Biosynthesis of the Cyclitol Moiety of Pyralomicin 1a in Nonomuraea spiralis MI178-34F18

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The biosynthetic pathway leading to the cyclitol moiety of pyralomicin 1a (<b>1</b>) in <i>Nonomuraea spiralis</i> MI178-34F18 has been studied using a series of <sup>2</sup>H-labeled potential precursors. The results demonstrate that 2-<i>epi</i>-5-<i>epi</i>-valiolone (<b>7</b>), a common precursor for acarbose (<b>4</b>) and validamycin A (<b>5</b>) biosynthesis, is an immediate precursor of pyralomicin 1a. 5-<i>epi</i>-Valiolone (<b>8</b>) was also incorporated into <b>1</b>, albeit less efficiently than <b>7</b>. Other potential intermediates, such as valiolone (<b>9</b>), valienone (<b>10</b>), valienol (<b>11</b>), 1-<i>epi</i>-valienol (<b>12</b>), 5-<i>epi</i>-valiolol (<b>13</b>), and 1-<i>epi</i>-5-<i>epi</i>-valiolol (<b>14</b>) were not incorporated into pyralomicin 1a. To explain this surprising observation, it is proposed that either 2-<i>epi</i>-5-<i>epi</i>-valiolone (<b>7</b>) is specifically activated (<i>e.g</i>., 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 <b>7</b> into <b>1</b> 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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