文献类型：期刊文献

英文题名：Biosynthesis of 4-Acyl-5-aminoimidazole Alkaloids Featuring a New Friedel-Crafts Acyltransferase

作者：Xia, Yuwei[1];Zhu, Guoliang[1,2];Zhang, Xingwang[3];Li, Shengying[3];Du, Lei[3];Zhu, Weiming[1,4]

机构：[1]Ocean Univ China, Sch Med & Pharm, Key Lab Marine Drugs, Minist Educ China, Qingdao 266003, Peoples R China;[2]East China Univ Sci & Technol, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[3]Shandong Univ, State Key Lab Microbial Technol, Qingdao 266237, Peoples R China;[4]Laoshan Lab, Lab Marine Drugs & Bioprod, Qingdao 266237, Peoples R China

年份：2023

卷号：145

期号：48

起止页码：26308

外文期刊名：JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

收录：;EI(收录号：20234915176075);WOS:【SCI-EXPANDED(收录号:WOS:001115536000001)】；

基金：This research was supported by National Key Research and Development Program of China (Grants 2022YFC2804100 and 2021YFA0911500), National Natural Science Foundation of China (Grants U1906213 and 32170088), and Shandong Provincial Natural Science Foundation (Grant ZR2020ZD23). The authors acknowledge Shandong University Core Facilities for Life and Environmental Sciences for their help in the protein ESI-Q-TOF-MS analysis. The authors acknowledge the ZCloud platform (https://cloud.zelixir.com, Shanghai ZELIXIR BIOTECH) for the help in part of the computations of multiple biomolecule structure modeling, simulation, and prediction algorithms.

语种：英文

外文关键词：Biochemistry - Biosynthesis - Catalysis - Catalyst activity - Chemical bonds - Genes - Reaction intermediates

摘要：Friedel-Crafts acylation (FCA) is a highly beneficial approach in organic chemistry for creating the important C-C bonds that are necessary for building intricate frameworks between aromatic substrates and an acyl group. However, there are few reports about enzyme catalyzed FCA reactions. In this study, 4-acyl-5-aminoimidazole alkaloids (AAIAs), streptimidazoles A-C (1-3), and the enantiopure (+)-nocarimidazole C (4) as well as their ribosides, streptimidazolesides A-D (5-8), were identified from the fermentation broth of Streptomyces sp. OUCMDZ-944 or heterologous S. coelicolor M1154 mutant. The biosynthetic gene cluster (smz) was identified, and the biosynthetic pathway of AAIAs was elucidated for the first time. In vivo and in vitro studies proved the catalytic activity of the four essential genes smzB, -C, -E, and -F for AAIAs biosynthesis and clarified the biosynthetic process of the alkaloids. The ligase SmzE activates fatty acyl groups and connects them to the acyl carrier protein (ACP) holo-SmzF. Then, the acyl group is transferred onto the key residue Cys49 of SmzB, a new Friedel-Crafts acyltransferase (FCase). Subsequently, the FCA reaction between the acyl groups and 5-aminoimidazole ribonucleotide (AIR) occurs to generate the key intermediate AAIA-nucleotides catalyzed by SmzB. Finally, the hydrolase SmzC catalyzes the N-glycosidic bond cleavage of the intermediates to form AAIAs. Structural simulation, molecular modeling, and mutational analysis of SmzB showed that Tyr26, Cys49, and Tyr93 are the key catalytic residues in the C-C bond formation of the acyl chain of AAIAs, providing mechanistic insights into the enzymatic FCA reaction.