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首页> 外文期刊>Biochemistry >Characterization of Dihydro-A2PE: An intermediate in the A2E biosynthetic pathway
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Characterization of Dihydro-A2PE: An intermediate in the A2E biosynthetic pathway

机译：Dihydro-A2PE的表征：A2E生物合成途径中的中间体

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Bisretinoid lipofuscin pigments that accumulate in retinal pigment epithelial cells are implicated in the etiology of several forms of macular degeneration, including juvenile onset Stargardt disease, Best vitelliform macular degeneration, and age-related macular degeneration. One of these compounds, A2E, is generated by phosphate hydrolysis of a phosphatidyl-pyridinium bisretinoid (A2PE) that forms within photoreceptor outer segments. Here, we demonstrate that the formation of the aromatic pyridinium ring of A2PE follows from the oxidation of a dihydropyridinium intermediate. Time-dependent density functional theory calculation, based on the structure of dihydro-A2E, produced a simulated UV-visible absorbance spectrum characterized by maxima of 494 and 344 nm. Subsequently, a compound exhibiting similar UV-visible absorbance maxima (lambda(max) 490 and 330 nm) was identified in the A2E biomimetic reaction mixture. By liquid chromatography-mass spectrometry (LC-MS) this bischromophore had the expected mass of the dihydro-pyridinium bisretinoid. The compound also exhibited the behavior of a biosynthetic intermediate since it formed in advance of the final product A2E and was consumed as A2E accumulated. Moreover, under deoxygenated conditions, conversion to the aromatic pyridinium bisretinoid was inhibited. Taken together, these findings indicate that A2E biosynthesis involves the oxidation of a dihydropyridinium intermediate dihydro-A2PE. An understanding of the biosynthetic pathways of retinal pigment epithelial lipofuscin pigments is critical to the development of therapies for macular degeneration that are based on limiting the formation of these damaging compounds.
机译：视网膜色素上皮细胞中积聚的类视黄醇脂褐素色素与多种黄斑变性的病因有关，包括青少年性Starstardt病，最佳玻璃状黄斑变性和年龄相关性黄斑变性。这些化合物之一A2E是通过在感光器外部片段中形成的磷脂酰吡啶鎓双视黄醛酸酯（A2PE）进行磷酸水解而生成的。在这里，我们证明了A2PE的芳族吡啶鎓环的形成是由于二氢吡啶鎓中间体的氧化。时变密度泛函理论计算基于二氢A2E的结构，产生了模拟的UV-可见吸收光谱，其最大特征是494和344 nm。随后，在A2E仿生反应混合物中鉴定出具有相似的UV-可见光吸收最大值（λ（最大值）490和330 nm）的化合物。通过液相色谱-质谱法（LC-MS），该双发色团具有预期质量的二氢吡啶鎓双维甲酸。该化合物还表现出生物合成中间体的性能，因为它在最终产物A2E之前形成并随着A2E的积累而被消耗。此外，在脱氧条件下，抑制了向芳族吡啶鎓双维甲酸的转化。综上所述，这些发现表明A2E的生物合成涉及二氢吡啶鎓中间体二氢-A2PE的氧化。视网膜色素上皮脂褐素色素的生物合成途径的理解对于黄斑变性治疗的发展至关重要，该疗法基于限制这些破坏性化合物的形成。

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