Inhibitory Investigations of Acyl-CoA Derivatives against Human Lipoxygenase Isozymes
- Author(s)
- Tran, M; Yang, K; Glukhova, A; Holinstat, M; Holman, T;
- Details
- Publication Year 2023-06-30,Volume 24,Issue #13,Page 10941
- Journal Title
- International Journal of Molecular Sciences
- Abstract
- Lipid metabolism is a complex process crucial for energy production resulting in high levels of acyl-coenzyme A (acyl-CoA) molecules in the cell. Acyl-CoAs have also been implicated in inflammation, which could be possibly linked to lipoxygenase (LOX) biochemistry by the observation that an acyl-CoA was bound to human platelet 12-lipoxygenase via cryo-EM. Given that LOX isozymes play a pivotal role in inflammation, a more thorough investigation of the inhibitory effects of acyl-CoAs on lipoxygenase isozymes was judged to be warranted. Subsequently, it was determined that C18 acyl-CoA derivatives were the most potent against h12-LOX, human reticulocyte 15-LOX-1 (h15-LOX-1), and human endothelial 15-LOX-2 (h15-LOX-2), while C16 acyl-CoAs were more potent against human 5-LOX. Specifically, oleoyl-CoA (18:1) was most potent against h12-LOX (IC(50) = 32 μM) and h15-LOX-2 (IC(50) = 0.62 μM), stearoyl-CoA against h15-LOX-1 (IC(50) = 4.2 μM), and palmitoleoyl-CoA against h5-LOX (IC(50) = 2.0 μM). The inhibition of h15-LOX-2 by oleoyl-CoA was further determined to be allosteric inhibition with a K(i) of 82 +/- 70 nM, an α of 3.2 +/- 1, a β of 0.30 +/- 0.07, and a β/α = 0.09. Interestingly, linoleoyl-CoA (18:2) was a weak inhibitor against h5-LOX, h12-LOX, and h15-LOX-1 but a rapid substrate for h15-LOX-1, with comparable kinetic rates to free linoleic acid (k(cat) = 7.5 +/- 0.4 s(-1), k(cat)/K(M) = 0.62 +/- 0.1 µM(-1)s(-1)). Additionally, it was determined that methylated fatty acids were not substrates but rather weak inhibitors. These findings imply a greater role for acyl-CoAs in the regulation of LOX activity in the cell, either through inhibition of novel oxylipin species or as a novel source of oxylipin-CoAs.
- Publisher
- MDPI
- Keywords
- acyl-coenzyme A; inhibition; lipoxygenase
- Research Division(s)
- Structural Biology
- PubMed ID
- 37446119
- Publisher's Version
- https://doi.org/10.3390/ijms241310941
- Open Access at Publisher's Site
https://doi.org/10.3390/ijms241310941- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-07-21 09:41:28
Last Modified: 2023-07-21 09:48:34