Tranylcypromine specificity for monoamine oxidase is limited by promiscuous protein labelling and lysosomal trapping,RSC Chemical Biology

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Tranylcypromine specificity for monoamine oxidase is limited by promiscuous protein labelling and lysosomal trapping
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-08-12 , DOI: 10.1039/d0cb00048e
Jonas Drechsel ₁ , Christina Kyrousi ₂ , Silvia Cappello ₂ , Stephan A Sieber ₁

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Monoamine oxidases MAOA and MAOB catalyze important cellular functions such as the deamination of neurotransmitters. Correspondingly, MAO inhibitors are used for the treatment of severe neuropsychiatric disorders such as depression. A commonly prescribed drug against refractory depression is tranylcypromine, however, the side effects are poorly understood. In order to decipher putative off-targets, we synthesized two tranylcypromine probes equipped with either an alkyne moiety or an alkyne-diazirine minimal photocrosslinker for in situ proteome profiling. Surprisingly, LC–MS/MS analysis revealed low enrichment of MAOA and relatively promiscuous labeling of proteins. Photoprobe labeling paired with fluorescent imaging studies revealed lysosomal trapping which could be largely reverted by the addition of lysosomotropic drugs.

中文翻译：

Tranylcypromine 对单胺氧化酶的特异性受到混杂蛋白质标记和溶酶体捕获的限制

单胺氧化酶 MAOA 和 MAOB 催化重要的细胞功能，例如神经递质的脱氨基作用。相应地，MAO抑制剂用于治疗严重的神经精神障碍如抑郁症。对抗难治性抑郁症的常用处方药是反苯环丙胺，然而，对其副作用知之甚少。为了破译假定的脱靶，我们合成了两个反苯环丙胺探针，配备了炔烃部分或炔烃-二氮丙啶最小光交联剂，用于原位蛋白质组分析。令人惊讶的是，LC-MS/MS 分析揭示了 MAOA 的低富集和相对混杂的蛋白质标记。光探针标记与荧光成像研究相结合，揭示了溶酶体捕获，这可以通过添加溶酶体药物在很大程度上恢复。

更新日期：2020-10-08

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