PERMEABILITY OF CELLS TO MALONATE 189 



dicular to the direction of passage and the degree of interaction of the 

 molecules with the walls of the pores. This interaction may be of various 

 types and includes steric repulsion and attractive forces (such as van der 

 Waals' forces or hydrogen bonds). The configuration of the ion must be 

 important in this connection. Maleate penetrates 10 times faster than fu- 

 marate and this must be mainly due to the structure of maleate wherein 

 the carboxylate groups are much closer than in fumarate. That both of 

 these ions penetrate more rapidly than succinate may be due to the greater 

 rigidity of the former, energy perhaps being required for succinate to change 

 from its statistically most probable configuration to that necessary for 

 penetration. It is evident, however, that none of these explanations satis- 

 factorily fits the experimental data and that we need to know much more 

 about the membrane before accurate interpretations can be made. It should 

 be mentioned that these results on erythrocytes do not apply to other 

 types of cells or tissues, inasmuch as erythrocyte permeability is in some 

 senses unique. 



Malonate inhibits the succinate dehydrogenase of calf thymus nuclei and 

 yet at 10 mM has no effect on the respiration or ATP level of intact nuclei 

 (McEwen et al., 1963 b). This indicated a failure to penetrate and it was 

 shown with labeled malonate that this is indeed the case, which is some- 

 what surprising in view of the usual concepts of the nuclear membrane. 



Malonic acid does not enter organic solvents from water readily, due 

 probably to the dipolar nature of the unionized carboxyl groups. The par- 

 tition ratios for malonic acid are given as (concentration in solvent/concen- 

 tration in water): oleyl alcohol 0.049 (Collander, 1951), ether 0.083, iso- 

 butanol 0.62, methylisobutylketone 0.15, and methylisobutylcarbinol 0.37 

 (Pearson and Levine, 1952). The partition ratios for succinic acid are always 

 somewhat higher, as expected. These data would indicate that even the 

 unionized malonic acid would not penetrate through the lipid phase of the 

 membrane too readily. The fact that the un-ionized forms penetrate better 

 than the ionized does not imply that passage through a lipid phase occurs. 

 The negative charge on the ions could impede movement through pores, 

 especially when it is considered that in most cells these ions must move 

 up an electrical potential gradient to cross the membrane. 



Variation of Malonate Inhibition with pH 



One of the strongest arguments for the preferential uptake of the less 

 ionized forms of malonic acid is the rise in the inhibition observed with a 

 lowering of the pH. This has been examined particularly in plant tissues 

 and the results are quite uniform. Such effects have been observed in to- 

 mato stem slices (Link et al., 1952), maize roots (Beevers, 1952), rhubarb 

 leaves (Morrison, 1950), barley roots (Laties, 1949 a), spinach leaves (Bon- 

 ner and Wildman, 1946), carrot root slices (Hanly et al, 1952), and Avena 



