犬尿氨酸氨基转移酶同工酶(KATs1-4)是吡哆醛-5'-磷酸(PLP)依赖性酶家族的成员,催化l-犬尿氨酸(l-KYN)永久转化为犬尿氨酸(KYNA),一种已知的神经活性剂。由于KATs存在于哺乳动物的大脑中,并且在犬尿氨酸通路中起关键作用,涉及不同类别的中枢神经系统(CNS)疾病,KATs是寻求治疗神经退行性疾病和认知障碍的主要目标。最近的研究表明,抑制这些酶会对患有这些疾病的患者产生有益的作用,因为观察到异常高水平的KYNA。KAT-1和KAT-3共享该家族中同工酶的最高序列相似性,它们的活动位点口袋也相似。重要的是,KAT-2在人脑中具有产生犬尿烯酸的主要作用(70%),因此,人们认为这种同工酶的适当抑制在控制CNS疾病的主要方面是最有效的。已经开发了人KAT-2抑制剂,但其中最有效的,被选中进行进一步调查,由于它们与PLP的不可逆相互作用引起的交叉毒性,没有进行临床研究,KAT同工酶所需的辅因子,和任何其他PLP依赖性酶。由于可能产生广泛的不良副作用,同样重要的是寻求可逆抑制KAT的KAT抑制剂,并包括寻找可能与PLP以外的活性位点区域实现实质性相互作用的化合物的策略。这篇论文的主要目的是回顾KAT同工酶抑制剂的最新进展。本论文还包括与该酶家族复杂的晶体结构分析,这为研究人员和相关研究提供了进一步的见解。
Kynurenine aminotransferase isozymes (KATs 1-4) are members of the pyridoxal-5\'-phosphate (PLP)-dependent enzyme family, which catalyse the permanent conversion of l-kynurenine (l-KYN) to kynurenic acid (KYNA), a known neuroactive agent. As KATs are found in the mammalian brain and have key roles in the kynurenine pathway, involved in different categories of central nervous system (CNS) diseases, the KATs are prominent targets in the quest to treat neurodegenerative and cognitive impairment disorders. Recent studies suggest that inhibiting these enzymes would produce effects beneficial to patients with these conditions, as abnormally high levels of KYNA are observed. KAT-1 and KAT-3 share the highest sequence similarity of the isozymes in this family, and their active site pockets are also similar. Importantly, KAT-2 has the major role of kynurenic acid production (70%) in the human brain, and it is considered therefore that suitable inhibition of this isozyme would be most effective in managing major aspects of CNS diseases. Human KAT-2 inhibitors have been developed, but the most potent of them, chosen for further investigations, did not proceed in clinical studies due to the cross toxicity caused by their irreversible interaction with PLP, the required cofactor of the KAT isozymes, and any other PLP-dependent enzymes. As a consequence of the possibility of extensive undesirable adverse effects, it is also important to pursue KAT inhibitors that reversibly inhibit KATs and to include a strategy that seeks compounds likely to achieve substantial interaction with regions of the active site other than the PLP. The main purpose of this treatise is to
review the recent developments with the inhibitors of KAT isozymes. This treatise also includes analyses of their crystallographic structures in complex with this enzyme family, which provides further insight for researchers in this and related studies.