ANALOGS OF THIAMINE 



515 



phoketolase). Thus three major metabolic sequences — the pentose-P path- 

 way, the tricarboxylate cycle, and photosynthetic carbon dioxide fixation — 

 are dependent on thiamine-PP, since a-cleavage occurs in all, and a variety 

 of other metabolic processes can be secondarily affected. Thiamine defi- 

 ciency, or interference with the formation or function of thiamine-PP, can 

 produce profound metabolic and physiological disturbances. Animals re- 

 quire preformed thiamine, most plants can synthesize the entire thiamine 

 molecule, and microorganisms vary widely from complete dependence on 

 exogenous supply to complete synthetic ability. The responses of organisms 

 to thiamine analogs wiU depend on these factors as well as the role of thia- 

 mine in metabolism. The pathways of thiamine biosynthesis are not com- 

 pletely understood and the accompanying scheme is to be taken as pro- 

 visional and not necessarily applicable to all organisms. Thiaminase is ap- 

 parently absent or relatively inactive in most tissues and thus the reactions 

 catalyzed by this enzyme are probably not common or important. The most 

 important reaction is the pyrophosphorylation of thiamine since certain 

 analogs can interfere here or be similarly phosphorylated. Thiamine-PPP 

 has been included because its formation from thiamine in yeast has been 

 demonstrated (Kiessling, 1956), although it is coenzymically inactive. It 

 may be noted that ATP is required for thiamine-PP synthesis and that 



"Pyrimidine" "Thiazole" 



+ PP 

 'pyrimidine -PP" 



+ P 

 "thiazole- P' 



"pyrimidine-B" 

 + : 



"thiazole" 



"pyrimidine-B" 



+ 

 "thiazole-PP" 



thiamine- P 



+ B 



Thiamine 



+ H,0 



thiamine-PP 



+ H,0 



"pyrimidine" 

 : + 



"thiazole" 



"pyrimidine" 



: + 



"thiazole-PP' 



thiamine- PPP 



enzyme-thiamine- PP 



(The pyrimidine portion of thiamine is indicated in quotes and is 2- 

 methyl-4-amino-5-hydroxymethylpyrimidine; the thiazole portion is 

 designated likewise and is 4-methyl-5-{2-hydroxyethyl)thiazole. B is 

 any base that can replace the thiazole in the exchange reaction catalyzed 

 by thiaminase. ) 



