Selective ability of rat 7-Dehydrocholesterol reductase (DHCR7) to act on some 7-Dehydrocholesterol metabolites but not on lumisterol metabolites.
Selective ability of rat 7-Dehydrocholesterol reductase (DHCR7) to act on some 7-Dehydrocholesterol metabolites but not on lumisterol metabolites.
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DOI：
10.1016/j.jsbmb.2021.105929
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Slominski AT
中科院分区：
文献类型：
--
作者：
Tuckey RC;Tang EKY;Chen YA;Slominski AT
7-脱氢胆固醇还原酶（DHCR 7）催化Kandutsch-Russel途径中胆固醇生物合成的最后一步，7-脱氢胆固醇（7 DHC）还原为胆固醇。7 DHC可以被一系列其他酶（包括CYP 27 A1和CYP 11 A1）以及UVB辐射作用，产生许多衍生物，包括羟基代谢物，其中一些保留C7-C8双键并具有生物活性。这些代谢物包括光甾醇（L3），它是通过UVB辐射7 DHC在皮肤中产生的7 DHC的立体异构体，以及维生素D3。本研究的目的是测试这些代谢产物是否可以作为底物或抑制剂的DHCR 7在大鼠肝微粒体。为了初步筛选这些代谢物与DHCR 7的活性位点相互作用的能力，测量了它们抑制麦角固醇转化为油菜甾醇的能力。显著抑制该反应的硬脂酸包括7 DHC（如预期的）、20 S（OH）7 DHC、27（OH）DHC、8DHC、20 S（OH）L3和22（OH）L3，但不包括7-脱氢双烯醇酮（7 DHP）、25（OH）7 DHC、L3或维生素D3及其羟基衍生物。直接测试抑制麦角固醇还原的硬脂酸作为DHCR 7的底物。以20 S（OH）7 DHC、27（OH）DHC和7-脱氢链甾醇为底物，得到C7-C8双键被去除的目标产物。没有观察到来自8DHC或20 S（OH）L3的产物，表明这些甾醇是DHCR 7的抑制剂而不是底物。光甾醇和7 DHP对细胞中DHCR 7还原的抗性将允许其他酶将这些甾醇代谢成保留C7-C8双键的活性形式，赋予其生物学作用特异性。
7-Dehydrocholesterol reductase (DHCR7) catalyses the final step of cholesterol biosynthesis in the Kandutsch-Russel pathway, the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. 7DHC can be acted on by a range of other enzymes including CYP27A1 and CYP11A1, as well as by UVB radiation, producing a number of derivatives including hydroxy-metabolites, some of which retain the C7–C8 double bond and are biologically active. These metabolites include lumisterol (L3) which is a stereoisomer of 7DHC produced in the skin by UVB radiation of 7DHC, as well as vitamin D3. The aim of this study was to test whether these metabolites could act as substrates or inhibitors of DHCR7 in rat liver microsomes. To initially screen the ability of these metabolites to interact with the active site of DHCR7, their ability to inhibit the conversion of ergosterol to brassicasterol was measured. Sterols that significantly inhibited this reaction included 7DHC (as expected), 20S(OH)7DHC, 27(OH) DHC, 8DHC, 20S(OH)L3 and 22(OH)L3 but not 7-dehydropregnenolone (7DHP), 25(OH)7DHC, L3 or vitamin D3 and its hydroxyderivatives. Sterols that inhibited ergosterol reduction were directly tested as substrates for DHCR7. 20S(OH)7DHC, 27(OH)DHC and 7-dehydrodesmosterol were confirmed to be substrates, giving the expected product with the C7–C8 double bond removed. No products were observed from 8DHC or 20S(OH)L3 indicating that these sterols are inhibitors and not substrates of DHCR7. The resistance of lumisterol and 7DHP to reduction by DHCR7 in cells will permit other enzymes to metabolise these sterols to their active forms retaining the C7–C8 double bond, conferring specificity to their biological actions.
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影响因子：
3.5
作者：
Ahn J;Yu K;Stolzenberg-Solomon R;Simon KC;McCullough ML;Gallicchio L;Jacobs EJ;Ascherio A;Helzlsouer K;Jacobs KB;Li Q;Weinstein SJ;Purdue M;Virtamo J;Horst R;Wheeler W;Chanock S;Hunter DJ;Hayes RB;Kraft P;Albanes D
通讯作者：
Albanes D
影响因子：
4.6
作者：
Ačimovič J;Goyal S;Košir R;Goličnik M;Perše M;Belič A;Urlep Ž;Guengerich FP;Rozman D
通讯作者：
Rozman D
影响因子：
2.7
作者：
Li, Wei;Chen, Jianjun;Slominski, Andrzej
通讯作者：
Slominski, Andrzej
DOI：
10.1002/ajmg.c.31343
发表时间：
2012-11-15
影响因子：
3.1
作者：
Nowaczyk, Malgorzata J. M.;Irons, Mira B.
通讯作者：
Irons, Mira B.
影响因子：
56.9
作者：
HOLICK, MF;MACLAUGHLIN, JA;DOPPELT, SH
通讯作者：
DOPPELT, SH