Biosynthetic Studies on the -Glucosidase Inhibitor Acarbose in Actinoplanes sp.: 2-epi-5-epi-Valiolone Is the D

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• 作者：Taifo Mahmud ; Ingo Tornus ; Erin Egelkrout ; Eckardt Wolf ; Charmaine Uy ; Heinz G. Floss ; and Sungsook Lee
• 刊名：Journal of the American Chemical Society
• 出版年：1999
• 出版时间：August 4, 1999
• 年：1999
• 卷：121
• 期：30
• 页码：6973 - 6983
• 全文大小：383K
• 年卷期：v.121,no.30(August 4, 1999)
• ISSN：1520-5126

文摘

The biosynthetic pathway leading to the mC₇N cyclitol (valienamine) moiety of acarbose (1) inActinoplanes sp. strain SN 223/29 has been studied using ³H-, ²H-, and ¹³C-labeled cyclitols. These precursorswere synthesized from D-glucose or D-mannose as starting materials. The feeding experiments demonstratedthat cyclitols having the same stereochemistry at C-2 as the valienamine moiety of acarbose; i.e., valienone,valienamine, valiolone, valiolamine, and 1-epi-valienol, were not incorporated and thus are not plausibleintermediates in 1 biosynthesis. 2-epi-Valiolone (10b), which has the same stereochemistry as the presumedopen-chain precursor, sedoheptulose 7-phosphate, was also not incorporated. However, its C-5 epimer (10a)was incorporated efficiently and specifically into the valienamine moiety of 1. Surprisingly, the dehydratedform of 2-epi-5-epi-valiolone, 2-epi-valienone, was not incorporated. This suggests that 2-epi-5-epi-valiolonemust be converted directly into the pseudodisaccharide moiety of acarbose without the intervention of otherfree cyclitol intermediates. This may occur by linkage to the amino group of TDP-4-amino-4,6-dideoxyglucoseto form the imine, epimerization at C-2 to the correct stereochemistry, dehydration between C-5 and C-6aided by enamine formation, and finally reduction to the amine. It is proposed that these reaction steps all takeplace on a single enzyme without free intermediates. Alternative mechanistic possibilities are also discussed.