8yla

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Crystal structures of terpene synthases complexed with a substrate mimic

Structural highlights

8yla is a 2 chain structure with sequence from Aspergillus fischeri NRRL 181. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NFSS_NEOFI Bifunctional terpene synthase; part of the gene cluster that mediates the biosynthesis of sesterfisheric acid (PubMed:26332841). The bifunctional terpene synthase NfSS converts dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP) into sesterfisherol (PubMed:26332841, PubMed:29410538). The C-terminal prenyltransferase (PT) domain of NfSS catalyzes formation of geranylfarnesyl pyrophosphate (GFPP), whereas the N-terminal terpene cyclase (TC) domain catalyzes the cyclization of GFPP to sesterfisherol (PubMed:26332841, PubMed:29410538). The cytochrome P450 monooxygenase NfP450 then catalyzes oxidative modifications of sesterfisherol into sesterfisheric acid (PubMed:26332841).^[1] ^[2]

Publication Abstract from PubMed

Little is known about the structures and catalytic mechanisms of sesterterpene synthases (StTSs), which greatly hinders the structure-based engineering of StTSs for structural diversity expansion of sesterterpenes. We here report on the crystal structures of the terpene cyclization (TC) domains of two fungal StTSs: sesterfisherol synthase (NfSS) and sesterbrasiliatriene synthase (PbSS). Both TC structures contain benzyltriethylammonium chloride (BTAC), pyrophosphate (PPi), and magnesium ions (Mg(2+)), clearly defining the catalytic active sites. A combination of theory and experiments including carbocationic intermediates modeling, site-directed mutagenesis, and isotope labeling provided detailed insights into the structural basis for their catalytic mechanisms. Structure-based engineering of NfSS and PbSS resulted in the formation of 20 sesterterpenes including 13 new compounds and four pairs of epimers with different configurations at C18. These results expand the structural diversity of sesterterpenes and provide important insights for future synthetic biology research.

Structural Insights Into the Terpene Cyclization Domains of Two Fungal Sesterterpene Synthases and Enzymatic Engineering for Sesterterpene Diversification.,Xu M, Xu H, Lei Z, Xing B, Dickschat JS, Yang D, Ma M Angew Chem Int Ed Engl. 2024 Jun 3;63(23):e202405140. doi: , 10.1002/anie.202405140. Epub 2024 May 2. PMID:38584136^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Ye Y, Minami A, Mandi A, Liu C, Taniguchi T, Kuzuyama T, Monde K, Gomi K, Oikawa H. Genome Mining for Sesterterpenes Using Bifunctional Terpene Synthases Reveals a Unified Intermediate of Di/Sesterterpenes. J Am Chem Soc. 2015 Sep 16;137(36):11846-53. PMID:26332841 doi:10.1021/jacs.5b08319
↑ Sato H, Narita K, Minami A, Yamazaki M, Wang C, Suemune H, Nagano S, Tomita T, Oikawa H, Uchiyama M. Theoretical Study of Sesterfisherol Biosynthesis: Computational Prediction of Key Amino Acid Residue in Terpene Synthase. Sci Rep. 2018 Feb 6;8(1):2473. PMID:29410538 doi:10.1038/s41598-018-20916-x
↑ Xu M, Xu H, Lei Z, Xing B, Dickschat JS, Yang D, Ma M. Structural Insights Into the Terpene Cyclization Domains of Two Fungal Sesterterpene Synthases and Enzymatic Engineering for Sesterterpene Diversification. Angew Chem Int Ed Engl. 2024 Jun 3;63(23):e202405140. PMID:38584136 doi:10.1002/anie.202405140