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The Biosynthetic Gene Cluster of Mushroom-Derived Antrocin Encodes Two Dual-Functional Haloacid Dehalogenase-like Terpene Cyclases |
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| Authors: | Dr. Tzu-Ho Chen Chien-Ting Chen Chi-Fang Lee Rou-Jie Huang Kuan-Lin Chen Yuan-Chun Lu Suh-Yuen Liang Dr. Mai-Truc Pham Dr. Yerra Koteswara Rao Dr. Shih-Hsiung Wu Dr. Rong-Jie Chein Dr. Hsiao-Ching Lin |
| Affiliation: | 1. Institute of Biological Chemistry, Academia Sinica, Institute of Biochemical Sciences, National Taiwan University, Taipei, 115 Taiwan R.O.C. These authors contributed equally to this work.;2. Institute of Biological Chemistry, Academia Sinica, Institute of Biochemical Sciences, National Taiwan University, Taipei, 115 Taiwan R.O.C.;3. Institute of Chemistry, Academia Sinica, Taipei, 115 Taiwan R.O.C. Department of Chemistry, National Taiwan University, Taipei, 106 Taiwan R.O.C.;4. Institute of Chemistry, Academia Sinica, Taipei, 115 Taiwan R.O.C. |
| Abstract: | (−)-Antrocin ( 1 ), produced by the medicinal mushroom Antrodia cinnamomea, is a potent antiproliferative compound. The biosynthetic gene cluster of 1 was identified, and the pathway was characterized by heterologous expression. We characterized a haloacid dehalogenase-like terpene cyclase AncC that biosynthesizes the drimane-type sesquiterpene (+)-albicanol ( 2 ) from farnesyl pyrophosphate (FPP). Biochemical characterization of AncC, including kinetic studies and mutagenesis, demonstrated the functions of two domains: a terpene cyclase (TC) and a pyrophosphatase (PPase). The TC domain first cyclizes FPP to albicanyl pyrophosphate, and the PPase domain then removes the pyrophosphate to form 2 . Intriguingly, AncA (94 % sequence identity to AncC), in the same gene cluster, converts FPP into (R)-trans-γ-monocyclofarnesol instead of 2 . Notably, Y283/F375 in the TC domain of AncA serve as a gatekeeper in controlling the formation of a cyclofarnesoid rather than a drimane-type scaffold. |
| Keywords: | Biosynthesis Medicinal Mushrooms Natural Products Terpene Cyclases Terpenes |