Oxidative C-C deoxysugar cleavage in baumycin biosynthesis
B. BACHMANN1, H-W. LIU2, AHMAD AL-MESTARIHI1
1Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA
2Department of Chemistry & Biochemistry, The University of Texas at Austin, Austin, TX 78712
.
Doxorubicin
(Adriamycin), is an important therapeutic in treatment regiments for a wide
variety of cancers, is a glycosylated anthracycline antibiotic isolated from
the actinomycete Streptomyces
peucetius. Gene sequence analysis of the
doxorubicin biosynthetic gene cluster (dox) suggests that the encoded secondary metabolite is
actually a dissacharide. This is consistent with the
observation of the production of the baumycins in S. peucetius,
which are bioactive anthracyclins homologated with a
highly unusual sugar ‘baumycin acetal' moiety, apparently the product of an
unknown deoxysugar cleaved between the C-3 and C-4
bond. Recently, a clue to this unprecedented cleavage was provided by the
discovery and characterization of nitrososynthase
enzymes, which are flavin-dependent amine monooxygenases involved in the double oxidation of aminosugars to nitrososugars. The
dnmZ gene
in the dox gene cluster possesses high translated
sequence similarity to nitrososynthase. In this
presentation, we reveal the surprising role of dnmZ
in the oxidative cleavage of deoxysugar precursors,
revealing a new biochemical mechanism of oxidative C-C bond cleavage.