The UBIAD1 prenyltransferase links menaquinone-4 [corrected] synthesis to cholesterol metabolic enzymes.
The UBIAD1 prenyltransferase links menaquinone-4 [corrected] synthesis to cholesterol metabolic enzymes.
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DOI：
10.1002/humu.22230
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发表时间：
2013-03
期刊：
影响因子：
3.9
通讯作者：
Dean M
中科院分区：
文献类型：
--
作者：
Nickerson ML;Bosley AD;Weiss JS;Kostiha BN;Hirota Y;Brandt W;Esposito D;Kinoshita S;Wessjohann L;Morham SG;Andresson T;Kruth HS;Okano T;Dean M
施奈德角膜营养不良（SCD）是一种常染色体显性遗传疾病，其特征在于UBIAD 1中的种系变体引入错义改变，导致角膜中胆固醇沉积、进行性浑浊和视力丧失。UBIAD 1最近被证明可以合成甲基萘醌-4（MK-4，维生素K2），但SCD的致病机制尚不清楚。我们报告了一个新的c.864G>A UBIAD 1突变改变甘氨酸177谷氨酸（p.G177E）在六个SCD家庭，包括四个家庭来自芬兰谁共享一个可能的创始人突变。我们观察到通过SCD突变p.N102S、p.G177R/E和p.D112N改变的UBIAD 1的MK-4合成减少，并且分子模型显示p.G177突变的UBIAD 1破坏跨膜螺旋和活性位点残基。我们显示UBIAD 1相互作用与HMGCR和SOAT 1，酶催化胆固醇合成和储存，分别使用酵母双杂交筛选和免疫沉淀。对接模拟表明胆固醇在底物结合裂缝中与UBIAD 1结合，并且与GGPP结合（MK-4底物）重叠，表明这些代谢物之间存在潜在竞争。MK-4合成受损是SCD中鉴定的生化缺陷，表明UBIAD 1通过酶和代谢物之间的物理接触将维生素K和胆固醇代谢联系起来。我们的数据表明内源性MK-4在维持角膜健康和视力方面的作用。
Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by germline variants in UBIAD1 introducing missense alterations leading to deposition of cholesterol in the cornea, progressive opacification, and loss of visual acuity. UBIAD1 was recently shown to synthesize menaquinone-4 (MK-4, vitamin K2, but causal mechanisms of SCD are unknown. We report a novel c.864G>A UBIAD1 mutation altering glycine 177 to glutamic acid (p.G177E) in six SCD families, including four families from Finland who share a likely founder mutation. We observed reduced MK-4 synthesis by UBIAD1 altered by SCD mutations p.N102S, p.G177R/E, and p.D112N, and molecular models showed p.G177-mutant UBIAD1 disrupted transmembrane helices and active site residues. We show UBIAD1 interacts with HMGCR and SOAT1, enzymes catalyzing cholesterol synthesis and storage, respectively, using yeast two-hybrid screening and immunoprecipitation. Docking simulations indicate cholesterol binds to UBIAD1 in the substrate binding cleft and binding overlaps with GGPP binding, a MK-4 substrate, suggesting potential competition between these metabolites. Impaired MK-4 synthesis is a biochemical defect identified in SCD suggesting UBIAD1 links vitamin K and cholesterol metabolism through physical contact between enzymes and metabolites. Our data suggests a role for endogenous MK-4 in maintaining cornea health and visual acuity.
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影响因子：
7.1
作者：
Lamon-Fava, S;Sadowski, JA;Schaefer, EJ
通讯作者：
Schaefer, EJ
影响因子：
8
作者：
COLOVOS, C;YEATES, TO
通讯作者：
YEATES, TO
影响因子：
8.7
作者：
Gaynor, PM;Zhang, WY;Kruth, HS
通讯作者：
Kruth, HS
影响因子：
13.7
作者：
Kobayashi, Akira;Fujiki, Keiko;Sugiyama, Kazuhisa
通讯作者：
Sugiyama, Kazuhisa
DOI：
10.1161/01.atv.14.11.1737
发表时间：
1994-11-01
期刊：
ARTERIOSCLEROSIS AND THROMBOSIS
影响因子：
--
作者：
HOFFMAN, CJ;LAWSON, WE;HULTIN, MB
通讯作者：
HULTIN, MB