The biosynthetic pathway leading to the cyclitol moiety of pyralomicin 1a (
1) in
Nonomuraea spiralis MI178-34F18 has been studied using a series of
2H-labeled potential precursors. The results demonstrate that 2-
epi-5-
epi-valiolone (
7), a common precursor for acarbose (
4) and validamycin A (
5) biosynthesis, is an immediate precursor of pyralomicin 1a. 5-
epi-Valiolone (
8) was also incorporated into
1, albeit less efficiently than
7. Other potential intermediates, such as valiolone (
9), valienone (
10), valienol (
11), 1-
epi-valienol (
12), 5-
epi-valiolol (
13), and 1-
epi-5-
epi-valiolol (
14) were not incorporated into pyralomicin 1a. To explain this surprising observation, it is proposed that either 2-
epi-5-
epi-valiolone (
7) is specifically activated (
e.g., to its phosphate) and that the further transformations take place on activated intermediates (which can not be generated directly from their unactivated counterparts), or that the transformation of
7 into
1 involves a substrate-channeling mechanism in which enzyme-bound intermediates are directly transferred from one enzyme active site to the next in a multi-enzyme complex.
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