ENZYME INHIBITION AND FEEDBACK CONTROL 75 



it was anticipated that in other pathways in which an effective feed- 

 back control existed, it would involve the first enzyme leading irre- 

 versibly to the end product. 



A subsequent studv on the biosvnthesis of valine offered an op- 

 portunitv to test the corollarv of tliis dogma: that an enzyme which 

 is inhibited b\' the end product of the reaction sequence of which 

 it is a part is the initial enzyme of that sequence (Umbarger and 

 Brown, 1958b). The reaction studied was the formation of a-aceto- 

 lactate ( see Fig. 3-2 ) . 



Acetolactate had earlier been postulated as an intermediate in 

 valine biosynthesis on the basis of isotopic experiments with yeast 

 by Strassman et al. ( 1953 ) . Proof of the obligatory nature of aceto- 

 lactate formation as a step in valine biosynthesis would be rigorous 

 only by demonstrating its presence in a wild-type organism and its 

 absence in an appropriateh blocked valine auxotroph. Unfortu- 

 nately, no mutants blocked in this step were available. However, 

 it was noted that the reaction fitted the dogma exactly as though it 

 was the first enzvme in the pathway ( Umbarger and Brown, 1958b) . 



Thus, as Fig. 3-4 shows, valine competitively inhibits the con- 

 version of pyruvate to acetolactate. In addition, it was observed 

 that the acetolactate-forming system was "derepressed" by growing 

 valine auxotrophs under conditions of limiting valine. In other 

 words, the formation of valine would occur maximally only when the 

 valine supplv was low. Although the evidence was not rigorous, it 

 was concluded that the sole function of this reaction in E. coli was 

 to provide acetolactate for valine biosynthesis. 



Recently, Dr. Richard Leavitt (Leavitt and Umbarger, 1959), 

 working with the corresponding reaction in the isoleucine pathway, 

 a-aceto-a-hydroxybutyrate formation (see Fig. 3-2), had obtained 

 evidence that this reaction is also catalyzed by the system forming 

 acetolactate. Although fractionation studies on the acetolactate- 

 acetohydroxybutyrate-forming system have not progressed very far, 

 the availability of a method for studving acetohydroxbutyrate for- 

 mation has made possible a further analysis of the inhibition of this 

 system by valine. 



In the competition between valine and pyruvate shown in Fig. 

 3-4, valine might have interfered with either the acetal donor func- 

 tion or the acetal acceptor function of pyruvate ( Fig. 3-2, Reactions 

 II and Ilia, respectively). In examining the other conversion (Re- 

 actions II and Illb) catalyzed by this enzyme system, Leavitt 



