Organic Letters
Letter
were imines generated by oxidative reactions. Unfortunately,
those macrocyclizations have not yet been characterized in
vitro, and it is still unknown whether their C−C bonds are
formed via spontaneous or enzymatic reactions.
Shoubin Tang − Peking University Shenzhen Graduate
School, Tsinghua University Shenzhen International
Graduate School, Shenzhen, China
Ee Ling Chang − Peking University Shenzhen Graduate
School, Tsinghua University Shenzhen International
Graduate School, Shenzhen, China
Yue Tang − Institute of Microbiology, Chinese Academy of
Sciences, Beijing, China, University of Chinese Academy of
Sciences, Beijing, China, and Peking University Shenzhen
Graduate School, Tsinghua University Shenzhen
International Graduate School, Shenzhen, China
Zhengyan Guo − Institute of Microbiology, Chinese
Academy of Sciences, Beijing, China, and University of
of Sciences, Beijing, China
Bian Wu − Institute of Microbiology, Chinese Academy of
The aldol addition is just the first reaction of the MubD-R
triggered three-step spontaneous process. The macrocyclized
intermediates can be further attacked at C3 by the thiol group
to generate different β-thiodiketones, including the intra-
molecular nucleophilic attack that forms the 1,4-thiazepane
ring. Actually, in several chemical syntheses from aldehydes,
diketones, and thiols, diverse β-thiodiketones were generated
via a similar two-step nucleophilic addition and thiolation
2
2,23
process.
Here we present an interesting case to show that
such a synthesis strategy has been adopted by S. mutans to
make MUBs and mutanolins in our mouths. Moreover, S.
mutans can further convert the macrocyclized β-thiodiketones
to linear lipopeptides with a hemithioacetal end via the retro-
aldol reaction, and the third step has no precedent in the
literature. This reductase-enabled three-step relay that includes
spontaneous C−C macrocyclization, C−S bond formation,
and C−C bond cleavage in S. mutans may provide inspiration
for the chemical synthesis of macrocycles, thiazepanes, and
hemithioacetals.
In conclusion, we present an interesting example of how
microbes efficiently expand their product spectra by recruiting
chemical reactions that can take place spontaneously under the
physiological conditions. The direct products of the MUB
biosynthetic machinery in S. mutans UA159 are linear
lipohexapeptides with an aldehyde end, which can undergo
three nonenzymatic reactions sequentially to generate MUBs
and their congeners. Our results not only explain why the
MUB synthetase can generate such diverse MUBs and
mutanolins but also can guide the discovery of more MUB
congeners from S. mutans, which should be meaningful in
understanding how the mub cluster helps its S. mutans hosts in
adapting the oral environment and causing dental caries.
Tao Ye − Peking University Shenzhen Graduate School,
Author Contributions
∥M.W., Z.X., and S.T. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
ASSOCIATED CONTENT
sı Supporting Information
■
We thank Dr. Jinwei Ren, Guomin Ai, and Wenzhao Wang,
Institute of Microbiology, CAS, for technical support. This
work was supported in part by the MOST of China
*
(
2018YFA0901901), the NSFC grants (31570050 and
Experimental details of the construction of the S. mutans
T-IFD mutant, enzymatic and autoconversion assays,
synthesis of substrates and standards, spectroscopic data,
and copies of NMR spectra (PDF)
3 1 5 2 2 0 0 1 ) , t h e S h e n z h e n P e a c o c k P l a n
(KQTD2015071714043444), and the Open Project of State
Key Laboratory of Chemical Oncogenomics.
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■
Yihua Chen − Institute of Microbiology, Chinese Academy
Other Authors
Min Wang − Institute of Microbiology, Chinese Academy
of Sciences, Beijing, China, Peking University Shenzhen
Graduate School, Tsinghua University Shenzhen
International Graduate School, Shenzhen, China, and
University of Chinese Academy of Sciences, Beijing, China
of Sciences, Beijing, China
(
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(
D
Org. Lett. XXXX, XXX, XXX−XXX