Inhibitory Investigations of Acyl-CoA Derivatives against Human Lipoxygenase Isozymes.
Inhibitory Investigations of Acyl-CoA Derivatives against Human Lipoxygenase Isozymes.
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DOI：
10.3390/ijms241310941
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发表时间：
2023-06-30
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
脂质代谢是一个对能量产生至关重要的复杂过程，会导致细胞内酰基辅酶A（acyl - CoA）分子水平升高。酰基辅酶A也与炎症有关，通过冷冻电镜观察到一种酰基辅酶A与人血小板12 - 脂氧合酶结合，这可能与脂氧合酶（LOX）的生物化学过程相关。鉴于脂氧合酶同工酶在炎症中起关键作用，对酰基辅酶A对脂氧合酶同工酶的抑制作用进行更深入的研究被认为是有必要的。随后，确定C18酰基辅酶A衍生物对人12 - 脂氧合酶（h12 - LOX）、人网织红细胞15 - 脂氧合酶 - 1（h15 - LOX - 1）和人内皮15 - 脂氧合酶 - 2（h15 - LOX - 2）抑制作用最强，而C16酰基辅酶A对人5 - 脂氧合酶抑制作用更强。具体而言，油酰辅酶A（18:1）对h12 - LOX（半数抑制浓度IC50 = 32 μM）和h15 - LOX - 2（IC50 = 0.62 μM）抑制作用最强，硬脂酰辅酶A对h15 - LOX - 1（IC50 = 4.2 μM）抑制作用最强，棕榈油酰辅酶A对h5 - LOX（IC50 = 2.0 μM）抑制作用最强。进一步确定油酰辅酶A对h15 - LOX - 2的抑制为别构抑制，抑制常数Ki为82 ± 70 nM，α为3.2 ± 1，β为0.30 ± 0.07，β/α = 0.09。有趣的是，亚油酰辅酶A（18:2）对h5 - LOX、h12 - LOX和h15 - LOX - 1是一种弱抑制剂，但对h15 - LOX - 1是一种快速底物，其动力学速率与游离亚油酸相当（催化常数kcat = 7.5 ± 0.4 s⁻¹，kcat / KM = 0.62 ± 0.1 µM⁻¹s⁻¹）。此外，还确定甲基化脂肪酸不是底物，而是弱抑制剂。这些发现表明酰基辅酶A在细胞内脂氧合酶活性的调节中具有更重要的作用，要么是通过抑制新型氧化脂质种类，要么是作为氧化脂质 - 辅酶A的新来源。
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 (IC50 = 32 μM) and h15-LOX-2 (IC50 = 0.62 μM), stearoyl-CoA against h15-LOX-1 (IC50 = 4.2 μM), and palmitoleoyl-CoA against h5-LOX (IC50 = 2.0 μM). The inhibition of h15-LOX-2 by oleoyl-CoA was further determined to be allosteric inhibition with a Ki 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 (kcat = 7.5 +/− 0.4 s−1, kcat/KM = 0.62 +/− 0.1 µM−1s−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.
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DOI：
10.1016/j.bbalip.2014.10.002
发表时间：
2015-04
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Kuhn H;Banthiya S;van Leyen K
通讯作者：
van Leyen K
影响因子：
3.7
作者：
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Podestá EJ
DOI：
10.1016/j.bbalip.2010.08.002
发表时间：
2010-12
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Bannenberg G;Serhan CN
通讯作者：
Serhan CN
影响因子：
5.1
作者：
Amagata, T;Whitman, S;Holman, TR
通讯作者：
Holman, TR
影响因子：
2.9
作者：
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通讯作者：
Holman, Theodore