Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
Chem Biol Interact. 2013 Feb 25;202(1-3):186-94. doi: 10.1016/j.cbi.2012.11.014. Epub 2012 Dec 3.
Biological activity of natural retinoids requires the oxidation of retinol to retinoic acid (RA) and its binding to specific nuclear receptors in target tissues. The first step of this pathway, the reversible oxidoreduction of retinol to retinaldehyde, is essential to control RA levels. The enzymes of retinol oxidation are NAD-dependent dehydrogenases of the cytosolic medium-chain (MDR) and the membrane-bound short-chain (SDR) dehydrogenases/reductases. Retinaldehyde reduction can be performed by SDR and aldo-keto reductases (AKR), while its oxidation to RA is carried out by aldehyde dehydrogenases (ALDH). In contrast to SDR, AKR and ALDH are cytosolic. A common property of these enzymes is that they only use free retinoid, but not retinoid bound to cellular retinol binding protein (CRBP). The relative contribution of each enzyme type in retinoid metabolism is discussed in terms of the different subcellular localization, topology of membrane-bound enzymes, kinetic constants, binding affinity of CRBP for retinol and retinaldehyde, and partition of retinoid pools between membranes and cytoplasm. The development of selective inhibitors for AKR enzymes 1B1 and 1B10, of clinical relevance in diabetes and cancer, granted the investigation of some structure-activity relationships. Kinetics with the 4-methyl derivatives of retinaldehyde isomers was performed to identify structural features for substrate specificity. Hydrophilic derivatives were better substrates than the more hydrophobic compounds. We also explored the inhibitory properties of some synthetic retinoids, known for binding to retinoic acid receptors (RAR) and retinoid X receptors (RXR). Consistent with its substrate specificity towards retinaldehyde, AKR1B10 was more effectively inhibited by synthetic retinoids than AKR1B1. A RARβ/γ agonist (UVI2008) inhibited AKR1B10 with the highest potency and selectivity, and docking simulations predicted that its carboxyl group binds to the anion-binding pocket.
天然视黄醇的生物活性需要视黄醇氧化为视黄酸（RA），并在靶组织中与特定的核受体结合。该途径的第一步，即视黄醇可逆地氧化为视醛，是控制 RA 水平的关键。视黄醇氧化的酶是细胞质中长链（MDR）和膜结合短链（SDR）脱氢酶/还原酶的 NAD 依赖性脱氢酶。视醛还原可以由 SDR 和醛酮还原酶（AKR）完成，而其氧化为 RA 则由醛脱氢酶（ALDH）完成。与 SDR 不同，AKR 和 ALDH 是细胞质的。这些酶的一个共同特性是它们仅使用游离的视黄醇，而不使用与细胞视黄醇结合蛋白（CRBP）结合的视黄醇。根据不同的亚细胞定位、膜结合酶的拓扑结构、动力学常数、CRBP 对视黄醇和视醛的结合亲和力以及视黄醇库在膜和细胞质之间的分配，讨论了每种酶类型在视黄醇代谢中的相对贡献。AKR 酶 1B1 和 1B10 的选择性抑制剂的开发具有临床相关性，在糖尿病和癌症中具有重要意义，这为一些结构-活性关系的研究提供了机会。对视醛异构体的 4-甲基衍生物进行了动力学研究，以确定底物特异性的结构特征。亲水性衍生物比疏水性化合物更适合作为底物。我们还探索了一些合成视黄醇的抑制特性，这些合成视黄醇已知可与视黄酸受体（RAR）和视黄醛受体（RXR）结合。与 AKR1B10 对视醛的底物特异性一致，AKR1B10 被合成视黄醇的抑制效果更好。一种 RARβ/γ 激动剂（UVI2008）对 AKR1B10 的抑制作用最强，选择性也最高，对接模拟预测其羧基结合在阴离子结合口袋中。
