VARIOUS METABOLIC PATHWAYS 887 



p-MB (Goodman, 1961). The sensitive enzymes are probably aU located in 

 the microsomes. One of the enzymes on the pathway from mevalonate to 

 farnesyl-PP, the isopentenyl-PP isomerase, is inhibited completely by 0.1 

 vnM p-MB (Agranoff et al., 1960), so this could account for part of the block 

 in squalene formation, but there are undoubtedly other sensitive steps. 



Fatty acid biosynthesis from acetate in mammary gland homogenates is 

 inhibited 95% by 0.1 mM Hg++ (Popjak and Tietz, 1955), and from acetyl- 

 CoA and malonyl-CoA in purified fractions from pigeon liver 95% by 0.075 

 mM p-MB (Bressler and Wakil, 1962). The inhibition is probably early in 

 the sequence, since various acyl-CoA's protect, but it is not on the NADPH: 

 acetoacetyl-CoA oxidoreductase. The incorporation of acetate- 1-C^^ into 

 lipid by chloroplast suspensions is also strongly depressed: 22% by 0.001 mM 

 p-MB, 50% by 0.01 mM, and 88% by 0.1 mM (Mudd and McManus, 1964). 

 Fatty acid oxidation is potently inhibited by the mercurials, and one likely 

 site is the initial activation by ATP (with or without Co A), catalyzed by 

 fatty acid thiokinase, since this is completely inhibited by 0.1 mM p-MB 

 (Jencks and Lipmann, 1957). The incorporation of P,^^ into mycobacterial 

 phospholipids is not depressed so readily, 1 mM p-MB inhibiting only 24% 

 (Tanaka, 1960), although the synthesis of phospholipid in rat liver mito- 

 chondria from of-glycerophosphate is completely blocked at this concentra- 

 tion (Wojtczak et al., 1963). 



The direct actions of the mercurials on lipid biosynthesis combined with 

 other actions which would secondarily inhibit these pathways, e.g., the re- 

 actions with coenzyme A or the depletion of available ATP, must lead to 

 serious interference in the formation of fatty acids and sterols in proliferat- 

 ing microorganisms and contribute to the suppression of growth, and it is 

 interesting to speculate whether they play a role in chronic mercurial poi- 

 soning in animals. 



Protein Synthesis 



In the preparations which have been examined it appears that protein 

 synthesis is not particularly sensitive to the mercurials. The incorporation 

 of leucine-C^* into chloroplast protein is inhibited only 30% by 5 mM mer- 

 salyl (Stephenson et al., 1956) and into reticulocyte protein only 9% by 

 0.1 mM p-MB, although 1 mM inhibits almost completely (Borsook et al., 

 1957), while the incorporation of phenylalanine-C^* into rat liver soluble 

 proteins is inhibited 85% by 1 mM p-MB (Haining et al., 1960), of amines 

 into guinea pig liver soluble proteins 100% by 1 mM p-MB (Clarke et al., 

 1959), and of amino acids into the acid-soluble proteins of frog egg super- 

 natant fractions 100% by 0.77 mM p-MB (Burr and Finamore, 1963). 

 Although these results do not conclusively indicate the exact sensitivity of 

 protein synthesis to the mercurials, one is somewhat surprised to find that 

 such high concentrations apparently must be used to inhibit effectively. 

 The only instance of potent inhibition of which I am aware is that found in 



