Guanylate synthetase

As will be discussed in Chapter 8, the following sequence is followed by guanylate synthetase ... 

Increased enzyme activity may be due to increased concentrations of nucleotide substrates, or by other mechanisms. For example, GTP is required as a substrate for adenylosuccinate synthetase, and ATP is required for guanylate synthetase in addition, ATP activates adenylate deaminase (33). 

The supply of nonnucleotide substrates may also be an important control mechanism for these pathways. In Ehrlich ascites tumor cells aspartate concentrations were found to be rate-limiting for adenylate synthesis from hypoxanthine (46), and glutamine levels limited guanylate synthetase activities in these cells and in erythrocytes (47)-... 

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). 

Psicofuranine (9-u-psicofuranosyl adenine) is an inhibitor of bacterial guanylate synthetase. It binds to a separate site on the enzyme and prevents the synthesis of the adenylate-xanthylate intermediate of this reaction (29, 53). 

CMP SYNTHETASE GTP CYCLOHYDROLASE II GUANYLATE CYCLASE HEXOSE-1-PHOSPHATE CUANYLYL-TRANSEERASE... 

As in other reactions in which either ammonia or the amide group of glutamine is utilized (amination of UTP to form CTP, synthesis of NAD from desamido-NAD, and of guanylate from xanthylate), the carbamyl phosphate synthetase II reaction is inhibited by the glutamine analogues, azaserine and diazo-oxo-norleucine (see Chapter 5). 

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. 

Alanosine (L-2-amino-3-(N-hydroxy, N-nitrosamino) propionic acid), another inhibitor of adenylosuccinate synthetase (7), did not appear to interfere with synthesis of adenosine nucleotides by malaria infected erythrocytes (Table 1). There was, however, an unexpected decrease in labelled GTP and total guanylates (EG). 

Biotin has a role in cellular processes such as survival, differentiation, and development. A role for biotin in the synthesis of specific proteins has been identified (28). Biotin holocarboxylase synthetase (HCS) catalyzes the biotinylation of apocarboxylases. HCS mRNA is significantly reduced in the biotin-deficient rat. A regulatory role for biotin in the control of biotin HCS mRNA levels via signaling cascades involving guanylate cyclase and cGMP-dependent protein kinase has been proposed (29). 

The enzyme catalyzing the amidation of the nicotinic acid- DPN to the active coenzyme has been detignated DPN synthetase q. (3c)]. The mechanism of the reaction is timilar to that involved in the formation of guanylic acid 13S, 1S4) as well as a-N-formylglycinamide in which the glutamine nitrogen is transferred to the acid yielding the amide 133). At present, there is no explanation of the reason for the ATP requirement in the reaction. 

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