ANALOG INHIBITION OF THE METABOLISM OF VARIOUS AMINO ACIDS 351 



opportunity to compete). A third group of interesting analogs is the halogen- 

 substituted amino acids, which are often potent inhibitors of protein syn- 

 thesis and growth. The fluoroamino acids are particularly active. The 

 m-, 0-, and p-fluorophenylalanines all inhibit the formation of the adaptive 

 maltase in yeast, the last being the most potent (Halvorson and Spiegelman, 

 1952). On the other hand the p-chloro- and js-bromophenylalanines do not 

 inhibit. The incorporation of phenylalanine and other amino acids into 

 ascites cell proteins is competitively inhibited by o-fluorophenylalanine; 

 this is in part due to a depression of transport into the cells and in part due 

 to block of some unknown steps in the incorporation (since labeled phenyl- 

 alanine accumulates in cells) (Rabinovitz et al., 1954). There is also an inhi- 

 bition of protein synthesis in rat liver in vitro by the fluorophenylalanines, 

 this leading to a net breakdown of tissue proteins since the constant bal- 

 ance of synthesis and degradation is disturbed (Steinberg and Vaughan, 

 1956). a-Amino-/?-chlorobutjTate is an analog of valine and inhibits valine 

 incorporation into rabbit reticulocyte proteins, including hemoglobin; it 

 was suggested that the analog enters a precursor protein which is unable 

 to assume the proper configuration of hemoglobin and thus there is accu- 

 mulation of protein intermediates (Rabinovitz and McGrath, 1959). As 

 pointed out previously, some of these analogs are incorporated into cell 

 proteins. p-Fluorophenylalanine-C^* is incorporated into the proteins of 

 muscle, blood, and liver when fed to rabbits, this being a replacement of 

 phenylalanine (Westhead and Boyer, 1961). The replacement of phenyl- 

 alanine in aldolase is 25% and in 3-phosphoglyceraldehyde dehydrogenase 

 16%, and in each case the enzyme activities are normal. Despite this ap- 

 preciable incorporation, the rabbits suffer no obvious biochemical or physi- 

 ological disturbances, so that mammals may well differ from microorgan- 

 isms in the response to this analog. 



Feedback inhibition in the biosynthetic pathways of amino acids is an 

 important aspect of regulation but we can touch only briefly on this prob- 

 lem. An interesting example of this has been studied in connection with 

 the synthesis of histidine, since the enzyme inhibited is the first in the 

 pathway and catalyzes a reaction not involving substrates structurally 

 similar to histidine (Martin, 1963). This enzyme is phosphoribosyl-ATP 

 pyrophosphorylase and the reaction catalyzed is: 



5'-P-ribosyI-PP + ATP :^ N-l-(5'-P-ribosyl)-ATP + PP 



Histidine is a surprisingly potent and specific inhibitor with K, = 0.1 mM. 

 Related compounds inhibit weakly or not at all; 2-methylhistidine, for 

 example, exhibits weak inhibition with K^ = 2.4 mM. The inhibition varies 

 with the pH but maximal inhibition is exerted at physiological pH. HgClg 

 at 0.03 mM does not inhibit the enzyme but blocks almost completely the 

 inhibition by histidine. This coupled with the fact that the inhibition by 



