title: Crystal structure and functional mapping of human ASMT, the last enzyme of the melatonin synthesis pathway.
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.
authors: Institut Pasteur, Human Genetics and Cognitive Functions Unit, Paris, France CNRS URA 2182 'Genes, synapses and cognition', Institut Pasteur, Paris, France University Paris Diderot, Sorbonne Paris Cité, Human Genetics and Cognitive Functions, Paris, France Synchrotron SOLEIL, L'Orme des Merisiers, Saint Aubin BP48, Gif-sur-Yvette, France Institut Pasteur, Plate forme 5, 25 rue Dr. Roux, Paris, France Institut Pasteur, Plate forme 6, CNRS-UMR3528, 25 rue Dr. Roux, Paris, France Institute for Anatomy III, Goethe University, Frankfurt, Germany.
authors: Hany Goubran
authors: HG
authors: Botros
authors: Pierre
authors: P
authors: Legrand
authors: Cecile
authors: C
authors: Pagan
authors: Vincent
authors: V
authors: Bondet
authors: Patrick
authors: P
authors: Weber
authors: Mariem
authors: M
authors: Ben-Abdallah
authors: Nathalie
authors: N
authors: Lemière
authors: Guillaume
authors: G
authors: Huguet
authors: Jacques
authors: J
authors: Bellalou
authors: Erik
authors: E
authors: Maronde
authors: Pierre
authors: P
authors: Beguin
authors: Ahmed
authors: A
authors: Haouz
authors: William
authors: W
authors: Shepard
authors: Thomas
authors: T
authors: Bourgeron
mesh_terms: D000121:Acetylserotonin O-Methyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics; D018360:Crystallography, X-Ray; D005787:Gene Frequency; D006801:Humans; D008550:Melatonin / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D016415:Sequence Alignment
chemical_list: C523771:ASMT protein, human; D000121:Acetylserotonin O-Methyltransferase; D008550:Melatonin