484 2. ANALOGS OF ENZYME REACTION COMPONENTS 



acid metabolism can secondarily bring about changes in systems not in- 

 volving pyridoxal phosphate through reduction in the concentrations of 

 amino donors or suppression of enzyme synthesis. Whether the coenzyme 

 analogs can be considered as specific or not will depend on the complexity 

 and general metabolic activity of the preparation being studied. 



Most coenzymes are derivatives of vitamins and it has usually been anti- 

 cipated that analogs would induce vitamin-deficiency states. This has been 

 demonstrated in some cases; that is, effective analogs have been found to 

 produce a pattern of symptoms roughly similar to those seen in deficiency 

 of the corresponding vitamin. Nevertheless, it should be clearly understood 

 that the situations are basically different. A dietary restriction of a vitamin 

 leading to a generalized depletion in the tissues would not necessarily bring 

 about functional changes identical to those caused by an analog, which 

 could be much more effective in interfering with certain functions of the 

 coenzyme than simple depletion and possibly leave other functions untouch- 

 ed. All of the various enzymes binding a particular coenzyme do not have 

 the same affinities for an analog. Even though the analog primarily inter- 

 fered with the transport of the vitamin into the cell, or blocked its further 

 metabolism to the active coenzyme, it is not justifiable to conclude that a 

 state of generalized depletion will result, because these effects will pre- 

 sumably not be exerted equally on all tissues. The differential penetration 

 of the analog into the various tissues will perhaps be one important factor 

 in determining the response. Contrary to vitamin depletion, analogs often 

 cause a rise in the renal excretion of coenzyme or its metabolites, due to 

 the displacement of the normal coenzyme by the analog in the tissues and 

 its release from the cells. The analog might also alter the formation of the 

 coenzyme from its precursors, or inhibit the metabolism of the active co- 

 enzyme, or in some manner change the renal excretion or resorption of the 

 coenzyme or its precursors, so that a variety of effects on over-all excretion 

 is possible. If it is desired to demonstrate metabolic or functional defects 

 due to an analog in a short period of time, it is usually necessary to restrict 

 the intake or reduce the medium concentration of the coenzyme or its pre- 

 cursor, since the relationship between the analog and the coenzyme is usual- 

 ly competitive or pseudocompetitive, but in such cases one must use the 

 coenzyme-depleted preparation as a control to characterize the effects of 

 the analog. 



ANALOGS OF NICOTINAMIDE 

 AND THE PYRIDINE NUCLEOTIDES 



The importance of nicotinate and nicotinamide is as precursors of the 

 coenzymes NAD and NADP, and they do not, as far as is known, act di- 

 rectly in any metabolic system, nor do they usually occur in significant 

 concentrations in living cells. Some of the reactions involved in NAD syn- 



