CHAPTER 4 



SUBSTRATE INHIBITION 

 AND PRODUCT INHIBITION 



Many enzymes conform to Michaelis-Menten kinetics over a limited lower 

 range of substrate concentration but deviate at higher substrate concen- 

 trations in that the rate progressively falls off, the expected maximal rate 

 not being attained; indeed, at very high concentrations of substrate the 

 rate may be reduced almost to zero. This phenomenon is termed substrate 

 inibition and in the 50 years since it was initially observed it has become 

 increasingly evident that several mechanisms may be responsible. Inhi- 

 bition of the rate by a product of the reaction has also been reported for 

 several enzymes and this is designated product inhibition. True product 

 inhibition is not a matter of a shift in the thermodynamic equilibrium be- 

 tween substrate and product (i.e., an increase in the reverse reaction) but 

 a specific interference with the forward reaction. These types of inhibition 

 will be discussed not only because of their inherent importance in enzyme 

 kinetics and their possible regulation of intracellular metabolism, but also 

 because systems which exhibit such phenomena demonstrate modified ki- 

 netics in inhibitions produced by other substances. Thus an instance of 

 pure competitive inhibition may be obscured if increasing substrate not 

 only displaces the inhibitor from the enzyme but inhibits the reaction itself. 



SUBSTRATE INHIBITION 



A variety of enzymes has been shown to be inhibited by substrate and 

 the following partial list will indicate that this is a rather general pheno- 

 menon: xanthine oxidase (Dixon and Thurlow, 1924; Hofstee. 1955), fu- 

 marase (Alberty et al., 1954), lactic dehydrogenase (Hakala et al. 1956), 

 /?-hydroxysteroid dehydrogenase (Marcus and Talalay, 1955), acetylcho- 

 linesterase (Myers, 1952c), enolase (Westhead and Malmstr5m, 1957), ri- 

 bonuclease (Dickman and Ring, 1958), urease (Laidler and Hoare, 1949; 

 Kistiakowsky and Shaw, 1953a), carboxypeptidase (Lumry et al., 1951), 

 lipases (Bamann and Schmeller, 1929; Murray, 1930), diamine oxidase 

 (Zeller et al., 1939), L-amino acid oxidase (Dixon and Webb, 1958, p. 86), 

 /3-fructofuranosidase (Nelson and Schubert, 1928), pyrophosphatase (Bailey 



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