INHIBITION BY MACROIONS 453 



the activity, although less than Ca++, and this may be competitive also. 

 Ca++ is a competitive inhibitor of rabbit muscle phosphorylase 6 kinase 

 with respect to the activator Mg++, but is noncompetitive with respect to 

 ATP {K,„ = 1.9 mM for Mg++, and K^ = 0.3 vaM for Ca++) (Krebs et al, 

 1959). Most ATPase are activated by Mg++ and some are inhibited by Ca++, 

 but L-myosin ATPase is activated by Ca++ and inhibited by Mg++; in both 

 cases competition may occur. One might speculate that the uncoupling of 

 oxidative phosphorylation by Ca++ may involve displacement of other ions 

 such as Mg++ or Mn++. The question of metal ion competition will be taken 

 up in greater detail in the chapters on inhibitions produced by Zn++, Pb++, 

 Cd++, and other metal cations. Some new ideas on the regulatory role of 

 simple cations in metabolism, especially glycolysis, may be found in the 

 interesting discussion of Wyatt (1964). One example of ion inhibition in an 

 enzyme system in which an ion is the substrate will be mentioned. This is 

 the formation of ^-chlorolevulinate from /5-ketoadipate by an enzyme, /?- 

 ketoadipate chlorinase, from Caldariomyces fumago (Shaw and Hager, 1959). 

 F~, Br-, and I" inhibit this reaction around 85% when they are present in 

 equimolar concentration with Ch (10 mM). The nature of the inhibition 

 is not known but it is rather surprising that the three inhibiting ions are of 

 the same degree of potency. 



INHIBITION BY MACROIONS 



The inhibition by high molecular weight substances of enzymes attacking 

 related high molecular weight substrates may be thought of as analog inhi- 

 bition in certain instances, especially where competitive kinetics has been 

 demonstrated (the type of inhibition has seldom been studied in work on 

 polymers). On the other hand, these inhibitions are probably often nonspe- 

 cific in the sense that the polymers interact with any or all regions of the 

 enzyme surface rather than just the active center. Spensley and Rogers 

 (1954) reviewed inhibitions of this type and suggested the terms macrocat- 

 ionic and macroanionic as applicable to effects exerted by positively charged 

 and negatively charged polymers, respectively. Early work was mainly with 

 naturally occurring macroions, such as heparin or protamine, but the pre- 

 paration and use of more homogeneous and physically characterized syn- 

 thetic poljoners and copolymers have enabled the nature of the interactions 

 to be better understood. Some of these inhibitions may well be physiologi- 

 cally important, for example, the intracellular effects of the various types of 

 nucleic acids on enzymes involved in nucleic acid metabolism or their role 

 in protein synthesis. The suggestion by Jones and Gutfreund (1964), that 

 certain enzymes participating in metabolic sequences may interact speci- 

 fically with each other to form complexes facilitating flow along the path- 

 way, brings up the possibility that macroions can interfere in this interaction 



