Hitzerd Sarina M, Verbrugge Sue Ellen, Ossenkoppele Gert, Jansen Gerrit, Peters Godefridus J
Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Rm 1.42, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands.
Amino Acids. 2014 Apr;46(4):793-808. doi: 10.1007/s00726-013-1648-0. Epub 2014 Jan 3.
Aminopeptidases represent a class of (zinc) metalloenzymes that catalyze the cleavage of amino acids nearby the N-terminus of polypeptides, resulting in hydrolysis of peptide bonds. Aminopeptidases operate downstream of the ubiquitin-proteasome pathway and are implicated in the final step of intracellular protein degradation either by trimming proteasome-generated peptides for antigen presentation or full hydrolysis into free amino acids for recycling in renewed protein synthesis. This review focuses on the function and subcellular location of five key aminopeptidases (aminopeptidase N, leucine aminopeptidase, puromycin-sensitive aminopeptidase, leukotriene A4 hydrolase and endoplasmic reticulum aminopeptidase 1/2) and their association with different diseases, in particular cancer and their current position as target for therapeutic intervention by aminopeptidase inhibitors. Historically, bestatin was the first prototypical aminopeptidase inhibitor that entered the clinic 35 years ago and is still used for the treatment of lung cancer. More recently, new generation aminopeptidase inhibitors became available, including the aminopeptidase inhibitor prodrug tosedostat, which is currently tested in phase II clinical trials for acute myeloid leukemia. Beyond bestatin and tosedostat, medicinal chemistry has emerged with additional series of potential aminopeptidases inhibitors which are still in an early phase of (pre)clinical investigations. The expanded knowledge of the unique mechanism of action of aminopeptidases has revived interest in aminopeptidase inhibitors for drug combination regimens in anti-cancer treatment. In this context, this review will discuss relevant features and mechanisms of action of aminopeptidases and will also elaborate on factors contributing to aminopeptidase inhibitor efficacy and/or loss of efficacy due to drug resistance-related phenomena. Together, a growing body of data point to aminopeptidase inhibitors as attractive tools for combination chemotherapy, hence their implementation may be a step forward in a new era of personalized treatment of cancer patients.
氨肽酶是一类（锌）金属酶，可催化多肽N端附近氨基酸的切割，导致肽键水解。氨肽酶在泛素-蛋白酶体途径的下游发挥作用，参与细胞内蛋白质降解的最后一步，即通过修剪蛋白酶体产生的肽以进行抗原呈递，或将其完全水解为游离氨基酸以便在新的蛋白质合成中循环利用。本综述重点关注五种关键氨肽酶（氨肽酶N、亮氨酸氨肽酶、嘌呤霉素敏感氨肽酶、白三烯A4水解酶和内质网氨肽酶1/2）的功能和亚细胞定位，以及它们与不同疾病（尤其是癌症）的关联，以及它们作为氨肽酶抑制剂治疗干预靶点的当前地位。从历史上看，贝司他汀是35年前进入临床的首个典型氨肽酶抑制剂，目前仍用于治疗肺癌。最近，新一代氨肽酶抑制剂问世，包括氨肽酶抑制剂前药托西司他，目前正在进行急性髓系白血病的II期临床试验。除了贝司他汀和托西司他，药物化学还出现了其他一系列潜在的氨肽酶抑制剂，它们仍处于（临床前）临床研究的早期阶段。对氨肽酶独特作用机制的深入了解，重新激发了人们对氨肽酶抑制剂用于抗癌治疗联合用药方案的兴趣。在此背景下，本综述将讨论氨肽酶的相关特征和作用机制，还将阐述影响氨肽酶抑制剂疗效和/或因耐药相关现象导致疗效丧失的因素。总之，越来越多的数据表明氨肽酶抑制剂是联合化疗的有吸引力的工具，因此它们的应用可能是癌症患者个性化治疗新时代向前迈出的一步。
