Adenylosuccinate synthesis from inosinate

A few steps convert inosinate into either AMP or GMP (Figure 25,9). Adenylate is synthesized from inosinate by the substitution of an amino group for the carbonyl oxygen atom at C-6. Again, the addition of aspartate followed by the elimination of fumarate contributes the amino group. GXP, rather than ATP, is the phosphoryl-group donor in the synthesis of the adenylosuccinate intermediate from inosinate and aspartate. In accord with the use of GTP, the enzyme that promotes this conversion, adenylsuccinate synthase, is structurally related to the G-protein family and does not contain an ATP-grasp domain. The same enzyme catalyzes the removal of fumarate from adenylosuccinate in the synthesis of adenylate and from 5-aminoimidazole-4-jV-succinocarboxamide ribonucleotide in the synthesis of inosinate. 

The glutamine analogue, diazo-oxo-norleucine, and the aspartate analogue, hadacidin (iV-formyl hydroxyaminoacetic acid), inhibit guanylate synthetase and adenylosuccinate synthetase, respectively. Alanosine (2-amino-3-nitrohydroxylaminopropionic acid) is also an inhibitor of adenylate synthesis from inosinate, but its mechanism of inhibition is not yet clear (52). 

In the second control mechanism, exerted at a later stage, an excess of GMP in the cell inhibits formation of xanthylate from inosinate by IMP dehydrogenase, without affecting the formation of AMP (Fig. 22-35). Conversely, an accumulation of adenylate inhibits formation of adenylosuccinate by adenylosuccinate synthetase, without affecting the biosynthesis of GMP. In the third mechanism, GTP is required in the conversion of IMP to AMP (Fig. 22-34, step (T)), whereas ATP is required for conversion of IMP to GMP (step (4)), a reciprocal arrangement that tends to balance the synthesis of the two ribonucleotides. 

L3. Lieberman, I., Involvement of guanosine triphosphate in the synthesis of adenylosuccinate from inosine-5 -phosphate. /. Am. Chem. Soc. 78, 251 (1956). 

Inosinate is the branch point in the synthesis of AMP and GMP. The reactions leading away from inosinate are sites of feedback inhibition. AMP inhibits the conversion of inosinate into adenylosuccinate, its immediate precursor. Similarly, GMP inhibits the conversion of inosinate into xanthylate, its immediate precursor. 

Althou adenylosuccinate is an intermediate in the synthesis of adenylate, it was first identified as a product of the reaction of adenylate and fumarate. Lieberman 11) showed that the s3mthesis of adenylosuccinate from inosinate and aspartate specifically required GTP and that... 

AMP synthesis (The two reactions of AMP synthesis minic steps in the purine pathway leading to IMP.) In Step 1, the 6-0 of inosine is displaced by aspartate to yield adenylosuccinate. The energy required to drive this reaction is derived from GTP hydrolysis. The enzyme is adenylosuccinate synthetase. 

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