806 



Discussion 



steps in the synthesis of guanyhc acid, the mechanism of the inter- 

 conversion of purine nucleotides, and the role of these reactions in 

 histidine biosynthesis. The reactions and the control points are shown 

 in the following scheme : 



Hist. 



Prot. 



Hist. 

 PR-AMP -•-#— AMP— ^N.A. 



,/' \ 



AMP-S 



AICAR 



GMP^ VaTP 



XMP-^GMP — 5 



Fig. 1. (Magasanik). 



N.A. 



It can easily be seen that IMP (inosine 5 '-phosphate) occupies 

 a central position in this scheme : it is converted to AMP (adenosine 

 5'-phosphate) via AMP-S (adenylosuccinate) (Lieberman, I., (1956). J. 

 biol. Chem., 223, 327), and to GMP (guanosine 5 '-phosphate) via XMP 

 (xanthosine 5'-phosphate) (Magasanik, B., et al., (1957). J. biol. Chem., 

 226, 339, 351). AMP and GMP produced in these reactions may be 

 converted to di- and tri-phosphates which are essential participants in 

 many enzymic reactions and building blocks for nucleic acids. 



Each of the two reactions between IMP and GMP is irreversible; 

 however, GMP can be converted back to IMP by still another irrevers- 

 ible reaction, catalysed by a TPNH-linked GMP-reductase (Mager, J., 

 and Magasanik, B., (1958). Fed. Proc., 17, 267). The three enzymes 

 responsible for these reactions together could catalyse the irreversible 

 cyclic conversion of IMP via GMP to IMP, and would obtain the energy 

 for the operation of this useless merry-go-round by the splitting of ATP, 

 an essential part of the amination of XMP to GMP. This, however, 

 does not happen. The reactions of the cycle are regulated in such a way 

 that AMP and GMP are produced in just the amounts needed for 

 metabolic reactions. 



The conversion of IMP to GMP is controlled by GMP, which inhibits 

 the action of the first of the three enzymes, IMP-dehydrogenase. Conse- 

 quently a high intracellular level of GMP will prevent the formation of 

 additional GMP from IMP, but will permit the conversion of GMP to 



