exquisitely sensitive tumour adenocarcinoma 755 was inhibited only at high levels of 6-mercaptopurine ribonucleotide [313]. Furthermore, hadacidin (A -formylhydroxyaminoacetic acid) is an excellent inhibitor of adenylosuccinate synthetase [314, 315], and yet it has little antitumour activity and is not cytotoxic, showing that this inhibition may be relatively unimportant to cells. 

The purine nucleotide cycle of muscle consists of the conversion of AMP —> IMP AMP and requires AMP deaminase, adenylosuccinate synthetase, and adenylosuccinate lyase (Figure 27-24). Flux through this cycle increases during exercise. Several mechanisms have been proposed to explain how the increase in flux is responsible for the maintenance of appropriate energy levels during exercise (Chapter 21). 

The enzymes that convert IMP to XMP and adenylosuccinate are both regulated. GMP inhibits the activity of IMP dehydrogenase, and AMP inhibits adenylosuccinate synthetase. Note that the synthesis of AMP is dependent on GTP (of which GMP is a precursor), whereas the synthesis of GMP is dependent on ATP (which is made from AMP). This serves as a type of positive regulatory mechanism to balance the pools of these precursors when the levels of ATP are high, GMP will be... 

Adenylosuccinate synthetase activity has been observed in almost all tissues examined. The only exception is the human erythrocyte (30). Davey (18) had reported that the enz3rme was absent in rabbit heart, lung, and kidney, but it was demonstrated subsequently in those tissues (31). Highest levels of enzyme activity occur in skeletal and heart muscle and the testes (24). 

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. 

The level of aspartate has been shown to influence the activity of adenylosuccinate synthetase in vivo both in Ehrlich ascites cells (26) and cultured fibroblasts 95). Addition of exogenous aspartate to either system increased the conversion of IMP to AMP and reduced breakdown of IMP to inosine and hypoxanthine 26, 95). 

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

Hadacidin (N-formyl hydroxy-aminoacetic acid), which is known to inhibit adenylosuccinate synthetase (7), blocked synthesis of adenosine nucleotides from IMP (Table 1). There was a significant decrease (83%, p <. 001 Student s T test for unpaired values) in newly synthesized ATP and in total adenylates (ZA). The concentration of ATP and the level of the adenylate pool were not decreased. There was a decrease in labelled guanylate in PRBC exposed to hadacidin. 

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