INHIBITIONS BY NUCLEOTIDES 465 



polyacrylate and chondroitin sulfate are relatively inactive. The inhibition 

 by polyxenylphosphate is noncompetitive, partially reversed by raising the 

 NaCl concentration, and maximal at pH 4.6, decreasing on either side. 



/?-Fructofuranosidase of yeast is inhibited by heparin and chitin disiilfate 

 at low pH's (Astrup and Thorsell, 1954). The glucuronidases from several 

 rat tissues are inhibited by heparin and hyaluronate (Becker and Frieden- 

 wald, 1949). Fumarase is inhibited 92% by heparin at a concentration of 

 0.2 mg/ml in a pH range of 5.5-6.0, whereas nucleic acid and chondroitin 

 sulfate inhibit only 26% and 11%, respectively, at 2 mg/ml (Fischer and 

 Herrmann, 1937). These examples indicate that inhibitions of this sort are 

 widespread. There has been only one investigation of the effects of ma- 

 croions on a complex metabolic sequence, the study of Dische and Ash well 

 (1955) on the actions of ribonucleate and some smaller anions, such as sul- 

 fate, on anaerobic glycolysis in pigeon hemolysates. RNA inhibits lactate 

 formation 48% at 1 mg/ml and the formation of phosphoglj^ceraldehyde 

 30% at 3 mg/ml. There would thus appear to be at least two sites of 

 action, the major effect being on the transformation of 3-phosphoglyceral- 

 dehyde to lactate. 



INHIBITIONS BY NUCLEOTIDES 

 AND RELATED SUBSTANCES 



Enzymes acting on pyrimidines, purines, nucleosides, nucleotides, or poly- 

 nucleotides are frequently inhibited by analogs of these substrates. Some- 

 times the inhibitors are normally occurring substances and it is here that 

 some of the most clear-cut and important examples of feedback control 

 and metabolic regulation have been demonstrated. In other cases the inhi- 

 bitors are synthetically derived abnormal analogs, which are frequently 

 quite depressant to rapidly growing cells where nucleotide metabolism is 

 active and have for this reason been studied with regard to carcinostasis. 

 Many instances of inhibition have been reported, some of which are sum- 

 marized in Table 2-28, but thorough quantitative work and studies of the 

 mechanisms are rather uncommon. 



Most of the inhibitions in Table 2-28 appear to be competitive and prob- 

 ably many of those in which the kinetics were not studied are competitive. 

 Although the inhibitory activity of most of these analogs is low or moderate, 

 a few analogs, particularly the abnormal aza and fluoro derivatives, are 

 quite potent. It seems that all parts of the nucleotide structure can con- 

 tribute to the binding. Where only the nature of the purine or pyrimidine 

 component is varied, the inhibitions may be very different, indicating that 

 the ring-substituted groups can be important. The pentose structure is also 

 a determinant since different activities are observed in nucleotides contain- 

 ing ribose or deoxyribose. Finally, the number of phosphate units in the 



