Chemodivergent C(sp3)-H and C(sp2)-H cyanomethylation using engineered carbene transferases
被引:13
|
作者:
Zhang, Juner
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机构:
CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Princeton Univ, Dept Chem, Princeton, NJ USACALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Zhang, Juner
[1
,3
]
Maggiolo, Ailiena O.
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机构:
CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USACALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Maggiolo, Ailiena O.
[1
]
Alfonzo, Edwin
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机构:
CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USACALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Alfonzo, Edwin
[1
]
Mao, Runze
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机构:
CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USACALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Mao, Runze
[1
]
Porter, Nicholas J.
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机构:
CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USACALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Porter, Nicholas J.
[1
]
Abney, Nayla M.
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机构:
CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Stanford Univ, Dept Bioengn, Stanford, CA USACALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Abney, Nayla M.
[1
,4
]
Arnold, Frances H.
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机构:
CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USACALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
Arnold, Frances H.
[1
,2
]
机构:
[1] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA
[2] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA
H BOND FUNCTIONALIZATION;
ARYL-ALPHA-DIAZOACETATES;
DIRECTED EVOLUTION;
HEME-PROTEINS;
IRON;
DIVERSIFICATION;
ACTIVATION;
MOLECULES;
CATALYSTS;
LIGAND;
D O I:
10.1038/s41929-022-00908-x
中图分类号:
O64 [物理化学(理论化学)、化学物理学];
学科分类号:
070304 ;
081704 ;
摘要:
The ubiquity of C-H bonds presents an opportunity to efficiently elaborate and build complexity in organic molecules. Methods for selective functionalization, however, must differentiate among multiple, chemically similar C-H bonds: enzymes are attractive because they can be finely tuned using directed evolution to achieve divergent reaction outcomes. Here we present engineered enzymes that effect a new-to-nature C-H alkylation (C-H carbene insertion) with distinct selectivities: cytochrome P450-based carbene transferases deliver an alpha-cyanocarbene either into the alpha-amino C(sp(3))-H bonds or the ortho-arene C(sp(2))-H bonds of N-substituted arenes. These two transformations proceed via different mechanisms, yet only minimal changes to the protein scaffold were needed to adjust the enzyme's chemoselectivity. Structural studies of the C(sp(3))-H alkylase reveal an active-site helical disruption, which alter the structure and electrostatics of the substrate-binding pocket compared to the native enzyme. Overall, this work demonstrates advantages of using highly tuneable enzymes as C-H functionalization catalysts for divergent molecular derivatization.
机构:
East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
East China Normal Univ, Shanghai Key Lab Green Chem & Chem Proc, Shanghai 200062, Peoples R ChinaEast China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
Cui, Xiao-Yuan
Ye, Zhong-Tian
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机构:
East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
East China Normal Univ, Shanghai Key Lab Green Chem & Chem Proc, Shanghai 200062, Peoples R ChinaEast China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
Ye, Zhong-Tian
Wu, Hai-Hong
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机构:
East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
East China Normal Univ, Shanghai Key Lab Green Chem & Chem Proc, Shanghai 200062, Peoples R ChinaEast China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
Wu, Hai-Hong
Ji, Chang-Ge
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机构:
East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
East China Normal Univ, Shanghai Key Lab Green Chem & Chem Proc, Shanghai 200062, Peoples R ChinaEast China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
Ji, Chang-Ge
Zhou, Feng
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机构:
East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
East China Normal Univ, Shanghai Key Lab Green Chem & Chem Proc, Shanghai 200062, Peoples R ChinaEast China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
Zhou, Feng
Zhou, Jian
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机构:
East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
East China Normal Univ, Shanghai Key Lab Green Chem & Chem Proc, Shanghai 200062, Peoples R China
Shanghai Inst Organ Chem, State Key Lab Organometall Chem, Shanghai 200032, Peoples R ChinaEast China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev, Shanghai 200062, Peoples R China
机构:
Zhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
Lai, Zhencheng
Wu, Rongkai
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机构:
Zhejiang Univ, Dept Chem, 38 Zheda Rd, Hangzhou 310027, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
Wu, Rongkai
Li, Jiaming
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机构:
Zhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
Li, Jiaming
Chen, Xing
论文数: 0引用数: 0
h-index: 0
机构:
Tianjin Univ, Inst Mol Plus, Tianjin 300072, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
Chen, Xing
Zeng, Linwei
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机构:
Zhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
Zeng, Linwei
Wang, Xi
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机构:
Beijing Jiaotong Univ, Sch Sci, Beijing 100044, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
Wang, Xi
Guo, Jingjing
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机构:
South China Univ Technol, State Key Lab Luminescent Mat & Devices, Guangzhou 510640, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
Guo, Jingjing
Zhao, Zujin
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机构:
South China Univ Technol, State Key Lab Luminescent Mat & Devices, Guangzhou 510640, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
Zhao, Zujin
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机构:
Sajiki, Hironao
Cui, Sunliang
论文数: 0引用数: 0
h-index: 0
机构:
Zhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R ChinaZhejiang Univ, Coll Pharmaceut Sci, Inst Drug Discovery & Design, 866 Yuhangtang Rd, Hangzhou 310058, Peoples R China
机构:
Univ Tehran Med Sci, Dept Med Chem, Fac Pharm, Tehran, Iran
Univ Tehran Med Sci, Pharmaceut Sci Res Ctr, Tehran, IranUniv Tehran Med Sci, Dept Med Chem, Fac Pharm, Tehran, Iran
Moghimi, Setareh
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机构:
Mahdavi, Mohammad
Shafiee, Abbas
论文数: 0引用数: 0
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机构:
Univ Tehran Med Sci, Dept Med Chem, Fac Pharm, Tehran, Iran
Univ Tehran Med Sci, Pharmaceut Sci Res Ctr, Tehran, IranUniv Tehran Med Sci, Dept Med Chem, Fac Pharm, Tehran, Iran
机构:
Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, JapanUniv Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan
Wang, Zhen
Ni, Jizhi
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机构:
Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, JapanUniv Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan
Ni, Jizhi
Kuninobu, Yoichiro
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机构:
Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan
ERATO Japan Sci & Technol Agcy JST, Kanai Life Sci Catalysis Project, Tokyo 1130033, JapanUniv Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan