Elaheh Mahootchi, Arne Raasakka, Weisha Luan, Gopinath Muruganandam, Remy Loris, Jan Haavik, Petri Kursula, Structure and substrate specificity determinants of the taurine biosynthetic enzyme cysteine sulphinic acid decarboxylase, Journal of Structural Biology, Volume 213, Issue 1, 2021, 107674, ISSN 1047-8477, https://doi.org/10.1016/j.jsb.2020.107674
Structure and substrate specificity determinants of the taurine biosynthetic enzyme cysteine sulphinic acid decarboxylase
|Author:||Mahootchi, Elaheh1; Raasakka, Arne1; Luan, Weisha2;|
1Department of Biomedicine, University of Bergen, Bergen, Norway
2Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
3VIB‐VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, Brussels, Belgium
4Structural Biology Brussels, Department of Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium
5Biocenter Oulu, University of Oulu, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 7.5 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2021051429874
|Publish Date:|| 2021-05-14
Pyridoxal 5́-phosphate (PLP) is an important cofactor for amino acid decarboxylases with many biological functions, including the synthesis of signalling molecules, such as serotonin, dopamine, histamine, γ-aminobutyric acid, and taurine. Taurine is an abundant amino acid with multiple physiological functions, including osmoregulation, pH regulation, antioxidative protection, and neuromodulation. In mammalian tissues, taurine is mainly produced by decarboxylation of cysteine sulphinic acid to hypotaurine, catalysed by the PLP-dependent cysteine sulphinic acid decarboxylase (CSAD), followed by oxidation of the product to taurine. We determined the crystal structure of mouse CSAD and compared it to other PLP-dependent decarboxylases in order to identify determinants of substrate specificity and catalytic activity. Recognition of the substrate involves distinct side chains forming the substrate-binding cavity. In addition, the backbone conformation of a buried active-site loop appears to be a critical determinant for substrate side chain binding in PLP-dependent decarboxylases. Phe94 was predicted to affect substrate specificity, and its mutation to serine altered both the catalytic properties of CSAD and its stability. Using small-angle X-ray scattering, we further showed that CSAD presents open/close motions in solution. The structure of apo-CSAD indicates that the active site gets more ordered upon internal aldimine formation. Taken together, the results highlight details of substrate recognition in PLP-dependent decarboxylases and provide starting points for structure-based inhibitor design with the aim of affecting the biosynthesis of taurine and other abundant amino acid metabolites.
Journal of structural biology
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
This work has received funding from the European Union Horizon 2020 research and innovation program under Grant Agreement No. 810384 (CoCA), Stiftelsen Kristian Gerhard Jebsen (SKJ-MED-02), and the Regional Health Authority of Western Norway (No. 25048). This publication reflects only the authors’ view, and the European Commission is not responsible for any use that may be made of the information it contains. We wish to acknowledge access to and excellent support on synchrotron beamlines at SOLEIL and ESRF.
© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).