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oai:repisalud.isciii.es:20.500.12105/227072024-11-28T23:25:09Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16967

00925njm 22002777a 4500 dc Gomez, Sara author Querol-Garcia, Javier author Sanchez-Barron, Gara author Subias, Marta author Gonzalez-Alsina, Alex author Franco-Hidalgo, Virginia author Alberti, Sebastian author Rodriguez de Cordoba, Santiago author Fernandez, Francisco J author Cristina Vega, M author 2019-02-26 The ubiquitous and highly abundant glycolytic enzyme D-glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is pivotal for the energy and carbon metabolism of most organisms, including human pathogenic bacteria. For bacteria that depend mostly on glycolysis for survival, GAPDH is an attractive target for inhibitor discovery. The availability of high-resolution structures of GAPDH from various pathogenic bacteria is central to the discovery of new antibacterial compounds. We have determined the X-ray crystal structures of two new GAPDH enzymes from Gram-positive bacterial pathogens, Streptococcus pyogenes and Clostridium perfringens. These two structures, and the recent structure of Atopobium vaginae GAPDH, reveal details in the active site that can be exploited for the design of novel inhibitors based on naturally occurring molecules. Two such molecules, anacardic acid and curcumin, have been found to counter bacterial infection in clinical settings, although the cellular targets responsible for their antimicrobial properties remain unknown. We show that both anacardic acid and curcumin inhibit GAPDH from two bacterial pathogens through uncompetitive and non-competitive mechanisms, suggesting GAPDH as a relevant pharmaceutical target for antibacterial development. Inhibition of GAPDH by anacardic acid and curcumin seems to be unrelated to the immune evasion function of pathogenic bacterial GAPDH, since neither natural compound interfere with binding to the human C5a anaphylatoxin. Gomez S, Querol-Garcia J, Sanchez-Barron G, Subias M, Gonzalez-Alsina A, Franco-Hidalgo V, et al. The Antimicrobials Anacardic Acid and Curcumin Are Not-Competitive Inhibitors of Gram-Positive Bacteria Pathogenic Glyceraldehyde-3-Phosphate Dehydrogenase by a Mechanism Unrelated to Human C5a Anaphylatoxin Binding. Front Microbiol. 2019 Feb 26;10:326. 1664-302X http://hdl.handle.net/20.500.13003/17643 https://hdl.handle.net/20.500.12105/22707 30863383 10.3389/fmicb.2019.00326 Frontiers in Microbiology 2-s2.0-85065915975 459660600001 L627729207 GAPDH - glyceraldehyde-3-phosphate dehydrogenase Streptococcus pyogenes Clostridium perfringens Anacardic acid Curcumin Complement - immunological term Enzyme inhibition X-ray crystallography The Antimicrobials Anacardic Acid and Curcumin Are Not-Competitive Inhibitors of Gram-Positive Bacteria Pathogenic Glyceraldehyde-3-Phosphate Dehydrogenase by a Mechanism Unrelated to Human C5a Anaphylatoxin Binding