J. Wyngaarden, H. Silberman, J. Sadler
Oct 1, 1958
Citations
0
Influential Citations
25
Citations
Journal
Annals of the New York Academy of Sciences
Abstract
The reactions involved in de novo synthesis of purine ribotides from low molecular weight precursors are now well known. The multienzyme system capable of effecting synthesis of purine ribotides from simple dietary precursors has been studied chiefly in the nonparticulate portion of pigeon liver homogen ate^.^' In this system a series of a dozen or more reactions takes place in the process of converting ribose-5-phosphate, glutamine, glycine, and other precursors into inosinic acid, the parent purine compound.6-12 Although the intimate details of many individual reactions have now been elucidated, less attention has been given to the factors influencing or controlling the over-all rate behavior of the entire sequence. Undoubtedly a number of factors influence the synthetic activity of this sequence. The usual ones of substrate and cofactor availability, enzyme activities, and energy sources have been considered to some extent in a previous discussion by G01dthwait.l~ In a multireaction sequence one might anticipate that a rate-limiting step might govern the maximal rate of the entire series of reactions, but no such rate-limiting step has been identified in the de novo synthesis of purines. I t has been suggested that purine ribotide synthesis is under regulation by feedback l5 Several feedback-control mechanisms for the regulation of biosynthetic processes have recently been described in microorganism^.^^-^^ In a t least two instances, a specific inhibition has been exhibited by an end product upon an enzyme concerned with its own production.'*. l6 In both cases the end-product inhibition operated a t the level of comparatively remote precursors, thus suggesting an economical control mechanism whereby the biosynthesis of energetically expensive intermediates might be curtailed when sufficient end product was present. One of the feedback controls mentioned above involved the regulation of de novo pyrimidine synthesis by the end product, cytidine mon~phosphate.'~ The existence of analogous feedback control mechanisms influencing purine biosynthesis is indicated by a number of observaiions. For example, the presence of unlabeled purines will suppress nucleic acid purine synthesis from labeled carbon dioxidez0. 21 or ammonium-K20 in bacteria, from glycine22 in the rat, or from formate in bacteria23 or intact ratsz4 Moreover, in certain purinerequiring mutants the presence of purine bases or compounds will prevent or suppress the accumulation of purine precursors a t the stage of genetically impaired l 8 Also, concomitant oral administration of 5-amino-4imidazolecarboxamide (AIC) significantly depresses the utilization of glycine-