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Structural Basis for the One-Pot Formation of the Diarylheptanoid Scaffold by Curcuminoid Synthase from Oryza Sativa

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Structural Basis for the One-Pot Formation of the Diarylheptanoid Scaffold by Curcuminoid Synthase from Oryza Sativa Structural basis for the one-pot formation of the diarylheptanoid scaffold by curcuminoid synthase from Oryza sativa Hiroyuki Moritaa, Kiyofumi Wanibuchia, Hirohiko Niia, Ryohei Katob, Shigetoshi Sugiob,1, and Ikuro Abea,1 aGraduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; and bBiotechnology Laboratory, Mitsubishi Chemical Group Science and Technology Research Center Inc., 1000 Kamoshida, Aoba, Yokohama, Kanagawa 227-8502, Japan Edited by Rodney B. Croteau, Washington State University, Pullman, WA, and approved September 28, 2010 (received for review August 3, 2010) Curcuminoid synthase (CUS) from Oryza sativa is a plant-specific Oryza sativa is another novel type III PKS that catalyzes the type III polyketide synthase (PKS) that catalyzes the remarkable “one-pot” formation of the C6-C7-C6 scaffold of bisdemethoxy- one-pot formation of the C6-C7-C6 diarylheptanoid scaffold of bis- curcumin (Fig. 1E). Although its physiological function remains demethoxycurcumin, by the condensation of two molecules of to be elucidated, it is remarkable that a single enzyme catalyzes 4-coumaroyl-CoA and one molecule of malonyl-CoA. The crystal the condensation of two molecules of 4-coumaroyl-CoA and one structure of O. sativa CUS was solved at 2.5-Å resolution, which re- molecule of malonyl-CoA through the formation of the C6-C5 vealed a unique, downward expanding active-site architecture, pre- 4-coumaroyldiketide acid (8). viously unidentified in the known type III PKSs. The large active-site Recent crystallographic and site-directed mutagenesis studies cavity is long enough to accommodate the two C6-C3 coumaroyl on plant and bacterial type III PKSs have revealed that the func- units and one malonyl unit. Furthermore, the crystal structure indi- tional diversity of the type III PKSs is principally derived from cated the presence of a putative nucleophilic water molecule, which modifications of the active-site cavity (1, 2). The amino acid se- forms hydrogen bond networks with Ser351-Asn142-H2O-Tyr207- quence of O. sativa CUS shares 40–51% identity with other plant Glu202, neighboring the catalytic Cys174 at the active-site center. type III PKSs; 49% identity with M. sativa CHS, 51% identity with These observations suggest that CUS employs unique catalytic ma- C. longa DCS, and 45% identity with C. longa CURS (Fig. S1). BIOCHEMISTRY chinery for the one-pot formation of the C6-C7-C6 scaffold. Thus, CUS Sequence comparisons revealed that the Cys-His-Asn catalytic utilizes the nucleophilic water to terminate the initial polyketide triad and most of the characteristic active-site residues of the CHSs chain elongation at the diketide stage. Thioester bond cleavage of are well conserved in CUS. However, Thr132, Thr197, Gly256, and the enzyme-bound intermediate generates 4-coumaroyldiketide Phe265, lining the active-site cavity of M. sativa CHS, are charac- acid, which is then kept within the downward expanding pocket teristically substituted with Asn, Tyr, Met, and Gly, respectively, for subsequent decarboxylative condensation with the second which may account for the catalytic activity of CUS. The first three 4-coumaroyl-CoA starter, to produce bisdemethoxycurcumin. The of these residues are altered in a number of functionally divergent structure-based site-directed mutants, M265L and G274F, altered type III PKSs and play crucial roles in controlling the substrate and the substrate and product specificities to accept 4-hydroxyphenyl- product specificities of the type III PKS enzyme reactions (1, 2). propionyl-CoA as the starter to produce tetrahydrobisdemethoxy- Indeed, recent structural analyses of Pinus sylvestris STS have de- curcumin. These findings not only provide a structural basis for monstrated that the backbone change of the loop leads to the the catalytic machinery of CUS but also suggest further strategies subtle displacement of Thr132, resulting in the rearrangement toward expanding the biosynthetic repertoire of the type III PKS of the hydrogen bond networks including Thr132 and a nucleophi- enzymes. lic water molecule at the active-site center (9). On the other hand, the “gatekeeper” Phe265 is located at the junction between the ype III polyketide synthases (PKSs) are structurally simple, active-site cavity and the CoA binding tunnel in M. sativa CHS Thomodimeric proteins that use a single active site to produce and is well conserved in a number of type III PKSs (Fig. S1). This pharmaceutically and biologically important, structurally diver- residue is thought to control the substrate entry into the active site gent natural polyketide scaffolds (1–3). For example, chalcone by forming part of the wall in the active-site cavity (10). synthase (CHS) and stilebene synthase (STS) catalyze the sequen- To clarify the three-dimensional structural details of the CUS- tial condensation of 4-coumaroyl-CoA as a starter substrate with catalyzed enzyme reaction and to elucidate the structure-function three C2 units from malonyl-CoA, to produce the C6-C3-C6 scaf- relationship of the type III PKS enzymes, we now present the fold of naringenin chalcone, the key intermediate in flavonoid crystal structure of CUS at 2.5-Å resolution. The crystal structure biosynthesis, and the C6-C2-C6 scaffold of resveratrol, respec- revealed a unique, downward expanding active-site architecture, tively (Fig. 1 A and B). On the other hand, it was recently reported previously unidentified in the known type III PKSs (1, 2), and that the C6-C7-C6 diarylheptanoid scaffold of curcumin is also indicated the presence of a putative nucleophilic water molecule produced by novel type III PKSs (Fig. 1 C and D) (4). Curcumin, that forms hydrogen bond networks at the active-site center. the principal component of the turmeric Curcuma longa, is widely These findings have led to the proposal that CUS utilizes the nu- used as a food additive and in traditional Asian medicine and has been shown to possess anti-inflammatory, anticarcinogenic, – Author contributions: H.M. and I.A. designed research; H.M., K.W., H.N., and I.A. and antitumor activities (5 7). Thus, in C. longa, diketide-CoA performed research; H.M., K.W., H.N., R.K., S.S., and I.A. analyzed data; and H.M. and synthase (DCS) and curcumin synthase (CURS) are two key I.A. wrote the paper. enzymes in the biosynthesis of curcumin; DCS catalyzes the con- The authors declare no conflict of interest. densation of feruloyl-CoA with malonyl-CoA to produce feruloyl- This article is a PNAS Direct Submission. diketide-CoA (Fig. 1C), and CURS then accepts the C6-C5 Data deposition: The coordinates and structure factors have been deposited in the feruloyldiketide acid, the hydrolyzed product of feruloyldike- Protein Data Bank, www.pdb.org (PDB ID code 3ALE). tide-CoA, and catalyzes decarboxylative condensation with the 1To whom correspondence may be addressed. E-mail: [email protected] or abei@ second feruloyl-CoA starter to produce the C6-C7-C6 diarylhep- mol.f.u-tokyo.ac.jp. tanoid scaffold of curcumin (Fig. 1D) (4). In contrast, very This article contains supporting information online at www.pnas.org/lookup/suppl/ interestingly, curcuminoid synthase (CUS) from the rice plant doi:10.1073/pnas.1011499107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1011499107 PNAS Early Edition ∣ 1of6 Downloaded by guest on September 29, 2021 alkylpyrone synthase PKS18 (Fig. 1F) (11) and Neurospora crassa 2′-oxoalkylresorcylic acid synthase (ORAS) (12). The catalytic triad of Cys174, His316, and Asn349 is buried deep within each monomer and sits at the intersection of a traditional 16-Å-long CoA binding tunnel and a large internal cavity, in a location and orientation very similar to those of the other plant type III PKSs. A structure-based similarity search using the Dali pro- gram (13) suggested that the overall structure of CUS is highly homologous to those of the previously reported plant type III PKSs (rmsds 1.0–1.2 Å and 2.0–2.2 Å for plant and bacterial type III PKSs, respectively), in which the most closely related structur- al homologue is that of Rheum palmatum benzalacetone synthase (BAS) (PDB entry 3A5Q, Z score ¼ 57.2, rmsd of 1.0 Å over 360 residues aligned with a sequence identity of 53%) (14). R. palma- tum BAS produces the diketide benzalacetone by the one-step condensation of 4-coumaroyl-CoA and malonyl-CoA through the formation of 4-coumaroyldiketide acid (Fig. 1G). Active-Site Architecture of CUS. A comparison of the active-site structure of O. sativa CUS with that of M. sativa CHS (10) revealed that in the crystal structure of CUS, the backbone torsion angle of Asn142ð−92; − 23Þ, as compared with that of Thr132 ð−112;6Þ of M. sativa CHS, is slightly shifted by a ϕ angle of −20° and a ψ angle of þ29°, and the amino moiety of Asn142 forms a hydrogen bond with Ser351, corresponding to Ser338 of M. sativa CHS (Fig. 2 A and B). Furthermore, the backbone torsion angle of Tyr207ð−92; − 40Þ, as compared with that of Thr197ð−111; − 22Þ of M. sativa CHS, is shifted by a ϕ angle of −19° and a ψ angle of þ18°, with a slight displacement of its Cα-atom, and the side chain of Tyr207 protrudes toward Ser351. The conformational differ- ences of Asn142 and Tyr207 cause the loss of the so-called CHS coumaroyl binding pocket that thought to bind the aromatic moiety of the tetraketide intermediate (10) from the active-site Fig. 1. Proposed mechanisms for the formation of polyketides. (A) Narin- cavity of CUS (Fig. 2 C and D). The coumaroyl binding pocket genin chalcone
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