614 2. ANALOGS OF ENZYME REACTION COMPONENTS 



Robinson et al., 1963). The mechanism of inhibition here, however, appears 

 to be by reaction with enzyme SH groups. The coenzyme A is necessary 

 since free tetrolate does not inhibit, and is split off during the reaction. 

 Palmityl-CoA noncompetitively inhibits the condensing enzyme with respect 

 to acetyl-CoA, and perhaps competitively with respect to oxalacetate (Wiel- 

 and and Weiss, 1963). The inhibition develops slowly and the authors sug- 

 gest configurational changes in the enzyme, although there is no direct 

 evidence for this. Such an inhibition might be regulatory with regard to 

 the operation of the cycle and the formation of acetoacetate in the liver by 

 controlling the rate of oxidation of acetyl-CoA through the cycle. Higher 

 acyl-CoA's inhibit rat liver acetyl-CoA carboxylase very strongly, oleyl- 

 CoA and stearyl-CoA being competitive with K/s of 0.0013 milf and 0.00071 

 mM, respectively, this possibly playing an important role in the homeo- 

 static control of fatty acid synthesis (Bortz and Lynen, 1963). 



Inhibition of cholesterol biosynthesis will be discussed in a subsequent 

 chapter, but it is worthwhile mentioning at this point that a-phenyl-n-bu- 

 tyrate not only lowers serum cholesterol but also inhibits the incorporation 

 of acetate into fatty acids, whereas the oxidation of acetate is only weakly 

 inhibited (Steinberg and Fredrickson, 1955). The evidence points to an ac- 

 tion early in acetate metabolism, possibly the acetylation of coenzyme A 

 or transacetylations from acetyl-CoA. 



Antagonism between Tungstate and Molybdate 



Molybdate is a necessary cof actor in the growth of many organisms and 

 has been found to participate in certain enzyme reactions, such as those 

 catalyzed by xanthine oxidase and nitrate reductase. If chicks are fed on 

 a low-Mo diet containing 4.5-9.4% mg sodium tungstate, the growth rates 

 are depressed and signs of molybdenum deficiency appear (Higgins et al., 

 1956 a). The levels of molybdenum in the tissues fall to less than 10% of 

 the normal and xanthine oxidase activity is severely depressed, leading to 

 an alteration in the excretory pattern of purines. These changes are re- 

 versed by adding 2-6 mg% sodium molybdate to the diet. Similar falls in 

 xanthine oxidase were observed in rats. 



Aspergillus niger requires molybdate especially when nitrate is the sole 

 source of nitrogen, since the enzymic reduction of nitrate by nitrate reduc- 

 tase involves molybdate as a prosthetic group (Higgins et al., 1956 b). Tung- 

 state is able to compete with molybdate and inhibition of growth occurs 

 when the (tungstate)/ (molybdate) ratio is 20. Azotobacter vinelandii is like- 

 wise inhibited by tungstate when nitrogen or nitrate is the source of amino 

 acids and proteins, but not when ammonia is provided. The uptake of Mo^^ 

 by the cells is also depressed by tungstate. The ability of tungstate to inhibit 

 growth is dependent on the level of molybdate in the medium and it requires 

 rather high ratios of (tungstate)/ (molybdate) to inhibit well (Bulen, 1961). 



