Biosynthesis of Streptomycin. Ii. Myo-inositol, a Precursor of the Streptidine Moiety.

Streptomycin, the antibiotic produced by Streptomyces griseus, contains as a part of its structure a diguanidine derivative of scyllo-inositol called streptidine. Two major precursors of the streptidine portion of the molecule have now been defined, n-arginine and n-glucose (1, 2). Arginine plays a role in the formation of the guanidine side chains, whereas glucose is involved in the synthesis of the cyclitol ring. However, the intermediates involved in streptidine synthesis remain unknown. The similarity in structure of myo-inositol and scyllo-inositol suggested to a number of investigators the possibility that myo-inositol might be involved in the biogenesis of the streptidine moiety. Definite enhancement of streptomycin production by S. griseus has been noted when the medium was supplemented with myo-inositol, suggesting a role for this cyclitol in the synthesis of the antibiotic (3, 4). More definitive information supporting this hypothesis was obtained recently by Majumdar and Kutzner (5) with an isotope dilution technique. Equal quantities of uniformly labeled glucose-14C were administered under similar conditions to four S. griseus cultures; two of the cultures were supplemented with myoinositol. When the “C specific activities of the streptomycin synthesized by the cultures were compared, a marked reduction was found in that of the antibiotic isolated from the myo-inositolsupplemented culture. Diminution of specific activity was found in both the streptidine and streptobiosamine moieties, but the greatest decrease was noted in the streptidine. Such evidence strongly suggests a role for myo-inositol in streptidine synthesis. In the present wo?k, direct evidence is presented indicating that myo-inositol is a precursor of streptomycin. Uniformly labeled myo-inositol-14C was markedly incorporated into streptomycin synthesized by cultures of S. griseus. Degradation studies disclosed that essentially all of the incorporated isotope was concentrated in the streptidine moiety.