Dihydrofolate reductase-like protein inactivates hemiaminal pharmacophore for self-resistance in safracin biosynthesis  

作　　者：Ning Shao Xueyang Ma Ying-Ying Zhang Donghui Yang Ming Ma Gong-Li Tang 

机构地区：[1]State Key Laboratory of Bioorganic and Natural Products Chemistry,Center for Excellence in Molecular Synthesis,Shanghai Institute of Organic Chemistry,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200032,China [2]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing 100191,China [3]School of Chemistry and Materials Science Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第3期1318-1325,共8页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.31930002,21621002,21877002,81991525,82273829 and 22077007);the key project at central government level:the ability establishment of sustainable use for valuable Chinese medicine resources(2060302-2201-17).

摘　　要：Dihydrofolate reductase(DHFR),a housekeeping enzyme in primary metabolism,has been extensively studied as a model of acid-base catalysis and a clinic drug target.Herein,we investigated the enzymology of a DHFR-like protein SacH in safracin(SAC)biosynthesis,which reductively inactivates hemiaminal pharmacophore-containing biosynthetic intermediates and antibiotics for self-resistance.Furthermore,based on the crystal structure of SacH−NADPH−SAC-A ternary complexes and mutagenesis,we proposed a catalytic mechanism that is distinct from the previously characterized short-chain dehydrogenases/reductases-mediated inactivation of hemiaminal pharmacophore.These findings expand the functions of DHFR family proteins,reveal that the common reaction can be catalyzed by distinct family of enzymes,and imply the possibility for the discovery of novel antibiotics with hemiaminal pharmacophore.

关 键 词：Catalytic mechanism Crystal structure Dihydrofolate reductase(DHFR) Hemiaminal pharmacophoreSacH Safracin biosynthesis Self-resistance Tetrahydroisoquinoline(THIQ)alkaloids 

分 类 号：TQ460.1[化学工程—制药化工]