TY - JOUR
T1 - β-Methyltryptamine Provoking the Crucial Role of Strictosidine Synthase Tyr151-OH for Its Stereoselective Pictet-Spengler Reactions to Tryptoline-type Alkaloids
AU - Liu, Haicheng
AU - Panjikar, Santosh
AU - Sheng, Xiang
AU - Futamura, Yushi
AU - Zhang, Chenghua
AU - Shao, Nana
AU - Osada, Hiroyuki
AU - Zou, Hongbin
N1 - Funding Information:
We thank H. Aono, J. Otaka, and K. Yamamoto for assisting with the antimalarial activity tests. This work was funded by the Key Projects of Natural Science Foundation of Zhejiang Province (LZ21B020001), the National Natural Science Foundation of China (no. 21472170), and Tianjin Synthetic Biotechnology Innovation Capacity Improvement Project (TSBICIP-CXRC-026). We thank the support of beamline BL17U1 at Shanghai Synchrotron Radiation Facility (SSRF) and J. Stöckigt for his continuous interest.
Publisher Copyright:
©
PY - 2022/1/21
Y1 - 2022/1/21
N2 - Strictosidine synthase (STR), the gate enzyme for monoterpenoid indole alkaloid biosynthesis, catalyzes the Pictet-Spengler reaction (PSR) of various tryptamine derivatives with secologanin assisted by "indole sandwich"stabilization. Continuous exploration with β-methyltryptamine (IPA) stereoselectively delivered the C6-methylstrictosidines and C6-methylvincosides by enzymatic and nonenzymatic PSR, respectively. Unexpectedly, the first "nonindole sandwich"binding mode was witnessed by the X-ray structures of STR1-ligand complexes. Site-directed mutagenesis revealed the critical cryptic role of the hydroxyl group of Tyr151 in IPA biotransformation. Further computational calculations demonstrated the adjustable IPA position in STR1 upon the binding of secologanin, and Tyr151-OH facilitates the productive PSR binding mode via an advantageous hydrogen-bond network. Further chemo-enzymatic manipulation of C6-methylvincosides successfully resulted in the discovered antimalarial framework (IC50 = 0.92 μM).
AB - Strictosidine synthase (STR), the gate enzyme for monoterpenoid indole alkaloid biosynthesis, catalyzes the Pictet-Spengler reaction (PSR) of various tryptamine derivatives with secologanin assisted by "indole sandwich"stabilization. Continuous exploration with β-methyltryptamine (IPA) stereoselectively delivered the C6-methylstrictosidines and C6-methylvincosides by enzymatic and nonenzymatic PSR, respectively. Unexpectedly, the first "nonindole sandwich"binding mode was witnessed by the X-ray structures of STR1-ligand complexes. Site-directed mutagenesis revealed the critical cryptic role of the hydroxyl group of Tyr151 in IPA biotransformation. Further computational calculations demonstrated the adjustable IPA position in STR1 upon the binding of secologanin, and Tyr151-OH facilitates the productive PSR binding mode via an advantageous hydrogen-bond network. Further chemo-enzymatic manipulation of C6-methylvincosides successfully resulted in the discovered antimalarial framework (IC50 = 0.92 μM).
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U2 - 10.1021/acschembio.1c00844
DO - 10.1021/acschembio.1c00844
M3 - Article
C2 - 34994203
AN - SCOPUS:85123813957
SN - 1554-8929
VL - 17
SP - 187
EP - 197
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 1
ER -