Two distinct pathways of formation of 4-hydroxynonenal - Mechanisms of nonenzymatic transformation of the 9-and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals
Two distinct pathways of formation of 4-hydroxynonenal - Mechanisms of nonenzymatic transformation of the 9-and 13-hydroperoxides of linoleic acid to 4-hydroxyalkenals
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DOI：
10.1074/jbc.m101821200
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发表时间：
2001-06-15
影响因子：
4.8
通讯作者：
Brash, AR
中科院分区：
文献类型：
--
作者：
Schneider, C;Tallman, KA;Brash, AR
自从1980年4-羟基-2E-壬烯醛(4-HNE)被发现是脂质过氧化的主要细胞毒性产物以来，其形成机制一直存在争议，最近的证据表明4-羟基-2E-壬烯醛(4-HPNE)是4-HNE的直接前体(Lee，S，H.，和Blair，I.A.(2000)Chem.Toxicol资源。13,698-702；Noordermeer，M.A.，Feussner，I.，Kolbe，A.，Veldink，G.A.和Vliegenthart，J.F.G.(2800)Biochem，BiPhys，Res.Commun，277,112-116)，以及通过9-羟基过氧亚油酸和3Z-壬烯醛的途径在植物提取物中被识别。以亚油酸的9-和13-羟基过氧化氢为起始原料，我们发现两种不同的机制导致茶叶生成4-H(P)NE和相应的保留原有羧基的4-氢(过氧基-12-氧-10E-十二烷酸)，手性分析表明，由13S-羟基过氧基-9Z，11E-十八碳二烯酸(13S-HPODE)形成的4-HPNE保留>；90%的S构型，而9S-羟基-10E，12Z-十八碳二烯酸(9S-HPODE)，9-羟基-12-氧代-10E-十二烯酸几乎是外消旋；90%的S来源于9S-HPODE，几乎外消旋来源于13S-HPODE，通过中间体和产物的分析，我们提供了证据：(1)13S-HPODE在C-8上的烯丙基氢提取导致10，13-二氢过氧化氢在C-9和C-10之间发生裂解得到4S-HPNE，而13S-HPODE直接Hock裂解得到12-氧代-9Z-十二烯酸，氧化生成外消旋的9-羟基过氧基-12-氧代-10E-十二烯酸；相反，(Ii)9S-HPODE作为外消旋4-HPNE的前体直接裂解为3Z-壬烯醛，而C-14上的烯丙基抽氢和9，12-二氢过氧化氢的氧化生成手性9S-羟基过氧基-12-氧代-10E-十二烯酸。我们的结果区分了两条形成4-HNE的主要途径，这两条途径也应该适用于其他脂肪酸过氧化氢。观察到的手性与上述机制中预测的手性略有不同(类似于10%)，这表明存在通往4-羟基烯的其他途径。
The mechanism of formation of 4-hydroxy-2E-nonenal (4-HNE) has been a matter of debate since it was discovered as a major cytotoxic product of lipid peroxidation in 1980, Recent evidence points to 4-hydroperoxy-2E-nonenal (4-HPNE) as the immediate precursor of 4-HNE (Lee, S, H., and Blair, I. A. (2000) Chem. Res. Toxicol. 13, 698-702; Noordermeer, M. A., Feussner, I., Kolbe, A., Veldink, G. A., and Vliegenthart, J. F. G. (2800) Biochem, Biophys, Res. Commun, 277, 112-116), and a pathway via 9-hydroperoxylinoleic acid and 3Z-nonenal is recognized in plant extracts. Using the 9- and 13-hydroperoxides of linoleic acid as starting material, we find that two distinct mechanisms lead tea the formation of 4-H(P)NE and the corresponding 4-hydro(pero)xyalkenal that retains the original carboxyl group (9-hydroperoxy-12-oxo-10E-dodecsnoic acid), Chiral analysis revealed that 4-HPNE formed from 13S-hydroperoxy-9Z,11E-octadecadienoic acid (13S-HPODE) retains >90% S configuration, whereas it is nearly racemic from 9S-hydroperoxy-10E,12Z-octadecadienoic acid (9S-HPODE), 9-Hydroperoxy-12-oxo-10E-dodecenoic acid is >90% S when derived from 9S-HPODE and almost racemic from 13S-HPODE, Through analysis of intermediates and products, we provide evidence that (i) allylic hydrogen abstraction at C-8 of 13S-HPODE leads to a 10,13-dihydroperoxide that undergoes cleavage between C-9 and C-10 to give 4S-HPNE, whereas direct Hock cleavage of the 13S-HPODE gives 12-oxo-9Z-dodecenoic acid, which oxygenates to racemic 9-hydroperoxy-12-oxo-10E-dodecenoic acid; by contrast, (ii) 9S-HPODE cleaves directly to 3Z-nonenal as a precursor of racemic 4-HPNE, whereas allylic hydrogen abstraction at C-14 and oxygenation to a 9,12-dihydroperoxide leads to chiral 9S-hydroperoxy-12-oxo-10E-dodecenoic acid. Our results distinguish two major pathways to the formation of 4-HNE that should apply also to other fatty acid hydroperoxides. Slight (similar to 10%) differences in the observed chiralities from those predicted in the above mechanisms suggest the existence of additional routes to the 4-hydroxyalkenals.