BIOSYNTHESIS OF PARAHERQUAMIDES & BREVIANAMIDES

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The SIR provided [1_13C, 90%proline; . 15g [1_13C, 98%]tryp; .35g [U_13C, ?9]isoleucine;. 159g The paraherquamides are complex, heptacyclic, toxic mold metabolites, isolated from various Penicillium sp.The brevianamides A and B are structurally related natural products that display potent insecticidal activity. The brevianamides are also produced by Penicillium sp. molds. We are pursuing the identification of a new mechanistic class of enzymes that are involved in constructing the bicyclo [2.2.21 nucleus of the brevianamides/paraherquamides. We have obtained compelling experimental evidence that this unique ring system is very possible constructed via an enzyme-catalyzed intramolecular Diels-Alder cycloaddition reaction. Despite its widespread use in synthetic organic chemistry, the Diels-Alder cycloaddition reaction does not occur frequently in nature and there is not a single documented example of an enzyme that catalyzes this most ubiquitous synthetic ring-forming reaction. The Penicillium sp. that produces the brevianamides/paraherquamides may be a rare, but vitally important example of the existence of Diels-Alderases. One of the most significant objectives of this project is to characterize this rare catalyzed, biosynthetic construction. Using amino acids provided to us by the SIR, we have established that the 0-methyl proline ring in paraherquamide is derived from L-He and not via the SAM-methylation of L-proline. In addition , we have recently shown that L-tryptophan is the biosynthetic precursor to the dioxepin oxindole half of paraherquamide and that the N-methyl group is derived from L-Met. We have previously synthesized the tritiated piperazinedione and have demonstrated that this substance is efficiently incorporated into brevianamides A and B. Our current efforts are directed toward synthesizing the P-methyloproline derivatives containing 13C-labels for biosynthetic feeding experiments. We wish to establish the exact pathway by which the L-Ile is converted into P-methyloproline and thence, into paraherquamide A.