Foglio M H, Duester G
Gene Regulation Program, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Biochim Biophys Acta. 1999 Jul 13;1432(2):239-50. doi: 10.1016/s0167-4838(99)00104-1.
Some members of the human alcohol dehydrogenase (ADH) family possess retinol dehydrogenase activity and may thus function in production of the active nuclear receptor ligand retinoic acid. Many diverse natural forms of retinol exist including all-trans-retinol (vitamin A(1)), 9-cis-retinol, 3,4-didehydroretinol (vitamin A(2)), 4-oxo-retinol, and 4-hydroxy-retinol as well as their respective carboxylic acid derivatives which are active ligands for retinoid receptors. This raises the question of whether ADHs can accommodate all these different retinols and thus participate in the activation of several retinoid ligands. The crystal structures of human ADH1B and ADH4 provide the opportunity to examine their active sites for potential binding to many diverse retinol structures using molecular docking algorithms. The criteria used to score successful docking included achievement of distances of 1.9-2.4 A between the catalytic zinc and the hydroxyl oxygen of retinol and 3.2-3.6 A between C-4 of the coenzyme NAD and C-15 of retinol. These distances are sufficient to enable hydride transfer during the oxidation of an alcohol to an aldehyde. By these criteria, all-trans-retinol, 4-oxo-retinol, and 4-hydroxy-retinol were successfully docked to both ADH1B and ADH4. However, 9-cis-retinol and 3,4-didehydroretinol, which have more restrictive conformations, were successfully docked to only ADH4 which possesses a wider active site than ADH1B and more easily accommodates the C-19 methyl group. Furthermore, docking of all retinols was more favorable in the active site of ADH4 rather than ADH1B as measured by force field and contact scores. These findings suggest that ADH1B has a limited capacity to metabolize retinols, but that ADH4 is well suited to function in the metabolism of many diverse retinols and is predicted to participate in the synthesis of the active ligands all-trans-retinoic acid, 9-cis-retinoic acid, 3, 4-didehydroretinoic acid, 4-oxo-retinoic acid, and 4-hydroxy-retinoic acid.
人类乙醇脱氢酶（ADH）家族的一些成员具有视黄醇脱氢酶活性，因此可能在活性核受体配体视黄酸的生成中发挥作用。存在多种不同的视黄醇天然形式，包括全反式视黄醇（维生素A(1)）、9-顺式视黄醇、3,4-二脱氢视黄醇（维生素A(2)）、4-氧代视黄醇和4-羟基视黄醇，以及它们各自的羧酸衍生物，这些都是类视黄醇受体的活性配体。这就提出了一个问题，即ADHs是否能够容纳所有这些不同的视黄醇，从而参与几种类视黄醇配体的激活。人类ADH1B和ADH4的晶体结构提供了一个机会，可使用分子对接算法检查它们的活性位点，以确定其与多种不同视黄醇结构的潜在结合情况。用于评估成功对接的标准包括催化锌与视黄醇的羟基氧之间的距离达到1.9 - 2.4 Å，以及辅酶NAD的C-4与视黄醇的C-15之间的距离达到3.2 - 3.6 Å。这些距离足以在醇氧化为醛的过程中实现氢化物转移。根据这些标准，全反式视黄醇、4-氧代视黄醇和4-羟基视黄醇成功对接至ADH1B和ADH4。然而，具有更受限构象的9-顺式视黄醇和3,4-二脱氢视黄醇仅成功对接至ADH4，ADH4的活性位点比ADH1B更宽，更容易容纳C-19甲基。此外，通过力场和接触得分衡量，所有视黄醇在ADH4的活性位点的对接比在ADH1B中更有利。这些发现表明，ADH1B代谢视黄醇的能力有限，但ADH4非常适合在多种视黄醇的代谢中发挥作用，并预计参与活性配体全反式视黄酸、9-顺式视黄酸、3,4-二脱氢视黄酸、4-氧代视黄酸和4-羟基视黄酸的合成。
