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Rearrangements in the Mechanisms of the Indole Alkaloid Prenyltransferases*

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Rearrangements in the Mechanisms of the Indole Alkaloid Prenyltransferases* Pure Appl. Chem., Vol. 85, No. 10, pp. 1935–1948, 2013. http://dx.doi.org/10.1351/PAC-CON-13-02-02 © 2013 IUPAC, Publication date (Web): 29 July 2013 Rearrangements in the mechanisms of the indole alkaloid prenyltransferases* Niusha Mahmoodi, Qi Qian, Louis Y. P. Luk, and Martin E. Tanner‡ Department of Chemistry, University of British Columbia, Vancouver, British Columbia, V6T 1Z1, Canada Abstract: The indole prenyltransferases are a family of metal-independent enzymes that cat- alyze the transfer of a prenyl group from dimethylallyl diphosphate (DMAPP) onto the indole ring of a tryptophan residue. These enzymes are remarkable in their ability to direct the prenyl group in either a “normal” or “reverse” fashion to positions with markedly differ- ent nucleophilicity. The enzyme 4-dimethylallyltryptophan synthase (4-DMATS) prenylates the non-nucleo philic C-4 position of the indole ring in free tryptophan. Evidence is presented in support of a mechanism that involves initial ion pair formation followed by a reverse prenylation at the nucleophilic C-3 position. A Cope rearrangement then generates the C-4 normal prenylated intermediate and deprotonation rearomatizes the indole ring. The enzyme tryprostatin B synthase (FtmPT1) catalyzes the normal C-2 prenylation of the indole ring in brevianamide F (cyclo-L-Trp-L-Pro). It shares high structural homology with 4-DMATS, and evidence is presented in favor of an initial C-3 prenylation (either normal or reverse) followed by carbo cation rearrangements to give product. The concept of a common intermediate that partitions to different products via rearrangements can help to explain how these evolution- arily related enzymes can prenylate different positions on the indole ring. Keywords: alkaloids; carbocation rearrangement; Cope rearrangement; enzymes; indole alka- loids; mechanism; prenyltransferase. INTRODUCTION The indole alkaloids are a diverse family of natural products that are derived from the amino acid tryp- tophan (Fig. 1). Many of these compounds possess potent biological activities and have long been used as human therapeutics, poisons, and psychedelic drugs. In many cases, the indole core has been pre - nylated to give the isoprenoid indole alkaloids [1–3]. Perhaps the best known of these compounds is ergotamine, which is produced from the ergot fungus, Claviceps purpurea. The ingestion of grain prod- ucts that are contaminated with this fungus and contain ergot alkaloids leads to a gangrenous poisoning called ergotism, or Saint Anthony’s fire. Taken in controlled doses, however, ergotamine acts as a vaso- constrictor and can be used in the treatment of migraine headaches. Finally, a semi-synthetic version of an ergot alkaloid, lysergic acid diethylamide or LSD, has been used as a recreational psychedelic drug. *Pure Appl. Chem. 85, 1919–2004 (2013). A collection of invited papers based on presentations at the 21st International Conference on Physical Organic Chemistry (ICPOC-21), Durham, UK, 9–13 September 2012. ‡Corresponding author: Mailing address: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia, V6T 1Z1, Canada 1935 1936 N. MAHMOODI et al. Fig. 1 Examples of prenylated indole alakloids. While many of the advanced steps in the biosynthesis of the complex indole alkaloids are still poorly understood, great advances in outlining the early steps have recently been reported. This is clearly the case with the isoprenoid indole alkaloids where the Li group has recently identified a large family of fungal prenyltransferases responsible for the prenylation of the indole ring [2,4,5]. While all of these enzymes share sequence similarities and a common ancestry, they display a remarkable diver- sity in the regiochemistry of the alkylation reaction. The five-carbon isoprene unit may be attached via the primary carbon to give a “normal” prenylated product or via the tertiary carbon to give a “reverse” prenylated product. In addition, examples of enzymes that are able to catalyze prenylation (either nor- mal, reverse, or both) at each of the seven potential positions on the indole ring have now been identi- fied (Fig. 2) [6]. Many of these enzymes act on free tryptophan, while others act on cyclic dipeptides or benzodiazopinediones containing Trp residues. Fig. 2 Examples of indole prenyltransferases that act on either free L-tryptophan or on cyclic dipeptides. © 2013, IUPAC Pure Appl. Chem., Vol. 85, No. 10, pp. 1935–1948, 2013 Indole alkaloid prenyltransferases 1937 An interesting aspect of these reactions is that the nucleophilicity of the various positions around the indole ring varies quite dramatically, yet Nature has discovered how to modify each of them selec- tively. The prenyl group donor is dimethylallyl diphosphate (DMAPP), which can ionize to give pyrophosphate and the dimethylallyl cation. This cation could participate in an electrophilic aromatic substitution reaction directly at the site of substitution. For a reverse prenylation, the aromatic ring would attack the tertiary carbon, and for a normal prenylation it would attack the primary carbon. The control over regioselectivity would be dictated by a careful positioning of the dimethylallyl cation within the active site. In order to promote prenylation at the least nucleophilic positions, the cation would have to be kept distant from the more nucleophilic positions (such as the indole C-3). While such a mechanism could be proposed for each of these enzymes, recent structural and mechanistic studies suggest that in some cases the carbocation adds to the nucleophilic C-3 position, and a subsequent rearrangement then occurs to migrate the prenyl group to an alternate position. Two such enzymes will be described in the following sections. A POTENTIAL COPE REARRANGEMENT IN THE REACTION CATALYZED BY DIMETHYLALLYLTRYPTOPHAN SYNTHASE The first of the indole prenyltransferases to be identified, and the most extensively studied from a mech- anistic point of view, is 4-dimethylallyltryptophan synthase (4-DMATS) [7–9]. This enzyme converts DMAPP and tryptophan into 4-dimethylallyltryptophan during the first step in the biosynthesis of the ergot alkaloids (Fig. 3) [10,11]. The enzyme is of interest from a mechanistic point of view since the C-4 position is one of the most weakly nucleophilic positions on the indole ring. Unlike most preny- transferases, this enzyme was reported to be active in metal-free buffers. Early mechanistic studies by Floss and co-workers demonstrated that the reaction proceeded with an inversion of stereochemistry at the methylene carbon of DMAPP [12]. In addition, the Poulter group showed that fluorination of either the indole ring, or the methyl groups of DMAPP, slowed the reaction, consistent with an electrophilic addition mechanism [13]. Thus, it was proposed that the DMAPP first ionizes to give the dimethylallyl Fig. 3 Proposed mechanisms for the 4-DMATS reaction involving a direct prenylation at C-4. Path A is an SN1-like mechanism involving a discrete carbocation intermediate. Path B is an SN2-like mechanism involving an “exploded” transition state and no distinct carbocation intermediate. © 2013, IUPAC Pure Appl. Chem., Vol. 85, No. 10, pp. 1935–1948, 2013 1938 N. MAHMOODI et al. carbocation and a subsequent electrophilic addition to the C-4 position of the indole ring gives an are- nium ion intermediate (Fig. 3, Path A). Deprotonation of the arenium ion causes rearomatization and product formation. Further studies on this enzyme were hampered by difficulties in producing recombinant protein on a large scale. A breakthrough came in the mid-2000s when the Li group demonstrated that 4-DMATS from the fungus Aspergillus fumigatus (FgaPT2) could be overproduced in Escherichia coli [7,14]. By this point, it was clear that this enzyme was a member of a larger family of indole prenyl- transferases that operated in a metal-independent fashion and that lacked the characteristic (N/D)DXXD diphosphate binding site of other prenyltransferases [2,4,5]. The ability to obtain these recombinant enzymes, many for the first time, has rejuvenated interest in mechanistic studies on the indole prenyl- transferases and in their potential use in the synthesis of unusual alkaloids. The SN1-like mechanism shown in Fig. 3, Path A predicts that the 4-DMATS reaction is initiated by the ionization of DMAPP to form a discrete dimethylallyl carbocation intermediate. This is similar to the accepted mechanism for farnesyl pyrophosphate synthase where ionization precedes attack by a poorly nucleophilic alkene [15,16]. An alternative possibility is that the indole nucleophile directly attacks DMAPP in an SN2 fashion and displaces pyrophosphate without carbocation formation (Fig. 3, Path B). This is similar to the mechanism proposed for protein farnesyltransferase where an excellent nucleophile (a cysteine thiolate) is prenylated by farnesyl diphosphate [17,18]. In order to provide evi- dence for the existence of a dimethylallyl carbocation intermediate in this reaction a positional isotope exchange (PIX) reaction was performed (Fig. 4) [19]. In this experiment a sample of isotopically labeled DMAPP is synthesized in which an 18O isotope is positioned in a “bridging” position between the prenyl group and the phosphorus atom (see darkened atoms in Fig. 4). This material is treated with 4-DMATS and L-Trp, and the reaction is allowed to proceed until approximately 70 % of the labeled DMAPP has been consumed. Analysis of the recovered DMAPP is performed in order to determine if any of the 18O label has scrambled from a bridging position into a nonbridging position. This is read- ily done using 31P NMR spectroscopy as an 18O isotopic substitution causes a chemical shift in the phosphorus signal and the magnitude of that shift is dependent on the magnitude of the P–O bond order (greater in the nonbridging material) [20]. In the case of 4-DMATS, this analysis indicated that approx- imately 15 % of the recovered starting material contained isotopic label that had scrambled into a non- bridging position, indicating that a reversible P–O bond cleavage event was occurring. While the Fig.
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