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.     

L’acylation des protéines : une fonction cellulaire importante des acides gras saturés

Fatty acid acylation of proteins corresponds to the co- or post-translational covalent linkage of a fatty acid, activated in the form of acyl-CoA, to an amino acid residue of the substrate protein. The cellular fatty acids which are involved in protein acylation are mainly saturated fatty acids. Palmitoylation (S-acylation) corresponds to the reversible attachment of palmitic acid (C16:0) to the side chain of a cysteine residue via a thioester bond. N-terminal myristoylation refers to the covalent attachment of myristic acid (C14:0) by an amide bond to the N-terminal glycine of many eukaryotic and viral proteins. Octanoylation (O-acylation) typically concerns the formation of an ester bond between octanoic acid (caprylic acid, C8:0) and the side chain of a serine residue of the gut and brain peptide ghrelin. An increasing number of proteins (enzymes, receptors, oncogenes, tumor suppressors, proteins involved in signal transduction, eukaryotic and viral structural proteins) have been shown to undergo fatty acid acylation. The acyl moiety can mediate protein subcellular localization, protein–protein interaction or protein–membrane interaction. Therefore, through the covalent modification of proteins, saturated fatty acids exhibit emerging specific and important roles in modulating protein functions. This review provides an overview of the recent findings on the various classes of protein acylation leading to the biological ability of saturated fatty acids to regulate many pathways. Finally, the links between these elucidated biochemical mechanisms and the physiological roles of dietary saturated fatty acids are discussed.     

Patients souffrant de schizophrénie en EHPAD et objectifs de prise en charge par l’équipe de psychiatrie de secteur ?

Old people's home welcomes old subjects presenting more and more numerous psychic and organic pathologies with the headway in age. What are the difficulties met in establishment and which tracks of solutions can be envisaged? What are coverages proposed for the residents living in establishment and who suffer from psychiatric chronic pathologies like the schizophrenia? What role then for the team of Psychiatry of sector?     

Left main coronary dissection after mild chest trauma. Favorable evolution with fibrinolytic and surgical therapies

A 32-year-old woman had acute anterior myocardial infarction after a mild chest trauma (automobile accident). Unstable angina recurred shortly after admission, and extensive dissection of the left coronary artery was demonstrated. Medical therapy including systemic fibrinolysis was started but clinical stabilization and good long-term result was achieved only by aortocoronary bypass grafting.