New Progress in Research on Biosynthesis of Relevant Prenyltransferases from Natural Product


On December 19, 2016, Nature Chemical Biology published online the full text of a research paper titled “Molecular insights into the enzyme promiscuity of an aromatic prenyltransferase” co-authored by CAMS Institute of Materia Medica and CAS Institute of Biophysics, reporting prenyltransferase (aromatic prenyltransferase, aPTase) AtaPT, a novel aromatic compound that is derived from microorganism and has significant substrates and promiscuity, revealing the molecular mechanism underlying the promiscuity of AtaPT and exhibiting the promising prospect of the enzyme in the biosynthesis of pharmacologically active compounds and synthetic biology of natural drugs.

Traditionally, enzymes are believed to have rigid substrate and reaction specificity. However, research findings have shown that many enzymes can catalyze other substrates than their “natural substrate” or reactions; that is, they have the property of promiscuity. The promiscuity of enzyme has drawn more attention from scientists, but the molecular mechanism of enzyme has not yet been completely clarified.

As an important source of original new drugs, the natural product replaced by isopentene group features varied structure and types and has different pharmacological activities. The introduction of isopentene group in the molecules of natural product can greatly enrich the structural diversity. Moreover, the affinity to drug targets and the bioavailability have been enhanced as a result of the increase of lipophicity, thereby improving the drug efficacy. Prenylation is difficult by chemical method since the structure of natural product is complicated, but such difficulty can be eased by using the new strategy of the promiscuity of prenyltransferases for prenylation.

In this study, a new aPTase, AtaPT, has been discovered for the first time from the genome of an Aspergillus terreus that stems from marine mangrove. The recombination of AtaPT can not only accept prenyl donors with different chain lengths (C5, C10, C15, and C20), but also catalyze aromatic compounds that have different structures including lignans, tryptophan ring dipeptide, quinoline alkaloid, xanthone, diphenyl ketone, flavone, and coumarin for such efficient prenylated reactions as substitution forms including single-site and multi-site O- and C- prenylated reactions, exhibiting unprecedented promiscuity of substrates and reactions (Fig. 1).

The study, through structural biology, expounds the molecular mechanism that AtaPT has significant promiscuity: 1) AtaPT three-dimensional structure has a spacious hydrophobic substrate-binding pocket that is remarkably larger than that of other reported prenyltransferases; 2) there are multiple different binding sites in the AtaPT substrate-binding pocket; 3) AtaPT has multiple conformations that are suitable for the binding of substrates with different structures. The study has realized artificial manipulation from “promiscuity” to “selectivity” through further rational structure-guided design and the gene site-directed mutagenesis technique.

The study is of great significance to the development of prenyl tool enzymes for biosynthesis of medicinal active compounds and research on synthetic biology, and provides a variety of innovative lead compounds for new drug research and development.




Fig.1. Conformational changes of catalysis of a single compound of different prenylation type by using AtaPT and substrate-binding pocket after the substrate binding

Jungui Dai, Researcher of the State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, the Institute of Materia Medica (IMM) at CAMS and Sun Fei, Researcher of the National Laboratory of Biomacromolecules of the CAS Institute of Biophysics are co-corresponding authors of this article. Dr. Ridao Chen and Dr. Xiao Liu of the research group led by Jungui Dai as well as Dr. Bingquan Gao of the research group led by Fei Qian are the co-first authors. The research group led by Researcher Jizhong Lou from the CAS Institute of Biophysics and the research group led by Professor Shuming Li from Philipps-Universitat Marburg took part in this study. The study was financially supported by National Natural Science Foundation of China, National Program on Key Basic Research Project (973 Program), and CAS Strategic Priority Program, etc.


(Scientific Research Office, IMM)