72 



NATURE, FORMATION, AND ACTIVITIES 



controlled biosynthesis in that it modifit^s 

 fermentation to result in the formation of an 

 antibiotic which contains mannose as an 

 integral unit. Mannose is known, however, 

 to inhibit the action of the enzyme mannosi- 

 dase, which converts mannosidostreptomy- 

 cin to streptomycin (HockenhuU et al., 1954). 

 The formation of mannosidostreptomycin 

 in a medium supplemented with mannose 

 is the result of controlled biosynthesis; the 

 organism has been induced to synthesize a 

 biologically undesirable compound rather 

 than an active antibiotic. The controlled bio- 

 synthesis techniciue may thus be employed 

 strategically to design new molecules with 

 desired chemical properties. 



The biosynthesis and the degradation of 

 mannosidostreptomycin, especially the for- 

 mation and action of the enzyme a-man- 

 nosidase, were also studied by Abalo and 

 Varela (1960). 



Further information on biosynthesis of 

 streptomycin is found in the work of Hunter 

 (1956). 



NEOMYCIN 



Sebek (1955) observed that when glucose 

 labelled uniformly with C" was added to a 

 growing culture, in a medium containing 9 

 gm of glucose per liter, 19.5 per cent of the 

 carbon of the sugar was incorporated in the 

 neomycin. The rest was distributed in the 

 CO2 , in the filtrate, and in the mycelium. 

 The fact that the antibiotic was also readily 

 produced in the presence of other sugars, 

 including mono-, di-, and polysaccharides, 

 pentoses, hexoses, and sugar acids, suggested 

 the operation of a general basic mechanism 

 of sugar breakdown and antibiotic synthesis. 



Antibiotics Dcrirabic from Amino Acids 



ACTIXOMYCINS 



An actinomycin-producing organism gen- 

 erally synthesizes a mixture of different 

 actinomycins. S. antibioticus, for example, 



gives a mixture of actinomycins I to V; 

 occasionally, trace amounts of a sixth com- 

 ponent are also formed. S. chrysomallus 

 produces actinomycins IV, VI, and VII. 

 The quantitative and qualitative nature of 

 the mixture synthesized can be modified 

 to a considerable degree by modifying the 

 medium in which the organism is growing. 

 The nitrogen source in particular was found 

 to influence the composition of a given mix- 

 ture of actinomycins. Actinomycin IV in- 

 creased from 10 to 83 per cent of the com- 

 plex produced by S. chrysomallus when 

 DL-\'aline was added to the medium; when 

 DL-isoleucine or sarcosine was added, new 

 actinomycins were formed (Schmidt-Kast- 

 ner, 1956). Hydroxy-L-proline brought 

 about an increase in the synthesis of actino- 

 mycin I from 6 to 7 to 31 per cent of the 

 complex produced by S. antibioticus (Katz 

 and Goss, 1958). 



Katz (1960) made a detailed study of the 

 effect of addition of sarcosine upon the syn- 

 thesis of actinomycins II and III by S. 

 ayitibioticus. The formation of these two 

 actinomycins was found to depend, in part, 

 on the concentration of sarcosine and on the 

 time and the number of additions of this 

 amino acid. The effect of sarcosine was 

 highly specific, compounds structurally and 

 biochemicall}^ related to it being ineffective. 

 The actinomycins were found in both the 

 mycelium and the medium. The addition of 

 L-proline reversed the effect of a given 

 concentration of sarcosine; larger amounts 

 of sarcosine nullified the effect of proline. 

 Incorporation of DL-pipecohc acid, a pro- 

 line analog, into the medium resulted in 

 synthesis of several new actinomycins. When 

 washed suspensions of *S. antibioticus were 

 incubated in the presence of 1 mil/ sarcosine, 

 there was a five fold increase in the synthesis 

 of actinomycin III but no change in that of 

 actinomycin II. 



Schmidt-Kastner (1956) suggested that 

 sarcosine interferes with the incorporation 



