Glutamine amidotransferases

The amino acid and nucleotide biosynthetic pathways make repeated use of the biological cofactors pyridoxal phosphate, tetrahydrofolate, and A-adenosylmethionine. Pyridoxal phosphate is required for transamination reactions involving glutamate and for other amino acid transformations. One-carbon transfers require S-adenosyhnethionine and tetrahydrofolate. Glutamine amidotransferases catalyze reactions that incorporate nitrogen derived from glutamine. 

FIGURE 22-48 Azaserine and acivicin, inhibitors of glutamine amidotransferases. These analogs of glutamine interfere in a number of amino acid and nucleotide biosynthetic pathways. 

Terms in bold are defined in the nitrogen cycle 834 nitrogen fixation 834 symbionts 834 nitrogenase complex 835 leghemoglobin 836 glutamine synthetase 838 glutamate synthase 838 glutamine amidotransferases 840 5-phosphoribosyl-l-... 

Inhibitors of Nucleotide Biosynthesis Suggest mechanisms for the inhibition of (a) alanine racemase by l-fluoroalanine and (b) glutamine amidotransferases by aza-serine. 

The diazo compound 0-(2-diazoacetyl)-L-serine, known also as azaserine (see Fig. 22-48), is a powerful inhibitor of glutamine amidotransferases. If growing cells are treated with azaserine, what intermediates of nucleotide biosynthesis would accumulate Explain. 

The first specific step in tryptophan biosynthesis is the glutamine-dependent conversion of chorismate to the simple aromatic compound anthranilate. Like most other glutamine-dependent reactions, the reaction can also occur with ammonia as the source of the amino group. However, high concentrations of ammonia are required. Thus far, almost all the anthranilate synthases examined have the glutamine amidotransferase activity (component II) and the choris-mate-to-anthranilate activity (component I) on separate proteins. 

Acivicin is a cjhostatic antibiotic, a glutamine analogue, which is a potent inhibitor of 1-asparagine synthetase and other 1-glutamine amidotransferases and has its cjhotoxic action by blocking nucleotide biosynthesis. 

Azaserine is an antibiotic that is a potent inhibitor of purine nucleotide synthesis. Azaserine is similar in structure to glutamine and is an irreversible inhibitor of glutamine amidotransferases, which catalyze the ATP-dependent transfer of the amido nitrogen of glutamine to an acceptor. Four such reactions occur in nucleotide synthesis. 

Fig. 2. The pathway of histidine biosynthesis. Enzymes a, ribosephosphate pyrophos-phokinase E.C. 2.7.6.1 b, ATP-phosphoribosyltransferase, E.C. 2.4.2.17 c, phosphoribosyl-AMP cyclohydrolase, E.C. 3.5.4.19 d, N-(5 -phospho-D-ribosylforminino)5-amino-l-(5"-phos-phoribo yl)-4-imidazole carboxamide isomerase, E.C. 5.3.1.16 e, glutamine amidotransferase f, imidazolglycerolphosphate dehydratase E.C. 4.2.1.19 g, histidinol-phosphate aminotransferase E.C. 2.6.1.9 h, histidinol phosphatase, E.C. 3.1.3.15 i, histidinol dehydrogenase, E.C. 1.1.1.23.

A., Glutamine-Binding Subunit of Glutamate Synthase and Partial Reactions Catalyzed by this Glutamine Amidotransferase, Proc. Natl. Acad. Sci. U.S., 71 4607 (1974). 

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