An enzymatic [4+2] cyclization cascade creates the pentacyclic core of pyrroindomycins.
The [4+2] cycloaddition remains one of the most intriguing transformations in synthetic and natural products chemistry. In nature, however, there are remarkably few enzymes known to have this activity. We herein report an unprecedented enzymatic [4+2] cyclization cascade that has a central role in the biosynthesis of pyrroindomycins, which are pentacyclic spirotetramate natural products. Beginning with a linear intermediate that contains two pairs of 1,3-diene and alkene groups, the dedicated cyclases PyrE3 and PyrI4 act in tandem to catalyze the formation of two cyclohexene rings in the dialkyldecalin system and the tetramate spiro-conjugate of the molecules. The two cyclizations are completely enzyme dependent and proceed in a regio- and stereoselective manner to establish the enantiomerically pure pentacyclic core. Analysis of a related spirotetronate pathway confirms that homologs are functionally exchangeable, establishing the generality of these findings and explaining how nature creates diverse active molecules with similar rigid scaffolds.
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Zhenhua
Z
Tian
1] State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [2] Research Center for Marine Drugs, School of Pharmacy, Second Military Medical University, Shanghai, China.
Peng
P
Sun
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Yan
Y
Yan
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Zhuhua
Z
Wu
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Qingfei
Q
Zheng
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Shuaixiang
S
Zhou
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Hua
H
Zhang
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Futao
F
Yu
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
Xinying
0000000228314605
X
Jia
Huzhou Center of Bio-Synthetic Innovation, Huzhou, China.
Dandan
D
Chen
Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary.
Attila
A
Mándi
Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary.
Tibor
T
Kurtán
1] State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. [2] Huzhou Center of Bio-Synthetic Innovation, Huzhou, China.
Wen
W
Liu
D000475:Alkenes / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry; D002384:Catalysis; D002621:Chemistry / Q000379:methods*; D003500:Cyclization; D053138:Cyclohexenes / Q000737:chemistry; D004269:DNA, Bacterial / Q000737:chemistry; D019753:Intramolecular Lyases / Q000138:chemical synthesis / Q000737:chemistry*; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D008956:Models, Chemical; D015394:Molecular Structure; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013237:Stereoisomerism; D013302:Streptomyces / Q000378:metabolism
D000475:Alkenes; D001688:Biological Products; D053138:Cyclohexenes; D004269:DNA, Bacterial; D018942:Macrolides; D011760:Pyrrolidinones; D011994:Recombinant Proteins; D019753:Intramolecular Lyases