Spiropentylacetyl-CoA, a mechanism-based inactivator of acyl-CoA dehydrogenases
Ding Li, Hui Qiang Zhou, Srikanth Dakoji, Injae Shin, Eugene Oh, Hung Wen Liu
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 de hydrogenation 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 metabolic 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 fight-binding inhibitor for ACDs. In contrast to early results, our data showed the 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 C(β)-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 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.
https://doi.org/10.1021/ja9737634
10.1021/ja9737634
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Acyl-CoA Chemistry 100%
Inhibitor Chemistry 60%
R Chemistry 40%
Medium-Chain Acyl-CoA Dehydrogenase Biochemistry, Genetics and Molecular Biology 40%
Acyl CoA Dehydrogenase Biochemistry, Genetics and Molecular Biology 40%
Lysozyme Biochemistry, Genetics and Molecular Biology 30%
Active Site Biochemistry, Genetics and Molecular Biology 20%
Li, D., Zhou, H. Q., Dakoji, S., Shin, I., Oh, E., & Liu, H. W. (1998). Spiropentylacetyl-CoA, a mechanism-based inactivator of acyl-CoA dehydrogenases. Journal of the American Chemical Society, 120(9), 2008-2017. https://doi.org/10.1021/ja9737634
Li, Ding ; Zhou, Hui Qiang ; Dakoji, Srikanth et al. / Spiropentylacetyl-CoA, a mechanism-based inactivator of acyl-CoA dehydrogenases. In: Journal of the American Chemical Society. 1998 ; Vol. 120, No. 9. pp. 2008-2017.
@article{8a6d83c768e2411d857e5f9bae640232,
title = "Spiropentylacetyl-CoA, a mechanism-based inactivator of acyl-CoA dehydrogenases",
abstract = "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 de hydrogenation 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 metabolic 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 fight-binding inhibitor for ACDs. In contrast to early results, our data showed the 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 C(β)-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 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.",
author = "Ding Li and Zhou, {Hui Qiang} and Srikanth Dakoji and Injae Shin and Eugene Oh and Liu, {Hung Wen}",
doi = "10.1021/ja9737634",
journal = "Journal of the American Chemical Society",
Li, D, Zhou, HQ, Dakoji, S, Shin, I, Oh, E & Liu, HW 1998, 'Spiropentylacetyl-CoA, a mechanism-based inactivator of acyl-CoA dehydrogenases', Journal of the American Chemical Society, vol. 120, no. 9, pp. 2008-2017. https://doi.org/10.1021/ja9737634
Spiropentylacetyl-CoA, a mechanism-based inactivator of acyl-CoA dehydrogenases. / Li, Ding; Zhou, Hui Qiang; Dakoji, Srikanth et al.
In: Journal of the American Chemical Society, Vol. 120, No. 9, 11.03.1998, p. 2008-2017.
T1 - Spiropentylacetyl-CoA, a mechanism-based inactivator of acyl-CoA dehydrogenases
AU - Li, Ding
AU - Zhou, Hui Qiang
AU - Dakoji, Srikanth
AU - Shin, Injae
AU - Oh, Eugene
AU - Liu, Hung Wen
N2 - 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 de hydrogenation 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 metabolic 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 fight-binding inhibitor for ACDs. In contrast to early results, our data showed the 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 C(β)-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 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.
AB - 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 de hydrogenation 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 metabolic 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 fight-binding inhibitor for ACDs. In contrast to early results, our data showed the 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 C(β)-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 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.
U2 - 10.1021/ja9737634
DO - 10.1021/ja9737634
JO - Journal of the American Chemical Society
JF - Journal of the American Chemical Society
Li D, Zhou HQ, Dakoji S, Shin I, Oh E, Liu HW. Spiropentylacetyl-CoA, a mechanism-based inactivator of acyl-CoA dehydrogenases. Journal of the American Chemical Society. 1998 Mar 11;120(9):2008-2017. doi: 10.1021/ja9737634