Simon Roman P, Robaa Dina, Alhalabi Zayan, Sippl Wolfgang, Jung Manfred
Institute of Pharmaceutical Sciences, University of Freiburg , Albertstraße 25, Freiburg 79104, Germany.
Department of Pharmaceutical Chemistry, University Halle-Wittenberg , Halle/Saale 06120, Germany.
J Med Chem. 2016 Feb 25;59(4):1249-70. doi: 10.1021/acs.jmedchem.5b01502. Epub 2016 Jan 7.
The reversible acetylation of lysines is one of the best characterized epigenetic modifications. Its involvement in many key physiological and pathological processes has been documented in numerous studies. Lysine deacetylases (KDACs) and acetyltransferases (KATs) maintain the acetylation equilibrium at histones but also many other proteins. Besides acetylation, also other acyl groups are reversibly installed at the side chain of lysines in proteins. Because of their involvement in disease, KDACs and KATs were proposed to be promising drug targets, and for KDACs, indeed, five inhibitors are now approved for human use. While there is a similar level of evidence for the potential of KATs as drug targets, no inhibitor is in clinical trials. Here, we review the evidence for the diverse roles of KATs in disease pathology, provide an overview of structural features and the available modulators, including those targeting the bromodomains of KATs, and present an outlook.
赖氨酸的可逆乙酰化是特征最为明确的表观遗传修饰之一。众多研究已证明其参与了许多关键的生理和病理过程。赖氨酸脱乙酰酶（KDACs）和乙酰转移酶（KATs）不仅维持组蛋白上的乙酰化平衡，还维持许多其他蛋白质的乙酰化平衡。除了乙酰化，其他酰基也可逆地连接在蛋白质赖氨酸的侧链上。由于KDACs和KATs与疾病相关，它们被认为是很有前景的药物靶点，事实上，目前已有五种KDAC抑制剂被批准用于人类。虽然有类似的证据表明KATs作为药物靶点具有潜力，但尚无抑制剂进入临床试验阶段。在此，我们综述了KATs在疾病病理学中多种作用的证据，概述了其结构特征和可用的调节剂，包括那些靶向KATs溴结构域的调节剂，并展望了未来发展。
