The energy landscape of human serine racemase
- 1Università degli Studi di Parma, Italy
Human serine racemase is a pyridoxal 5’-phosphate (PLP)-dependent dimeric enzyme that catalyzes the reversible racemization of L-serine and D-serine and their dehydration to pyruvate and ammonia. As D-serine is the co-agonist of the N-methyl D-aspartate receptors for glutamate, the most abundant excitatory neurotransmitter in the brain, the structure, dynamics, function, regulation and cellular localization of serine racemase have been investigated in detail. Serine racemase belongs to the fold-type II of the PLP-dependent enzyme family and structural models from several orthologs are available. The comparison of structures of serine racemase co-crystallized with or without ligands indicates the presence of at least one open and one closed conformation, suggesting that conformational flexibility plays a relevant role in enzyme regulation. ATP, Mg2+, Ca2+, anions, NADH and protein interactors, as well as the post-translational modifications nitrosylation and phosphorylation, finely tune the racemase and dehydratase activities and their relative reaction rates. Further information on serine racemase structure and dynamics resulted from the search for inhibitors with potential therapeutic applications. The cumulative knowledge on human serine racemase allowed obtaining insights into its conformational landscape and into the mechanisms of cross-talk between the effector binding sites and the active site.
Keywords: pyridoxal 5’ -phosphate,, Enzyme Catalysis, Allosteric Regulation, Conformational Landscape, d-serine, serine racemase, N-methyl D-aspartate (NMDA) receptor
Received: 28 Sep 2018;
Accepted: 26 Nov 2018.
Edited by:Sandra Macedo-Ribeiro, Instituto de Biologia Molecular e Celular (IBMC), Portugal
Reviewed by:Anastassios C. Papageorgiou, University of Turku, Finland
Gianluca Molla, Università degli Studi dell'Insubria, Italy
Copyright: © 2018 Raboni, Marchetti, Faggiano, Campanini, Bruno, Margiotta, Marchesani and Mozzarelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Prof. Andrea Mozzarelli, Università degli Studi di Parma, Parma, Italy, firstname.lastname@example.org