Edmondson Dale E, Binda Claudia
Department of Biochemistry, Emory University, Atlanta, GA, USA.
Department of Biology and Biotechnology, University of Pavia, Pavia, Italy.
Subcell Biochem. 2018;87:117-139. doi: 10.1007/978-981-10-7757-9_5.
Monoamine oxidases A and B (MAO A and B) are mammalian flavoenzymes bound to the outer mitochondrial membrane. They were discovered almost a century ago and they have been the subject of many biochemical, structural and pharmacological investigations due to their central role in neurotransmitter metabolism. Currently, the treatment of Parkinson's disease involves the use of selective MAO B inhibitors such as rasagiline and safinamide. MAO inhibition was shown to exert a general neuroprotective effect as a result of the reduction of oxidative stress produced by these enzymes, which seems to be relevant also in non-neuronal contexts. MAOs were successfully expressed as recombinant proteins in Pichia pastoris, which allowed a thorough biochemical and structural characterization. These enzymes are characterized by a globular water-soluble main body that is anchored to the mitochondrial membrane through a C-terminal α-helix, similar to other bitopic membrane proteins. In both MAO A and MAO B the enzyme active site consists of a hydrophobic cavity lined by residues that are conserved in the two isozymes, except for few details that determine substrate and inhibitor specificity. In particular, human MAO B features a dual-cavity active site whose conformation depends on the size of the bound ligand. This article provides a comprehensive and historical review of MAOs and the state-of-the-art of these enzymes as membrane drug targets.
单胺氧化酶A和B（MAO A和MAO B）是与线粒体外膜结合的哺乳动物黄素酶。它们在近一个世纪前被发现，由于其在神经递质代谢中的核心作用，一直是许多生物化学、结构和药理学研究的对象。目前，帕金森病的治疗涉及使用选择性MAO B抑制剂，如雷沙吉兰和沙芬酰胺。MAO抑制已被证明可通过减少这些酶产生的氧化应激发挥普遍的神经保护作用，这在非神经元环境中似乎也很重要。MAO已成功在毕赤酵母中表达为重组蛋白，这使得能够对其进行全面的生物化学和结构表征。这些酶的特征是一个球状水溶性主体，通过C端α螺旋锚定在线粒体膜上，类似于其他双位膜蛋白。在MAO A和MAO B中，酶活性位点均由一个疏水腔组成，腔内衬有两种同工酶中保守的残基，除了少数决定底物和抑制剂特异性的细节。特别是，人MAO B具有双腔活性位点，其构象取决于结合配体的大小。本文对MAO以及这些酶作为膜药物靶点的最新研究状况进行了全面的历史回顾。
