The Biosynthesis of Flavin Cofactors in Listeria monocytogenes |
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| Institution: | 1. Departamento de Bioquímica y Biología Molecular y Celular, Facultad de Ciencias and Instituto de Biocomputación y Física de Sistemas Complejos, Universidad de Zaragoza, 50009 Zaragoza, Spain;2. Plateforme de Protéines Recombinantes, Institut Pasteur, CNRS-UMR 3528, Paris, France;3. Estación Experimental de Aula Dei, National Spanish Research Council (CSIC), Zaragoza, Spain;4. Group of Biochemistry, Biophysics and Computational Biology (BIFI-Unizar) Joint Unit to CSIC Spain;1. Department of Chemistry and Biochemistry, The City College of New York, NewYork, NY 10031, USA;2. Graduate Program in Biochemistry, The Graduate Center of CUNY, New York, NY 10016, USA;3. Graduate Program in Cell and Molecular Biology, University of Texas, Austin, TX 78712, USA;4. Division of Chemical Biology and Medicinal Chemistry, University of Texas, Austin, TX 78712, USA;5. Graduate Program in Chemistry, The Graduate Center of CUNY, New York, NY 10016, USA;6. Graduate Program in Physics, The Graduate Center of CUNY, New York, NY 10016, USA;1. Cardiovascular Research Institute, University of California, San Francisco, CA 94148, USA;2. Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel;3. Rappaport Family School of Medicine, Technion-Israel Institute of Technology, Haifa 31096, Israel;4. Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA;5. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA;6. California Institute for Quantitative Biomedical Research, University of California, San Francisco, CA 94158, USA;7. Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Fancisco, CA 94158, USA;8. Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA;1. Nucleic Acids Structure Research Group, University of Dundee, Dundee, United Kingdom;2. Department of Biology, University of Konstanz, 78457 Konstanz, Germany;3. Department of Molecular Physiology and Biological Physics, University of Virginia, 22908 Charlottesville, VA, USA;4. Department of Chemistry, University of Virginia, Charlottesville, Virginia, USA |
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| Abstract: | Listeria monocytogenes is riboflavin auxotrophic, but it has two genes envisaged to transform riboflavin into FMN and FAD after its uptaked by specialized transporters. One encodes a bifunctional type I FAD synthase (FADS, herein LmFADS-1), while the other produces a protein similar to type I at the FMN:ATP adenylyltransferase (FMNAT) site but with a shorter C-terminal that lacks any riboflavin kinase (RFK) motif. This second protein is rare among bacteria and has been named FADS type II (LmFADS-2). Here we present a biochemical and biophysical study of LmFADS-1 and LmFADS-2 by integrating kinetic and thermodynamic data together with sequence and structural prediction methods to evaluate their occurrence in Listeria, as well as their function and molecular properties. Despite LmFADS-1 similarities to other type I FADSs, (i) its RFK activity has not riboflavin substrate inhibition and occurs under reducing and oxidizing conditions, (ii) its FMNAT activity requires strong reducing environment, and (iii) binding of reaction products, but not substrates, favors binding of the second ligand. LmFADS-2 produces FAD under oxidizing and reducing environments, but its C-terminus module function remains unknown. Listeria species conserve both FADSs, being sequence identity high within L. monocytogenes strains. Our data exemplify alternative strategies for FMN and FAD biosynthesis and homeostasis, envisaging that in Listeria two FADSs might be required to fulfill the supply of flavin cofactors under niches that can go from saprophytism to virulence. As FADSs are attractive antimicrobial targets, understanding of FADSs traits in different species is essential to help in the discovery of specific antimicrobials. |
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