The structure and the inhibition of the activity of Human Monoamine Oxidase A

Laboratory of Protein Crystallography., Institute for Protein Research in Osaka University.
â—‹Seyoung Son Yoshimura Masato Ma Jichun Tsukihara Tomitake

Monoamine oxidase(MAO) is a mitochondrial outer-membrane protein containing a FAD(flavin adenine dinucleotide). This enzyme catalyzes the oxidative deamination of several important monoamine neurotransmitters - in the central nervous system, such as serotonin (5-HT), norepinephrine (NE) and dopamine (DA). MAO plays a critical role in some psychiatric and neurological disorders, like depression and Parkinson's disease. Because MAO inhibition increases the level of neurotransmitters in the central nervous system, Searching for the effective inhibitors is one of the attractive means to treat neurodegenerative illnesses. MAO has two subtypes, MAOA and MAOB, which are similar in sequence with identities of approximately 70%. But each of them has unique substrate and inhibitor specificities. For example, MAOA oxidizes serotonin, but MAOB does not; MAOA is selectively inhibited by clorgyline and MAOB is highly inhibited by deprenyl. For developing the more effective and the newer inhibitors, it is important to understand the inhibitory and the catalytic mechanism with the three-dimensional structure. We determined the crystal structure of human MAOA protein at 3.0Å resolution using BL44XU beam-line at SPring-8. And also, we could confirm the structure of the single trans-membrane helix at C-terminal region. The inhibition and the catalytic mechanisms will be discussed.