Biosynthesis of the aminocyclitol subunit of hygromycin A in Streptomyces hygroscopicus NRRL 2388.
The antibacterial activity of hygromycin A (HA) arises from protein synthesis inhibition and is dependent upon a methylenedioxy bridged-aminocyclitol moiety. Selective gene deletions and chemical complementation in Streptomyces hygroscopicus NRRL 2388 showed that the hyg18 and hyg25 gene products, proposed to generate a myo-inositol intermediate, are dispensable for HA biosynthesis but contribute to antibiotic yields. Hyg8 and Hyg17, proposed to introduce the amine functionality, are essential for HA biosynthesis. Hyg6 is a methyltransferase acting on the aminocyclitol, and a Deltahyg6 mutant produces desmethylenehygromycin A. Deletion of hyg7, a metallo-dependant hydrolase homolog gene, resulted in methoxyhygromycin A production, demonstrating that the corresponding gene product is responsible for the proposed oxidative cyclization step of methylenedioxy bridge formation. The methyl/methylene group is not required for in vitro protein synthesis inhibition but is essential for activity against Escherichia coli.
Palaniappan
Nadaraj
N
Department of Chemistry, Portland State University, OR 97207-0751, USA.
Dhote
Vidya
V
Ayers
Sloan
S
Starosta
Agata L
AL
Wilson
Daniel N
DN
Reynolds
Kevin A
KA
D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D054812:Cyclitols / Q000737:chemistry*; D003500:Cyclization; D017353:Gene Deletion; D006921:Hygromycin B / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000494:pharmacology; D005810:Multigene Family; D009154:Mutation; D010084:Oxidation-Reduction; D014176:Protein Biosynthesis / Q000187:drug effects; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics*
D000900:Anti-Bacterial Agents; D002934:Cinnamates; D054812:Cyclitols; D006921:Hygromycin B; C026273:hygromycin A