Acyl-CoA dehydrogenases (ACDs) are FAD-dependent enzymes that catalyze the conversion of an appropriate fatty acyl-CoA thioester substrate to the corresponding trans-α,β-enoyl-CoA product. Early studies have shown that the dehydrogenation is stereospecific and is initiated by the abstraction of the pro-R α-H, followed by the transfer of the pro-R β-H, as a hydride equivalent, to the bound FAD. However, recent studies of the inactivation of ACDs by a metabolite of hypoglycin A, (methylenecyclopropyl)acetyl-CoA (MCPA-CoA), led to an alternative mechanism in which the reducing equivalent is delivered from the initially formed α-anion to the bound FAD via a single electron transfer process. To further explore the observed mechanistic discrepancy, we have reexamined the inhibitory properties of a closely related MCPA-CoA analogue, spiropentylacetyl-CoA (SPA-CoA), which was previously reported as a tight-binding inhibitor for ACDs. In contrast to early results, our data showed that SPA-CoA is a mechanism-based inhibitor for pig kidney medium-chain acyl-CoA dehydrogenase (MCAD) and Megasphaera elsdenii short-chain acyl-CoA dehydrogenase (SCAD) and that the inactivation is time-dependent, active-site-directed, and irreversible. More importantly, both (R)- and (S)-SPA-CoA could effectively inactivate MCAD, and the resulting inhibitor−FAD adducts appear to have one of the three-membered rings of the spiropentyl moiety cleaved. Since the inactivation is nonstereospecific with respect to Cβ−C bond scission, the ring opening of SPA-CoA leading to enzyme inactivation is likely initiated by a spiropentylcarbinyl radical. Such a radical-induced ring fragmentation is expected to be extremely facile and may bypass the chiral discrimination normally imposed by the enzyme. Thus, these results are consistent with our early notion that MCAD is capable of mediating one-electron redox chemistry. Interestingly, it was also found that (R)-SPA-CoA is an irreversible inhibitor for SCAD, while the S-epimer is only a competitive inhibitor for the same enzyme. The selective inhibition exhibited by these compounds against two closely related dehydrogenases is likely a consequence of the distinct steric and electronic demands imposed by the active sites of MCAD and SCAD. Such information is important for the design of novel class-selective inhibitors to control and/or regulate fatty acid metabolism.
One of nature's designs to control the European corn borer (Ostrinia nubilalis) population involves deployment of its natural enemy, the larval parasitoid Macrocentrus grandii.1 In light of the increasing emphasis toward more ecologically sound methods of solving agricultural problems,2 an approach analogous to that employed by nature in containing the population, and hence, the damage inflicted by the corn borer, is quite appealing.3 This particular strategy hinges on enhancing the fluctuating M. grandii population, and toward this objective, an exploration of the insect's courtship behavior, as well as the chemical nature of their sex pheromones, could be beneficial. Recently, a tetrahydropyranone derivative, (3S*,5fi*,6S*)-3,5-dimethyl-6-isopropyl-2,4,5,6-tetrahydropyran-2-one (1), had been isolated and identified as the third and most interesting component of the M. grandii sex pheromone.4 Of particular interest is the structural similarity of the isolated tetrahydropyranone from this insect with the Prelog-Djerassi lactonic acid 2, a wellknown oxidative degradation product of a number of microbial macrolide antibiotics.5 In order to confirm the identity of this natural product, as well as to establish its absolute stereochemistry, the two possible enantiomers(1) (a) Chiang, H. C.;
In a previous study we reported identification of (3R*,5S*,6R*)-3,5-dimethyl-6-(methylethyl)-3,4,5,6-tetrahydropyran-2-one as a component of the pheromone ofMacrocentrus grandii Goidanich. The lactone was present in male and female wasps, and laboratory and field bioassays demonstrated that both sources of the lactone elicit flight initiation, upwind anemotaxis, and casting in male wasps. In the present study, the synthetic (3R,5S,6R)- and (3S,5R,6S)-lactone enantiomers (RSR andSRS, respectively) were bioassayed for biological activity. In wind tunnel studies theSRS enantiomer elicited flight initiation, upwind anemotaxis, and casting by male wasps comparable to lactone derived from male and female wasps. Flight response to theRSR enantiomer averaged 14 percent of theSRS enantiomer. No specific ratio of the stereoisomers was found more attractive than theSRS enantiomer alone. Field studies demonstrated theSRS enantiomer was active alone in attracting male wasps. When paired with (Z)-4-tridecenal (a previously identified female-derived sex pheromone), theSRS enantiomer yielded a synergistic response comparable to (Z)-4-tridecenal plus female-derived lactone.
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