The transfer of prenyl moieties, as mediated by aromatic prenyltransferases (aPTases), is a ubiquitous reaction in natural product biosynthesis. The prenylation of aromatic compounds and a variety of subsequent tailoring reactions, including oxidation, reduction and cyclization, give rise to a plethora of ‘hybrid’ natural products that exhibit diverse biological properties. In particular, the introduction of prenyl moieties often increases the lipophilicity of these compounds, enhancing their interactions with biological membranes. Modification of drug-like natural products via one-step prenylation is seen as a convenient approach for the synthesis of bioactive compounds in drug discovery programs. However, the present lack of a widely applicable method for the prenylation of diverse aromatic scaffolds remains a challenge.
Recently, an article entitled "Molecular insights into the enzyme promiscuity of an aromatic prenyltransferase" was published in Nature Chemical Biology . In this work, the researchers discovered a new aPTase, AtaPT (Aspergillus terreus aromatic prenyltransferase), that exhibits unprecedented promiscuity toward diverse aromatic acceptors and prenyl donors and also yields products with a range of prenylation patterns. Systematic crystallographic studies revealed various discrete conformations for ligand binding with donor-dependent acceptor specificity and multiple binding sites within a spacious hydrophobic substrate-binding pocket. Further structure-guided mutagenesis of active sites at the substrate-binding pocket is responsible for altering the specificity and promiscuity toward substrates and the diversity of product prenylations. With an appropriately deep understanding of the molecular mechanisms of AtaPT–catalyzed prenylations, it should be possible to use structure-guided mutagenesis to fine tune both the prenyl donor and the prenylation selectivity of AtaPT. This would increase the utility of AtaPT in the synthesis of new, possibly rationally designed prenylated derivatives for applications in drug discovery programs.
This work was co-accomplished by Prof. DAI Jungui's group of the State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica (IMM), CAMS & PUMC, and Prof. SUN Fei's group of the National Laboratory of Biomacromolecules, Institute of Biophysics (IBP), CAS. The first authors, Drs. CHEN Ridao (IMM), GAO Bingquan (IBP), and LIU Xiao (IMM) together other authors collectively completed this research.
Full Text Link:http://dx.doi.org/10.1038/nchembio.2263
