TY - JOUR
T1 - Synthesis and Identification of Key Biosynthetic Intermediates for the Formation of the Tricyclic Skeleton of Saxitoxin
AU - Tsuchiya, Shigeki
AU - Cho, Yuko
AU - Yoshioka, Renpei
AU - Konoki, Keiichi
AU - Nagasawa, Kazuo
AU - Oshima, Yasukatsu
AU - Yotsu-Yamashita, Mari
N1 - Funding Information:
TA04 was provided by Dr. Susan Blackburn, CSIRO, Australia. Axat-2 was provided by Dr. Takuo Omura, Laboratory of Aquatic Science Consultant Co., Ltd. and Prof. Takashi Ishimaru, Tokyo University of Marine Science and Technology. Prof. Shigefumi Kuwahawa and Prof. Masaru Enomoto, Tohoku University and Prof. Hiromasa Kiyota, Okayama University helped with the synthesis. This work was funded by the JSPS (no. LS012) and KAKENHI no. 26292057 (to M.Y.-Y.) and no. 15K07569 (to Y.C.). S.T. was a research fellow of the JSPS (DC2) (no. 15J00480) and was the recipient of a SUNBOR scholarship.
Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2017/5/2
Y1 - 2017/5/2
N2 - Saxitoxin (STX) and its analogues are potent voltage-gated sodium channel blockers biosynthesized by freshwater cyanobacteria and marine dinoflagellates. We previously identified genetically predicted biosynthetic intermediates of STX at early stages, Int-A′ and Int-C′2, in these microorganisms. However, the mechanism to form the tricyclic skeleton of STX was unknown. To solve this problem, we screened for unidentified intermediates by analyzing the results from previous incorporation experiments with 15N-labeled Int-C′2. The presence of monohydroxy-Int-C′2 and possibly Int-E′ was suggested, and 11-hydroxy-Int-C′2 and Int-E′ were identified from synthesized standards and LC-MS. Furthermore, we observed that the hydroxy group at C11 of 11-hydroxy-Int-C′2 was slowly replaced by CD3O in CD3OD. Based on this characteristic reactivity, we propose a possible mechanism to form the tricyclic skeleton of STX via a bicyclic intermediate from 11-hydroxy-Int-C′2.
AB - Saxitoxin (STX) and its analogues are potent voltage-gated sodium channel blockers biosynthesized by freshwater cyanobacteria and marine dinoflagellates. We previously identified genetically predicted biosynthetic intermediates of STX at early stages, Int-A′ and Int-C′2, in these microorganisms. However, the mechanism to form the tricyclic skeleton of STX was unknown. To solve this problem, we screened for unidentified intermediates by analyzing the results from previous incorporation experiments with 15N-labeled Int-C′2. The presence of monohydroxy-Int-C′2 and possibly Int-E′ was suggested, and 11-hydroxy-Int-C′2 and Int-E′ were identified from synthesized standards and LC-MS. Furthermore, we observed that the hydroxy group at C11 of 11-hydroxy-Int-C′2 was slowly replaced by CD3O in CD3OD. Based on this characteristic reactivity, we propose a possible mechanism to form the tricyclic skeleton of STX via a bicyclic intermediate from 11-hydroxy-Int-C′2.
KW - biosynthesis
KW - mass spectrometry
KW - natural products
KW - reaction mechanisms
KW - saxitoxin
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U2 - 10.1002/anie.201612461
DO - 10.1002/anie.201612461
M3 - Article
C2 - 28370934
AN - SCOPUS:85017356192
SN - 1433-7851
VL - 56
SP - 5327
EP - 5331
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
IS - 19
ER -
