Background: The molecular etiology of Pseudoxanthoma Elasticum (PXE), an autosomal recessive connective tissue disorder, has become increasingly complex as not only mutations in the ABCC6, but also in ENPP1 and GGCX, can cause resembling phenotypes.

Methods: To get insights on the common pathway, the overlapping metabolites for these three proteins were predicted through 3D homology modeling and virtual screening. 3D homology models of ABCC6, ENPP1, and GGCX were generated by the MODELLER program, which were further validated using RAMPAGE and ERRAT servers. Substrate binding sites of ABCC6 were predicted using blind docking of reported in vitro substrates.

Results: Virtual screening against the substrate binding site of ABCC6 using metabolites listed in Human Metabolome Databases (HMDB) revealed the best possible substrate of ABCC6. Those listed metabolites were further docked against predicted substrate binding sites of GGCX and ENPP1. Molecular docking and virtual screening revealed a list of 133 overlapping metabolites of these three proteins. Most of them are Phosphatidylinositol (PI), Phosphatidylserine (PS), Diacylglycerol (DAG), phosphatidic acid, oleanolic acid metabolites and were found to have links with calcification.

Conclusion: These predicted overlapping metabolites may give novel insights for searching common pathomechanism for PXE and PXE-like diseases.

背景：常染色体隐性结缔组织疾病弹性假黄瘤（PXE）的分子病因变得越来越复杂，因为不仅ABCC6中的突变，而且ENPP1和GGCX中的突变都可能引起相似的表型。

方法：为了了解常见途径，通过3D同源性建模和虚拟筛选预测了这三种蛋白质的重叠代谢产物。通过MODELLER程序生成了ABCC6，ENPP1和GGCX的3D同源性模型，并使用RAMPAGE和ERRAT服务器对其进行了进一步验证。ABCC6的底物结合位点使用已报道的体外底物的盲对接进行预测。

结果：使用人类代谢组数据库（HMDB）中列出的代谢物对ABCC6的底物结合位点进行了虚拟筛选，发现了ABCC6的最佳底物。那些列出的代谢物进一步与GGCX和ENPP1的预期底物结合位点对接。分子对接和虚拟筛选揭示了这三种蛋白质的133种重叠代谢物的列表。其中大多数是磷脂酰肌醇（PI），磷脂酰丝氨酸（PS），二酰基甘油（DAG），磷脂酸，齐墩果酸代谢产物，并发现与钙化有关。

结论：这些预测的重叠代谢物可能为寻找PXE和PXE样疾病的常见病机提供新的见解。