These authors contributed equally to this work.
Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway
Article first published online: 9 JUL 2012
© 2012 John Wiley & Sons A/S
Journal of Pineal Research
Volume 54, Issue 1, pages 46–57, January 2013
How to Cite
Botros, H. G., Legrand, P., Pagan, C., Bondet, V., Weber, P., Ben-Abdallah, M., Lemière, N., Huguet, G., Bellalou, J., Maronde, E., Beguin, P., Haouz, A., Shepard, W. and Bourgeron, T. (2013), Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway. Journal of Pineal Research, 54: 46–57. doi: 10.1111/j.1600-079X.2012.01020.x
- Issue published online: 6 DEC 2012
- Article first published online: 9 JUL 2012
- Accepted manuscript online: 12 JUN 2012 02:16PM EST
- Received April 21, 2012; Accepted June 1, 2012.
- Genetic variants;
- crystal structure;
- O-methyl transferase
Abstract: Melatonin is a synchronizer of many physiological processes. Abnormal melatonin signaling is associated with human disorders related to sleep, metabolism, and neurodevelopment. Here, we present the X-ray crystal structure of human N-acetyl serotonin methyltransferase (ASMT), the last enzyme of the melatonin biosynthesis pathway. The polypeptide chain of ASMT consists of a C-terminal domain, which is typical of other SAM-dependent O-methyltransferases, and an N-terminal domain, which intertwines several helices with another monomer to form the physiologically active dimer. Using radioenzymology, we analyzed 20 nonsynonymous variants identified through the 1000 genomes project and in patients with neuropsychiatric disorders. We found that the majority of these mutations reduced or abolished ASMT activity including one relatively frequent polymorphism in the Han Chinese population (N17K, rs17149149). Overall, we estimate that the allelic frequency of ASMT deleterious mutations ranges from 0.66% in Europe to 2.97% in Asia. Mapping of the variants on to the 3-dimensional structure clarifies why some are harmful and provides a structural basis for understanding melatonin deficiency in humans.