450 9. INHIBITION IN CELLS AND TISSUES 



must stop if it is operating under self-regenerating conditions, but if there 

 is a supply of oxalacetate (or fumarate or malate), pyruvate will continue 

 to enter the cycle and the oxygen uptake will be depressed to a limited 

 degree. The cycle blocked at aconitase by fluorocitrate will continue to 

 incorporate pyruvate and take up oxygen as long as some source of oxal- 

 acetate is available, which in this case could even be glutamate. 



III. Maintenance of the steady state in multienzyme systems. In Chapter 7 

 it has been shown that many types of multienzyme systems can be re- 

 sistant towards inhibition, principally because of the adjustment that is 

 possible in the concentrations of the intermediates. This is particularly 

 true for competitive inhibition where the accumulation of the substrate 

 for the inhibited enzyme counteracts this inhibition. One of the reasons 

 for the failure of malonate to depress significantly the respiration of many 

 tissues may be the increase in the succinate concentration resulting from 

 the inhibition. 



IV. Shift in metabolic pathway. Initially the total rate may be due to a 

 single pathway or enzyme but upon inhibition another pathway becomes 

 available. The increase in one branch of a divergent chain as a result of 

 the depression of the other branch has been discussed, but one may note 

 here that under normal conditions one pathway may be almost inactive 

 due to kinetic factors and yet may contribute to the inhibitor-stable me- 

 tabolism when the substrate concentration rises. Another type of adjust- 

 ment that can take place is a true adaptation of the cell in the synthesis 

 of enzymes catalyzing a new pathway; this, however, is not so much a 

 mechanism to explain the stable metabolism as a means of achieving 

 this condition. 



V. Failure to inhibit the enzyme or pathway completely. Although the ex- 

 ternal concentration of inhibitor may be high enough to inhibit an enzyme 

 completely when it is isolated from the cell, only partial inhibition of the 

 intracellular enzyme may occur for reasons discussed earlier in this chapter, 

 namely the failure of the inhibitor to enter the cell at the external level 

 or the fact that the environment of the intracellular enzyme is different. 

 When the metabolism is stable to an inhibitor simply because it does not 

 enter the cell readily, it is perhaps best not to consider this as inhibitor- 

 stable metabolism in the sense of this section, because basically it is not 

 the metabolism that is stable. However, this factor can lead to errors in 

 interpretation and in most cases it is difficult to determine the extent of 

 inhibition within the cell. 



VI. A reserve store of intermediate past the block. In any sequence of en- 

 zyme reactions, complete block of a step need not necessarily stop the 

 formation of final product immediately since a supply of the intermediates 



