Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.
Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates.
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Smith-Lemli-Opitz综合征患者绕过胆固醇的胆汁酸生物合成：途径中间产物的潜在重要性。
DOI：
10.1016/j.jsbmb.2020.105794
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Abdel-Khalik J;Hearn T;Dickson AL;Crick PJ;Yutuc E;Austin-Muttitt K;Bigger BW;Morris AA;Shackleton CH;Clayton PT;Iida T;Sircar R;Rohatgi R;Marschall HU;Sjövall J;Björkhem I;Mullins JGL;Griffiths WJ;Wang Y
避免胆固醇的胆汁酸生物合成新途径。3 β，7 β-二羟基-5-烯胆汁酸的生物合成机制3 β-羟基-7-氧代-5-烯胆汁酸的生物合成。途径中间体结合并激活Smo。SLOS和混乱的Hh信令之间的新联系。胆汁酸是胆固醇代谢的终产物，分泌到胆汁中。它们是从肠吸收脂质和脂溶性化合物所必需的。在这里，我们已经在Smith-Lemli-Opitz综合征（SLOS）患者的血浆和尿液中鉴定了一系列不寻常的Δ 5-不饱和胆汁酸，SLOS是一种胆固醇生物合成缺陷，导致胆固醇的直接前体7-脱氢胆固醇（7-DHC）水平升高。使用液相色谱-质谱法（LC-MS），我们已经揭示了SLOS中胆汁酸生物合成的途径，其避免了从7-DHC开始的胆固醇，并通过7-氧代和7 β-羟基中间体进行。该途径也在健康人中以较小程度发生，但途径中间体水平升高可能是SLOS的一些特征的原因。羊水分析显示，该途径在SLOS影响的妊娠中也很活跃。重要的是，该途径中的中间体25-羟基-7-氧代胆固醇、（25R）26-羟基-7-氧代胆固醇、3 β-羟基-7-氧代胆甾-5-烯-（25R）26-酸和类似的7 β-羟基甾醇是Smoothened（Smo）活性的调节剂，Smo是一种在胚胎发生期间和胚后组织再生中介导Hedgehog（Hh）信号传导穿过膜的癌蛋白。7-氧代和7 β-羟基化合物与Smo的细胞外富含半胱氨酸的结构域的计算对接揭示了它们与20S-羟基胆固醇和胆固醇（Hh途径的已知激活剂）结合在相同的沟中。
New pathway of bile acid biosynthesis avoiding cholesterol. Mechanism for biosynthesis of 3β,7β-dihydroxy-5-ene bile acids. Biosynthesis of 3β-hydroxy-7-oxo-5-ene bile acids. Pathway intermediates bind to and activate Smo. A new link between SLOS and deranged Hh signalling. Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography – mass spectrometry (LC–MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway.
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影响因子：
9.3
作者：
Griffiths, William J.;Wang, Yuqin;Karu, Kersti;Samuel, Emmanuel;McDonnell, Shane;Hornshaw, Martin;Shackleton, Cedric
通讯作者：
Shackleton, Cedric
DOI：
10.1016/j.jsbmb.2019.03.011
发表时间：
2019-06-01
影响因子：
4.1
作者：
Beck, Katharina R.;Kanagaratnam, Sharavan;Odermatt, Alex
通讯作者：
Odermatt, Alex
影响因子：
15.9
作者：
DUANE, WC;POOLER, PA;HAMILTON, JN
通讯作者：
HAMILTON, JN
影响因子：
6.5
作者：
Griffiths WJ;Gilmore I;Yutuc E;Abdel-Khalik J;Crick PJ;Hearn T;Dickson A;Bigger BW;Wu TH;Goenka A;Ghosh A;Jones SA;Wang Y
通讯作者：
Wang Y
成绩：声音刺猬信号传导和神经细胞命运的控制。
影响因子：
11.4
作者：
Briscoe, James
通讯作者：
Briscoe, James