564 BIOTIN 



The guanido analogs of (^-biotin and di-oxybiotin have been synthesized by treat- 

 ment of the respective czs-diaminocarboxylic acid with cj^anogen bromide. These 

 compounds were practically devoid of biological activity for Lactohacillus casei 

 and L. arabinosus, as well as for Saccharomyces cerevisiae, thus emphasizing the 

 essential character of the cyclic urea portion for the biological activitj- of biotin and 

 oxybiotin."* 



Autoclaving of extremely dilute solutions of biotin with hydrochloric acid but 

 not with sulfuric acid resulted in almost complete loss of its growth-promoting po- 

 tency for Lactobacillus casei and Streptococcus faecalis and approximately 50% of 

 L. arabinosus and S. cerevisiae. It has been assumed"^ that this partial loss of potency 

 of biotin was due to its conversion under the influence of heat and HCl into a mixture 

 of biotin sulfoxide and biotin sulfone. Biotin sulfoxide is as active as biotin (Table 

 III) for L. arabinosus and S. cerevisiae and inactive for L. casei or S. fecalis, as well 

 as well as for rats.'^"- ^"^ "^ In contrast, biotin sulfone is practically inactive for all 

 four organisms and also for rats.^"^- "'• ^" Many natural products are capable of 

 preventing the conversion of biotin to its sulfoxide and sulfone through the action 

 of hydrochloric acid. Such a "protection" is not found in grass juice. "^ 



The conversion of biotin into sulfone via sulfoxide may also be accomplished by 

 11262^^ • ^' and even by rancid oils and fats with a high peroxide content.'*' 



With hydrogen peroxide biotin has been found to give a mixture of two diastereo- 

 isomeric biotin sulfoxides, the dextro form predominating.'*^ This form has also been 

 isolated from milk. The levo isomer of biotin sulfoxide has been isolated from Asper- 

 gillus niger culture filtrates."^* Since none of the dextro isomer was detectable, it is 

 presumed that biotin ^-sulfoxide is the product of enz^^matic reactions. 



3. Unspecific Stimulatory Precursors and Substitutes 



a. Pimelic Acid 



The growth of Corynebacterium diphtheriae is stimulated by pimehc 

 acid.^^"' 1^^ In some strains of this organism pimelic acid appears to be used 

 for the synthesis of biotin. For such strains biotin not only replaces pimelic 

 acid but is found to be more effective than pimelic acid, especially at lo\v 

 concentrations . ^ ^^ 



b. Oleic Acid and Related Compounds 



Oleic acid and related compounds, such as lecithin, may, in the presence 

 of aspartic acid, effectively replace biotin for Lactobacillus casei and cer- 

 tain other lactobacilli, even for yeast, for which biotin constitutes an es- 



"« K. Hofmann and A. E. Axelrod, J. Biol. Chem. 187, 29 (1950). 



1" A. E. Axelrod and K. Hofmann, J. Biol. Chem. 187, 23 (1950). 



i« D. B. Melville, D. S. Genghof, and J. M. Lee, Federation Proc. 9, 204 (1950); J. 

 Biol. Chem. In press; D. B. Melville, ./. Biol. Chem. In press. 



"8» L. D. Wright and E. L. Cresson, /. Am. Chem. Soc. In press; L. D. Wright, E. L. 

 Cresson, J. Valiant. D. E. Wolf, and K. Folkers, ibid. In press; L. D. Wright, 

 E. L. Cresson, J. Valiant, D. E. Wolf, and K. Folkers, ibid. In press. 



"9 P. L. Pavcek and G. M. Shull, J. Biol. Chem. 146, 351 (1942). 



160 J. H. Mueller, Science 85, 502 (1937). 



1" J. H. Mueller, /. Biol. Chem. 119, 124 (1937). 



i'2 V. du Vigneaud, K. Dittmer, E. Hague, and B. Long, Science 96, 186 (1942). 



