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Enzymatic Synthesis of a Bicyclobutane Fatty Acid by a Hemoprotein–Lipoxygenase Fusion Protein from the Cyanobacterium Anabaena PCC 7120

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Enzymatic Synthesis of a Bicyclobutane Fatty Acid by a Hemoprotein–Lipoxygenase Fusion Protein from the Cyanobacterium Anabaena PCC 7120 Enzymatic synthesis of a bicyclobutane fatty acid by a hemoprotein–lipoxygenase fusion protein from the cyanobacterium Anabaena PCC 7120 Claus Schneider*, Katrin Niisuke*, William E. Boeglin*, Markus Voehler†, Donald F. Stec†, Ned A. Porter†, and Alan R. Brash*‡ Departments of *Pharmacology and †Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232 Edited by Judith P. Klinman, University of California, Berkeley, CA, and approved October 5, 2007 (received for review July 30, 2007) Biological transformations of polyunsaturated fatty acids often that the catalase-related allene oxide synthase (AOS) is proto- lead to chemically unstable products, such as the prostaglandin typical of an enzyme family that also has diversified functions. endoperoxides and leukotriene A4 epoxide of mammalian biology Accordingly, the unusual catalytic activity of the catalase-related and the allene epoxides of plants. Here, we report on the enzy- coral AOS provided the impetus for the present investigation, matic production of a fatty acid containing a highly strained bicyclic namely to explore other possible occurrences of catalase-related four-carbon ring, a moiety known previously only as a model proteins with novel functions in the biotransformation of poly- compound for mechanistic studies in chemistry. Starting from unsaturated fatty acids. linolenic acid (C18.3␻3), a dual function protein from the cyanobac- By using BLAST searches for sequences similar to the coral terium Anabaena PCC 7120 forms 9R-hydroperoxy-C18.3␻3ina catalase-related domain, one of the top matching hits besides lipoxygenase domain, then a catalase-related domain converts the other coral homologues was identified in the cyanobacterium 9R-hydroperoxide to two unstable allylic epoxides. We isolated Anabaena sp. strain PCC 7120. The Anabaena genus of cya- and identified the major product as 9R,10R-epoxy-11trans-C18.1 nobacteria are photosynthetic prokaryotes that grow in long containing a bicyclo[1.1.0]butyl ring on carbons 13–16, and the strings or filaments and that can develop a nitrogen-fixing ability minor product as 9R,10R-epoxy-11trans,13trans,15cis-C18.␻3, an in specialized heterocysts. They are studied as a model for epoxide of the leukotriene A type. Synthesis of both epoxides can prokaryotic developmental biology (12). Anabaena PCC 7120 be understood by initial transformation of the hydroperoxide to an has a genome of 6.4 Mb, and the cells also contain several large epoxy allylic carbocation. Rearrangement to an intermediate bicy- plasmids. The novel gene resides on the 102 kb gamma plasmid. clobutonium ion followed by deprotonation gives the bicyclobu- Enticingly, this small catalase-related sequence was found in the tane fatty acid. This enzymatic reaction has no parallel in aqueous same ORF as a LOX-like sequence, albeit a highly unusual one, or organic solvent, where ring-opened cyclopropanes, cyclobu- much smaller than any previously known member of the LOX tanes, and homoallyl products are formed. Given the capability superfamily. In a separate study, we show that this C-terminal shown here for enzymatic formation of the highly strained and domain of the fusion protein is a catalytically complete lipoxy- unstable bicyclobutane, our findings suggest that other transfor- genase that specifically forms 9R-hydroperoxides from C18 mations involving carbocation rearrangement, in both chemistry polyunsaturated fatty acid substrates (Y. Zheng, W.E.B., C.S., and biology, should be examined for the production of the high A.R.B., unpublished data). Here, we report characterization of energy bicyclobutanes. the catalytic activities of the N terminus of the fusion protein, the heme-containing domain with sequence similarity to catalase. catalase ͉ carbocation ͉ epoxide ͉ leukotriene ͉ bicyclobutonium ion This unusual enzyme utilizes the 9R-hydroperoxylinolenic acid (C18.3␻3) product of the LOX domain as a substrate and he ability of lipoxygenase (LOX) enzymes to oxygenate converts it to two epoxy fatty acids, the major one of which Tpolyunsaturated fatty acids to specific fatty acid hydroper- contains a bicyclic four-carbon ring. Its synthesis has important oxides is used throughout the eukaryotic world for the produc- implications for the possible existence of novel carbocation tion of signaling molecules and other complex products (1–4). rearrangements in both chemistry and biology. The initial hydroperoxy fatty acid product is often further transformed to a highly unstable biosynthetic intermediate. Results Thus, plants express specialized cytochrome P450 enzymes of Protein Sequences and Alignments. The novel hemoprotein from the CYP74 family that convert hydroperoxy-C18 fatty acids to Anabaena and the AOS domain from the coral Plexaura homomalla allene oxides, the best characterized of which is an intermediate share an overall 35% amino acid identity. Particularly significant in biosynthesis of the hormone jasmonic acid (5). In the leuko- matches are conserved around the distal heme His residue and the cytes of higher animals, the 5-LOX enzyme forms the initial distal heme Asn [supporting information (SI) Fig. 5]. A very 5-hydroperoxy-C20.4 product and converts it into the highly significant mismatch occurs around the heme proximal ligand, unstable epoxide leukotriene A4 (LTA4), from which the other leukotriene family members arise (6). As yet another facet of this theme, marine corals express a natural fusion protein (7) in Author contributions: A.R.B. designed research; C.S., K.N., W.E.B., M.V., and D.F.S. per- CHEMISTRY formed research; C.S., K.N., W.E.B., M.V., D.F.S., N.A.P., and A.R.B. analyzed data; and C.S., which a LOX domain converts arachidonic acid to its 8R- N.A.P., and A.R.B. wrote the paper. hydroperoxide and a catalase-related domain effects a further The authors declare no conflict of interest. transformation to an unstable allene oxide, a potential interme- This article is a PNAS Direct Submission. diate in formation of marine prostanoids (8). This catalase- ‡To whom correspondence should be addressed at: Department of Pharmacology, Vander- related domain of the coral fusion protein is structurally similar bilt University School of Medicine, 23rd Avenue South at Pierce, Nashville, TN 37232-6602. to true catalases (9) yet quite distinct in function. Based on the E-mail: [email protected]. knowledge that the plant CYP74 enzyme family exhibits a This article contains supporting information online at www.pnas.org/cgi/content/full/ spectrum of catalytic reactions, including formation of allene 0707148104/DC1. BIOCHEMISTRY oxides, aldehydes, or vinyl ethers (10, 11), there is the possibility © 2007 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0707148104 PNAS ͉ November 27, 2007 ͉ vol. 104 ͉ no. 48 ͉ 18941–18945 Downloaded by guest on September 25, 2021 A B C ω λ Fig. 1. Preparation, purification, and UV analysis of unstable epoxides. An ice-cold solution of 9R-hydroperoxylinolenic acid (90 ␮M) in 10 ml of ice-cold hexane was vortex-mixed for 2 min with Anabaena catalase–LOX enzyme (0.8 nmol) in 0.2 ml of phosphate buffer, pH 8; reaction with the same sample of enzyme was repeated twice more using fresh substrate in ice-cold hexane. The combined hexane phases were evaporated to Ϸ2 ml under a strong stream of nitrogen, treated with diazomethane and 1% ethanol for 10 s at 0°C, and then evaporated to dryness and stored in hexane at Ϫ70°C. (A) UV spectrum of the hydroperoxy substrate in hexane before reaction and the hexane phase after mixing with enzyme. (B) Reversed-phase HPLC analysis of the product methyl esters with UV detection at 205 and 270 nm. A Waters Symmetry C18 column (25 ϫ 0.46 cm) was eluted with methanol/20 mM aqueous triethylamine at pH 8 [80:20 (vol/vol)] at a flow rate of 1 ml/min. (C) Normalized UV spectra of the two main products. which is a Tyr in the coral AOS, as is characteristic of all catalase mophores, one near 200 nm and the other with ␭max at 278 nm family members, yet by alignment this residue is replaced by His in characteristic of the leukotriene A class of allylic epoxides (Fig. Anabaena. Remarkably, therefore, the Anabaena sequence appears 1A) (18). The resulting hexane extract was treated with dia- to represent a His-ligated heme in the context of a catalase-related zomethane for 10 s at 0°C to form the methyl ester derivative (19) protein framework. We should note that, whereas Anabaena is a and the fatty acid derivatives subsequently analyzed by reversed- prokaryotic cyanobacterium and other cyanobacteria are found as phase HPLC using conditions adapted from a method for symbionts in corals (13), the P. homomalla AOS–LOX is unam- analysis of synthetic leukotriene A4 (Fig. 1B) (20). HPLC biguously eukaryotic based on the presence of multiple introns in analysis showed near quantitative conversion to two products, the DNA (unpublished observations). Nonetheless, such coexist- present in a 2:1 ratio as determined by using a 14C substrate. The ence could have provided the opportunity for an earlier gene more prominent product 1 displays a UV spectrum with end transfer one way or the other. absorbance extending beyond 230 nm, and product 2 has the spectrum of a conjugated triene, ␭max 278 nm (Fig. 1C). LC-MS Expression and Purification of the Anabaena Fusion Protein. We analysis using positive ion electrospray ionization revealed that expressed the whole Anabaena fusion protein as well as the the two products have the same molecular weight (306 for the isolated LOX domain in Escherichia coli and partially purified methyl ester) as indicated by their identical adduct ions with the proteins by nickel affinity chromatography by using N- sodium, potassium, and triethylamine. terminal His6-tags; (expression of the catalase-related domain by itself gave protein containing no heme and exhibiting no cata- Identification of the Major Allylic Epoxide Product.
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