ANALOGS OF RIBOFLAVIN AND FAD 539 



Metabolism of Riboflavin Analogs and Effects on Riboflavin Metabolism 



Certain analogs, such as the 6,7-diethyl derivative, are able to replace 

 riboflavin to some extent at low concentration but are inhibitory at higher 

 concentration. This analog supports the growth of L. casei, and Lambooy 

 (1950) believed that it must be phosphorylated. This was demonstrated in 

 the rat where 6,7-diethylriboflavin-5'-P was found in the liver although no 

 FAD analog was demonstrable (Aposhian and Lambooy, 1955). L. lactis is 

 able to incorporate lyxoflavin into lyxoflavin-5'-P and the corresponding 

 dinucleotide (Huennekens et al., 1957 b). Scala and Lambooy (1958) were 

 able to modify L. casei by prolonged riboflavin deficiency and high con- 

 centrations of the 6-chloro analog so that the organism could use either ribo- 

 flavin or the analog. They believe that the analog inhibits the phosphor- 

 ylation of riboflavin. It is interesting that the adapted organism cannot 

 use the 7-chloro analog. 



Flavokinase catalyzes the phosphorylation of riboflavin and shows a high 

 degree of specificity toward substrates. The yeast enzyme phosphorylates 

 dichlororiboflavin as well as riboflavin, arabitylflavin poorly, and all other 

 analogs tested not at all (including isoriboflavin, galactoflavin, dulcitylfla- 

 vin, and sorbitylflavin) (Kearney, 1952). The only analog that inhibits the 

 enzyme is lumiflavin (35% at 0.18 mM with riboflavin 0.051 mM) and this 

 occurs only when the analog is in excess of the riboflavin. McCormick (1962) 

 has extended this work to partially purified rat liver flavokinase and found 

 similar behavior, only riboflavin, dichlororiboflavin, and arabitylflavin be- 

 ing phosphorylated (all with KJs between 0.012 and 0.017 mM). Four 

 analogs were found to be inhibitory: lumichrome {K^ = 0.048 mM), lumi- 

 flavin {K^ = 0.031 mM), the 9-formylmethyl analog {K^ = 0.0097 mM), 

 and the 9-(2'-hydroxyethyl) analog {K^ = 0.0068 mM). The following are 

 not phosphorylated and do not inhibit: isoriboflavin, galactoflavin, sorbityl- 

 flavin, dichloroarabitylflavin, 7-methylmannitylflavin, and 7-methyldulci- 

 tyLflavin. The fact that most analogs are not attacked by flavokinase is per- 

 haps the primary reason for the failure of these compounds to replace ribo- 

 flavin. It is also clear that the data are insufficient to draw conclusions 

 relative to the possibility of some of the most commonly used analogs inhi- 

 biting the phosphorylation of riboflavin, but what evidence we have would 

 indicate that such inhibition is unlikely to be important. The synthesis of 

 riboflavin from 6,7-dimethyl-8-(r-D-ribityl)lumazine by an enzyme system 

 from Ashbya gossypii is potently inhibited by a variety of analogs of this 

 precursor, of which the 6,7-dihydroxy derivative is the most active {K^ = 

 0.000009 mM) (Winestock et al, 1963). It is interesting that 5'-deoxyribo- 

 flavin is fairly inhibitory {K, = 0.019 mM) and, indeed, it was concluded 

 that the sugar moiety is necessary for inhibition. 



Very little information on the effects of analogs on the tissue levels of 

 riboflavin compounds is available. Rats given galactoflavin for 10-28 days 



