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Phosphorylation of Streptomycin and Dihydrostreptomycin by Streptomyces

ENZYMATIC SYNTHESIS OF DIFFERENT DIPHOSPHORYLATED DERIVATIVES

From the ¹ From the Department of Biochemistry, Rice University, Houston, Texas 77001

Extracts of Streptomyces griseus ATCC 10971, which does not secrete streptomycin, contain a labile kinase which phosphorylates the N-methyl-l-glucosamine moieties of streptomycin, dihydrostreptomycin, and 3'-deoxydihydrostreptomycin, with adenosine 5'-triphosphate as the phosphate donor. Periodate degradation studies indicate that phosphate is esterified with the 3''-hydroxyl group. Diphosphorylated derivatives with phosphate also esterified at position 6 of the streptidine moiety can be synthesized by utilizing streptomycin streptidinokinase. Streptomycin 6-phosphate phosphatase, acting on these diphosphates, removes phosphate rapidly from position 6 and more slowly from position 3'' both phosphates are esterified with secondary hydroxyl groups adjacent to basic nitrogenous moieties.

Extracts of S. bikiniensis ATCC 11062, and other streptomycin-secreting strains, contain a different labile kinase, which cannot phosphorylate streptomycin derivatives containing a 3'--aldehyde group. This kinase phosphorylates the dihydrostreptobiosamine moieties of dihydrostreptomycin 6-phosphate and 3'-deoxydihydrostreptomycin 6-phosphate, with adenosine 5'-triphosphate as the phosphate donor. Lability of the kinase precludes separation from the stable streptidinokinase present in these extracts, so diphosphorylated derivatives are formed. Streptomycin 6-phosphate phosphatase removes phosphate only from position 6 of these diphosphorylated derivatives. Substrate specificity studies thus suggest that the 3'--hydroxymethyl group is the site of phosphorylation by the labile S. bikiniensis kinase.

Triphosphorylated derivatives of dihydrostreptomycin could not be prepared enzymatically. Diphosphorylated derivatives could be prepared only if one phosphate were at position 6 of the streptidine moiety. Methods of synthesizing and distinguishing various phosphorylated derivatives of streptomycin, dihydrostreptomycin, and 3'-deoxydihydrostreptomycin are described.

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