{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T01:27:58Z","timestamp":1784683678391,"version":"3.55.0"},"reference-count":104,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T00:00:00Z","timestamp":1689033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Multiple drug resistance is the main obstacle in the treatment of bacterial diseases. Resistance against antibiotics demands the exploration of new antimicrobial drug targets. A variety of <jats:italic>in silico<\/jats:italic> and genetic approaches show that the enzymes of the riboflavin biosynthetic pathway are crucial for the survival of bacteria. This pathway is absent in humans thus enzymes of the riboflavin biosynthetic pathway are emerging drug targets for resistant pathogenic bacterial strains. Exploring the structural details, their mechanism of action, intermediate elucidation, and interaction analysis would help in designing suitable inhibitors of these enzymes. The riboflavin biosynthetic pathway consists of seven distinct enzymes, namely, 3,4-dihydroxy-2-butanone 4-phosphate synthase, GTP cyclohydrolase II, pyrimidine deaminase\/reductase, phosphatase, lumazine synthase, and riboflavin synthase. The present review summarizes the research work that has been carried out on these enzymes in terms of their structures, active site architectures, and molecular mechanism of catalysis. This review also walks through small molecule inhibitors that have been developed against several of these enzymes.<\/jats:p>","DOI":"10.3389\/fmolb.2023.1228763","type":"journal-article","created":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T04:37:20Z","timestamp":1689050240000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Inhibitors of riboflavin biosynthetic pathway enzymes as potential antibacterial drugs"],"prefix":"10.3389","volume":"10","author":[{"given":"Zeyaul","family":"Islam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pankaj","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"966","DOI":"10.1073\/pnas.012602299","article-title":"A genome-scale analysis for identification of genes required for growth or survival of Haemophilus influenzae","volume":"99","author":"Akerley","year":"2002","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B2","doi-asserted-by":"publisher","first-page":"0008","DOI":"10.1038\/msb4100050","article-title":"Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: The keio collection","volume":"2","author":"Baba","year":"2006","journal-title":"Mol. Syst. Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1016\/s0021-9258(19)86223-3","article-title":"Riboflavin synthases of Bacillus subtilis. Purification and properties","volume":"255","author":"Bacher","year":"1980","journal-title":"J. Biol. Chem."},{"key":"B4","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1042\/bst0240089","article-title":"Biosynthesis of riboflavin: Structure and mechanism of lumazine synthase","volume":"24","author":"Bacher","year":"1996","journal-title":"Biochem. Soc. Trans."},{"key":"B5","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1038\/nature04616","article-title":"Robust Salmonella metabolism limits possibilities for new antimicrobials","volume":"440","author":"Becker","year":"2006","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1039\/b108916c","article-title":"Flavoenzymes that catalyse reactions with no net redox change","volume":"19","author":"Bornemann","year":"2002","journal-title":"Nat. Prod. Rep."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1006\/jmbi.2000.3640","article-title":"Divergence in macromolecular assembly: X-Ray crystallographic structure analysis of lumazine synthase from Brucella abortus","volume":"297","author":"Braden","year":"2000","journal-title":"J. Mol. Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1128\/jb.136.2.657-667.1978","article-title":"Presence of Escherichia coli of a deaminase and a reductase involved in biosynthesis of riboflavin","volume":"136","author":"Burrows","year":"1978","journal-title":"J. Bacteriol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.1016\/j.jmb.2006.04.045","article-title":"Biosynthesis of riboflavin: Structure and properties of 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5\u2019-phosphate reductase of Methanocaldococcus jannaschii","volume":"359","author":"Chatwell","year":"2006","journal-title":"J. Mol. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.ab.2004.11.033","article-title":"A high-throughput screen utilizing the fluorescence of riboflavin for identification of lumazine synthase inhibitors","volume":"338","author":"Chen","year":"2005","journal-title":"Anal. Biochem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"7605","DOI":"10.1074\/jbc.M510254200","article-title":"Crystal structure of a bifunctional deaminase and reductase from Bacillus subtilis involved in riboflavin biosynthesis","volume":"281","author":"Chen","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1074\/jbc.M805820200","article-title":"Complex structure of Bacillus subtilis RibG: The reduction mechanism during riboflavin biosynthesis","volume":"284","author":"Chen","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B13","doi-asserted-by":"publisher","first-page":"27662","DOI":"10.1074\/jbc.M604900200","article-title":"The iron-sulfur clusters in Escherichia coli succinate dehydrogenase direct electron flow","volume":"281","author":"Cheng","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B14","doi-asserted-by":"publisher","first-page":"8162","DOI":"10.1021\/jo051332v","article-title":"Design, synthesis, and biochemical evaluation of 1,5,6,7-tetrahydro-6,7-dioxo-9-D-ribitylaminolumazines bearing alkyl phosphate substituents as inhibitors of lumazine synthase and riboflavin synthase","volume":"70","author":"Cushman","year":"2005","journal-title":"J. Org. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"8944","DOI":"10.1021\/jo9712963","article-title":"Design and synthesis of (Ribitylamino)uracils bearing fluorosulfonyl, sulfonic acid, and carboxylic acid functionality as inhibitors of lumazine synthase","volume":"62","author":"Cushman","year":"1997","journal-title":"J. Org. Chem."},{"key":"B16","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/s0968-0896(98)00013-3","article-title":"Synthesis of 2,6-dioxo-(1H,3H)-9-N-ribitylpurine and 2,6-dioxo-(1H,3H)-8-aza-9-N-ribitylpurine as inhibitors of lumazine synthase and riboflavin synthase","volume":"6","author":"Cushman","year":"1998","journal-title":"Bioorg. Med. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"4635","DOI":"10.1021\/jo9821731","article-title":"Synthesis and biochemical evaluation of bis(6,7-dimethyl-8-D-ribityllumazines) as potential bisubstrate analogue inhibitors of riboflavin synthase","volume":"64","author":"Cushman","year":"","journal-title":"J. Org. Chem."},{"key":"B18","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/s0960-894x(98)00687-8","article-title":"Design and synthesis of 6-(6-D-ribitylamino-2,4-dihydroxypyrimidin-5-yl)-1-hexyl phosphonic acid, a potent inhibitor of lumazine synthase","volume":"9","author":"Cushman","year":"","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"B19","doi-asserted-by":"publisher","first-page":"3838","DOI":"10.1021\/jo9821729","article-title":"Design, synthesis, and biological evaluation of homologous phosphonic acids and sulfonic acids as inhibitors of lumazine synthase","volume":"64","author":"Cushman","year":"","journal-title":"J. Org. Chem."},{"key":"B20","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1021\/jo030278k","article-title":"Design, synthesis, and evaluation of 9-D-ribitylamino-1,3,7,9-tetrahydro-2,6,8-purinetriones bearing alkyl phosphate and alpha,alpha-difluorophosphonate substituents as inhibitors of tiboflavin synthase and lumazine synthase","volume":"69","author":"Cushman","year":"2004","journal-title":"J. Org. Chem."},{"key":"B21","doi-asserted-by":"publisher","first-page":"5807","DOI":"10.1021\/jo0201631","article-title":"Design, synthesis, and evaluation of 6-carboxyalkyl and 6-phosphonoxyalkyl derivatives of 7-oxo-8-ribitylaminolumazines as inhibitors of riboflavin synthase and lumazine synthase","volume":"67","author":"Cushman","year":"","journal-title":"J. Org. Chem."},{"key":"B22","doi-asserted-by":"publisher","first-page":"8320","DOI":"10.1021\/jo010706r","article-title":"Design, synthesis, and evaluation of 9-D-ribityl-1,3,7-trihydro-2,6,8-purinetrione, a potent inhibitor of riboflavin synthase and lumazine synthase","volume":"66","author":"Cushman","year":"2001","journal-title":"J. Org. Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"6871","DOI":"10.1021\/jo020144r","article-title":"Incorporation of an amide into 5-phosphonoalkyl-6-D-ribitylaminopyrimidinedione lumazine synthase inhibitors results in an unexpected reversal of selectivity for riboflavin synthase vs lumazine synthase","volume":"67","author":"Cushman","year":"","journal-title":"J. Org. Chem."},{"key":"B24","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1124\/jpet.103.059972","article-title":"Structures and models of transporter proteins","volume":"309","author":"Dahl","year":"2004","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"B25","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1107\/S174430911301292X","article-title":"Structure of diaminohydroxyphosphoribosylaminopyrimidine deaminase\/5-amino-6-(5-phosphoribosylamino)uracil reductase from Acinetobacter baumannii","volume":"69","author":"Dawson","year":"2013","journal-title":"Acta Crystallogr. Sect. F. Struct. Biol. Cryst. Commun."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1016\/j.jmb.2004.06.053","article-title":"Potential anti-infective targets in pathogenic yeasts: Structure and properties of 3,4-dihydroxy-2-butanone 4-phosphate synthase of Candida albicans","volume":"341","author":"Echt","year":"2004","journal-title":"J. Mol. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"670","DOI":"10.1002\/cbic.201000681","article-title":"Biosynthesis of vitamin B2: A unique way to assemble a xylene ring","volume":"12","author":"Fischer","year":"2011","journal-title":"Chembiochem"},{"key":"B28","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1016\/j.abb.2008.02.008","article-title":"Biosynthesis of vitamin B2: Structure and mechanism of riboflavin synthase","volume":"474","author":"Fischer","year":"2008","journal-title":"Arch. Biochem. Biophys."},{"key":"B29","doi-asserted-by":"publisher","first-page":"36299","DOI":"10.1074\/jbc.M404406200","article-title":"Evolution of vitamin B2 biosynthesis: Structural and functional similarity between pyrimidine deaminases of eubacterial and plant origin","volume":"279","author":"Fischer","year":"2004","journal-title":"J. Biol. Chem."},{"key":"B30","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/0076-6879(80)66473-8","article-title":"GTP cyclohydrolase II from Escherichia coli","volume":"66","author":"Foor","year":"1980","journal-title":"Methods Enzymol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"3545","DOI":"10.1016\/s0021-9258(19)41549-4","article-title":"Purification and properties of guanosine triphosphate cyclohydrolase II from Escherichia coli","volume":"250","author":"Foor","year":"1975","journal-title":"J. Biol. Chem."},{"key":"B32","doi-asserted-by":"publisher","first-page":"4555","DOI":"10.1128\/JB.184.16.4555-4572.2002","article-title":"From genetic footprinting to antimicrobial drug targets: Examples in cofactor biosynthetic pathways","volume":"184","author":"Gerdes","year":"2002","journal-title":"J. Bacteriol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1317","DOI":"10.1016\/s0022-2836(02)00116-x","article-title":"The structural basis of riboflavin binding to Schizosaccharomyces pombe 6,7-dimethyl-8-ribityllumazine synthase","volume":"318","author":"Gerhardt","year":"","journal-title":"J. Mol. Biol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1371","DOI":"10.1016\/s0969-2126(02)00864-x","article-title":"Studies on the reaction mechanism of riboflavin synthase: X-Ray crystal structure of a complex with 6-carboxyethyl-7-oxo-8-ribityllumazine","volume":"10","author":"Gerhardt","year":"","journal-title":"Structure"},{"key":"B35","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1073\/pnas.0510013103","article-title":"Essential genes of a minimal bacterium","volume":"103","author":"Glass","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B36","doi-asserted-by":"publisher","first-page":"e0221446","DOI":"10.1371\/journal.pone.0221446","article-title":"An in silico approach towards identification of novel drug targets in pathogenic species of Leptospira","volume":"14","author":"Gupta","year":"2019","journal-title":"PLoS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2120","DOI":"10.1016\/s0021-9258(18)96675-5","article-title":"Riboflavin synthetase from yeast","volume":"241","author":"Harvey","year":"1966","journal-title":"J. Biol. Chem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"6977","DOI":"10.1021\/ja043404q","article-title":"Electron transfer and catalytic control by the iron-sulfur clusters in a respiratory enzyme, E. coli fumarate reductase","volume":"127","author":"Hudson","year":"2005","journal-title":"J. Am. Chem. Soc."},{"key":"B39","doi-asserted-by":"publisher","first-page":"7224","DOI":"10.1073\/pnas.131610698","article-title":"A pentacyclic reaction intermediate of riboflavin synthase","volume":"98","author":"Illarionov","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B40","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1515\/BC.2005.016","article-title":"Pre-steady-state kinetic analysis of riboflavin synthase using a pentacyclic reaction intermediate as substrate","volume":"386","author":"Illarionov","year":"2005","journal-title":"Biol. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"11293","DOI":"10.1074\/jbc.M114.611830","article-title":"Structural basis for competitive inhibition of 3,4-dihydroxy-2-butanone-4-phosphate synthase from Vibrio cholerae","volume":"290","author":"Islam","year":"2015","journal-title":"J. Biol. Chem."},{"key":"B42","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.ab.2007.02.033","article-title":"A high-throughput screening platform for inhibitors of the riboflavin biosynthesis pathway","volume":"365","author":"Kaiser","year":"2007","journal-title":"Anal. Biochem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"5264","DOI":"10.1046\/j.1432-1033.2002.03239.x","article-title":"Biosynthesis of vitamin B2","volume":"269","author":"Kaiser","year":"2002","journal-title":"Eur. J. Biochem."},{"key":"B44","doi-asserted-by":"publisher","first-page":"12769","DOI":"10.1021\/jacs.2c03376","article-title":"Evidence for the chemical mechanism of RibB (3,4-dihydroxy-2-butanone 4-phosphate synthase) of riboflavin biosynthesis","volume":"144","author":"Kenji\u0107","year":"2022","journal-title":"J. Am. Chem. Soc."},{"key":"B45","doi-asserted-by":"publisher","first-page":"2883","DOI":"10.1021\/bi00009a019","article-title":"Biosynthesis of riboflavin. Studies on the reaction mechanism of 6,7-dimethyl-8-ribityllumazine synthase","volume":"34","author":"Kis","year":"1995","journal-title":"Biochemistry"},{"key":"B46","doi-asserted-by":"publisher","first-page":"4678","DOI":"10.1073\/pnas.0730515100","article-title":"Essential Bacillus subtilis genes","volume":"100","author":"Kobayashi","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B47","doi-asserted-by":"publisher","first-page":"3292","DOI":"10.1002\/prot.22837","article-title":"Potential anti-bacterial drug target: Structural characterization of 3,4-dihydroxy-2-butanone-4-phosphate synthase from Salmonella typhimurium LT2","volume":"78","author":"Kumar","year":"2010","journal-title":"Proteins"},{"key":"B48","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1107\/S0907444910053370","article-title":"Crystal structure analysis of icosahedral lumazine synthase from Salmonella typhimurium, an antibacterial drug target","volume":"67","author":"Kumar","year":"2011","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"B49","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1111\/febs.12255","article-title":"The lumazine synthase\/riboflavin synthase complex: Shapes and functions of a highly variable enzyme system","volume":"280","author":"Ladenstein","year":"2013","journal-title":"FEBS J."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.1111\/j.1432-1033.1994.tb19079.x","article-title":"The lumazine synthase\/riboflavin synthase complex of Bacillus subtilis. X-ray structure analysis of hollow reconstituted beta-subunit capsids","volume":"223","author":"Ladenstein","year":"1994","journal-title":"Eur. J. Biochem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/0022-2836(88)90128-3","article-title":"Heavy riboflavin synthase from Bacillus subtilis. Crystal structure analysis of the icosahedral beta 60 capsid at 3.3 A resolution","volume":"203","author":"Ladenstein","year":"1988","journal-title":"J. Mol. Biol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"7213","DOI":"10.1073\/pnas.1231432100","article-title":"A postgenomic method for predicting essential genes at subsaturation levels of mutagenesis: Application to Mycobacterium tuberculosis","volume":"100","author":"Lamichhane","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B53","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/0301-4622(93)85006-4","article-title":"Lumazine protein and the excitation mechanism in bacterial bioluminescence","volume":"48","author":"Lee","year":"1993","journal-title":"Biophys. Chem."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1021\/bi015652u","article-title":"Structural definition of the active site and catalytic mechanism of 3,4-dihydroxy-2-butanone-4-phosphate synthase","volume":"41","author":"Liao","year":"2002","journal-title":"Biochemistry"},{"key":"B55","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/s0969-2126(00)00550-5","article-title":"Crystal structure of 3,4-dihydroxy-2-butanone 4-phosphate synthase of riboflavin biosynthesis","volume":"9","author":"Liao","year":"","journal-title":"Structure"},{"key":"B56","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/s0969-2126(01)00600-1","article-title":"Crystal structure of riboflavin synthase","volume":"9","author":"Liao","year":"","journal-title":"Structure"},{"key":"B57","doi-asserted-by":"publisher","first-page":"2833","DOI":"10.1073\/pnas.0511100103","article-title":"An ordered, nonredundant library of Pseudomonas aeruginosa strain PA14 transposon insertion mutants","volume":"103","author":"Liberati","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B58","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1111\/j.1747-0285.2010.00946.x","article-title":"Riboflavin biosynthetic and regulatory factors as potential novel anti-infective drug targets","volume":"75","author":"Long","year":"2010","journal-title":"Chem. Biol. Drug Des."},{"key":"B59","doi-asserted-by":"publisher","first-page":"2625","DOI":"10.1111\/j.1742-4658.2011.08202.x","article-title":"Flavogenomics-a genomic and structural view of flavin-dependent proteins","volume":"278","author":"Macheroux","year":"2011","journal-title":"FEBS J."},{"key":"B60","doi-asserted-by":"publisher","first-page":"6499","DOI":"10.1021\/bi800264g","article-title":"Kinetic and mechanistic analysis of the Escherichia coli ribD-encoded bifunctional deaminase-reductase involved in riboflavin biosynthesis","volume":"47","author":"Magalh\u00e3es","year":"2008","journal-title":"Biochemistry"},{"key":"B61","doi-asserted-by":"publisher","first-page":"6329","DOI":"10.1021\/jo0703092","article-title":"The diverse roles of flavin coenzymes-nature\u2019s most versatile thespians","volume":"72","author":"Mansoorabadi","year":"2007","journal-title":"J. Org. Chem."},{"key":"B62","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1016\/s0022-2836(03)00844-1","article-title":"The structure of the N-terminal domain of riboflavin synthase in complex with riboflavin at 2.6A resolution","volume":"331","author":"Meining","year":"2003","journal-title":"J. Mol. Biol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1006\/jmbi.2000.3742","article-title":"The atomic structure of pentameric lumazine synthase from Saccharomyces cerevisiae at 1.85 A resolution reveals the binding mode of a phosphonate intermediate analogue","volume":"299","author":"Meining","year":"2000","journal-title":"J. Mol. Biol."},{"key":"B64","doi-asserted-by":"publisher","first-page":"2746","DOI":"10.1021\/bi047848a","article-title":"Crystal structure of lumazine synthase from Mycobacterium tuberculosis as a target for rational drug design: Binding mode of a new class of purinetrione inhibitors","volume":"44","author":"Morgunova","year":"2005","journal-title":"Biochemistry"},{"key":"B65","doi-asserted-by":"publisher","first-page":"17231","DOI":"10.1074\/jbc.M701724200","article-title":"Lumazine synthase from Candida albicans as an anti-fungal target enzyme: Structural and biochemical basis for drug design","volume":"282","author":"Morgunova","year":"2007","journal-title":"J. Biol. Chem."},{"key":"B66","volume-title":"Chemistry and biochemistry of flavoenzymes","author":"Muller","year":"2018"},{"key":"B67","doi-asserted-by":"publisher","first-page":"12120","DOI":"10.1073\/pnas.92.26.12120","article-title":"Active site topology and reaction mechanism of GTP cyclohydrolase I","volume":"92","author":"Nar","year":"1995","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B68","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/0005-2744(81)90044-9","article-title":"Biosynthesis of riboflavin. Characterization of the product of the deaminase","volume":"662","author":"Nielsen","year":"1981","journal-title":"Biochim. Biophys. Acta"},{"key":"B69","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1039\/c29690000290","article-title":"Deuterium exchange of C-methyl protons in 6,7-dimethyl-8-D-ribityl-lumazine, and studies of the mechanism of riboflavin biosynthesis","volume":"290","author":"Paterson","year":"1969","journal-title":"J. Chem. Soc. D. Chem. Commun."},{"key":"B70","doi-asserted-by":"publisher","first-page":"2355","DOI":"10.1110\/ps.8.11.2355","article-title":"Crystal structure analysis of a pentameric fungal and an icosahedral plant lumazine synthase reveals the structural basis for differences in assembly","volume":"8","author":"Persson","year":"1999","journal-title":"Protein Sci."},{"key":"B71","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1111\/j.1432-1033.1997.00790.x","article-title":"Purification and characterization of flavoproteins and cytochromes from the yellow bioluminescence marine bacterium Vibrio fischeri strain Y1","volume":"245","author":"Petushkov","year":"1997","journal-title":"Eur. J. Biochem."},{"key":"B72","doi-asserted-by":"publisher","first-page":"2225","DOI":"10.1016\/s0021-9258(18)67964-5","article-title":"Studies on the nature of the enzymic conversion of 6,7-dimethyl-8-ribityllumazine to riboflavin","volume":"238","author":"Plaut","year":"1963","journal-title":"J. Biol. Chem."},{"key":"B73","doi-asserted-by":"publisher","first-page":"1224","DOI":"10.1074\/jbc.M509440200","article-title":"Crystal structure of an archaeal pentameric riboflavin synthase in complex with a substrate analog inhibitor: Stereochemical implications","volume":"281","author":"Ramsperger","year":"2006","journal-title":"J. Biol. Chem."},{"key":"B74","doi-asserted-by":"publisher","first-page":"36912","DOI":"10.1074\/jbc.M507725200","article-title":"GTP cyclohydrolase II structure and mechanism","volume":"280","author":"Ren","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B75","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1128\/jb.179.6.2022-2028.1997","article-title":"Biosynthesis of riboflavin: Characterization of the bifunctional deaminase-reductase of Escherichia coli and Bacillus subtilis","volume":"179","author":"Richter","year":"1997","journal-title":"J. Bacteriol."},{"key":"B76","doi-asserted-by":"publisher","first-page":"4050","DOI":"10.1128\/jb.174.12.4050-4056.1992","article-title":"Biosynthesis of riboflavin: Cloning, sequencing, and expression of the gene coding for 3,4-dihydroxy-2-butanone 4-phosphate synthase of Escherichia coli","volume":"174","author":"Richter","year":"1992","journal-title":"J. Bacteriol."},{"key":"B77","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1006\/jmbi.1995.0542","article-title":"Studies on the lumazine synthase\/riboflavin synthase complex of Bacillus subtilis: Crystal structure analysis of reconstituted, icosahedral beta-subunit capsids with bound substrate analogue inhibitor at 2.4 A resolution","volume":"253","author":"Ritsert","year":"1995","journal-title":"J. Mol. Biol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"22273","DOI":"10.1074\/jbc.M100752200","article-title":"Biosynthesis of riboflavin: Studies on the mechanism of GTP cyclohydrolase II","volume":"276","author":"Ritz","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B79","doi-asserted-by":"publisher","first-page":"48914","DOI":"10.1074\/jbc.M309630200","article-title":"A self-sufficient cytochrome p450 with a primary structural organization that includes a flavin domain and a [2Fe-2S] redox center","volume":"278","author":"Roberts","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B80","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1128\/IAI.74.3.1649-1660.2006","article-title":"Salmonella enterica highly expressed genes are disease specific","volume":"74","author":"Rollenhagen","year":"2006","journal-title":"Infect. Immun."},{"key":"B81","doi-asserted-by":"publisher","first-page":"6416","DOI":"10.1074\/jbc.M412018200","article-title":"Competitive inhibitors of Mycobacterium tuberculosis ribose-5-phosphate isomerase B reveal new information about the reaction mechanism","volume":"280","author":"Roos","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B82","doi-asserted-by":"publisher","first-page":"12357","DOI":"10.1073\/pnas.221455298","article-title":"An optomechanical transducer in the blue light receptor phototropin from Avena sativa","volume":"98","author":"Salomon","year":"2001","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B83","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1046\/j.1365-2958.2003.03425.x","article-title":"Genes required for mycobacterial growth defined by high density mutagenesis","volume":"48","author":"Sassetti","year":"2003","journal-title":"Mol. Microbiol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"12686","DOI":"10.1016\/s0021-9258(19)38398-x","article-title":"The lumazine synthase-riboflavin synthase complex of Bacillus subtilis. Crystallization of reconstituted icosahedral beta-subunit capsids","volume":"265","author":"Schott","year":"1990","journal-title":"J. Biol. Chem."},{"key":"B85","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1515\/znc-1987-0416","article-title":"Enzymatic synthesis of riboflavin and FMN specifically labeled with 13C in the xylene ring","volume":"42","author":"Sedlmaier","year":"1987","journal-title":"Z. Naturforsch. C"},{"key":"B86","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1107\/S1399004714005161","article-title":"Crystallographic and kinetic study of riboflavin synthase from Brucella abortus, a chemotherapeutic target with an enhanced intrinsic flexibility","volume":"70","author":"Serer","year":"2014","journal-title":"Acta Crystallogr. D. Biol. Crystallogr."},{"key":"B87","doi-asserted-by":"publisher","first-page":"2522","DOI":"10.1111\/febs.14829","article-title":"A high-throughput screening for inhibitors of riboflavin synthase identifies novel antimicrobial compounds to treat brucellosis","volume":"286","author":"Serer","year":"2019","journal-title":"FEBS J."},{"key":"B88","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1016\/j.jsb.2011.01.013","article-title":"Structural basis for pH dependent monomer-dimer transition of 3,4-dihydroxy 2-butanone-4-phosphate synthase domain from Mycobacterium tuberculosis","volume":"174","author":"Singh","year":"2011","journal-title":"J. Struct. Biol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"42256","DOI":"10.1074\/jbc.M307301200","article-title":"Structure of 3,4-dihydroxy-2-butanone 4-phosphate synthase from methanococcus jannaschii in complex with divalent metal ions and the substrate ribulose 5-phosphate: Implications for the catalytic mechanism","volume":"278","author":"Steinbacher","year":"2003","journal-title":"J. Biol. Chem."},{"key":"B90","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.jmb.2006.12.009","article-title":"The crystal structure of the bifunctional deaminase\/reductase RibD of the riboflavin biosynthetic pathway in Escherichia coli: Implications for the reductive mechanism","volume":"373","author":"Stenmark","year":"2007","journal-title":"J. Mol. Biol."},{"key":"B91","doi-asserted-by":"publisher","first-page":"5123","DOI":"10.1021\/jo900238q","article-title":"Discovery and development of a small molecule library with lumazine synthase inhibitory activity","volume":"74","author":"Talukdar","year":"2009","journal-title":"J. Org. Chem."},{"key":"B92","doi-asserted-by":"publisher","first-page":"6239","DOI":"10.1021\/jo3010364","article-title":"O-Nucleoside, S-nucleoside, and N-nucleoside probes of lumazine synthase and riboflavin synthase","volume":"77","author":"Talukdar","year":"2012","journal-title":"J. Org. Chem."},{"key":"B93","doi-asserted-by":"publisher","first-page":"9043","DOI":"10.1038\/sj.onc.1205958","article-title":"Photolyase\/cryptochrome blue-light photoreceptors use photon energy to repair DNA and reset the circadian clock","volume":"21","author":"Thompson","year":"2002","journal-title":"Oncogene"},{"key":"B94","doi-asserted-by":"publisher","first-page":"20610","DOI":"10.1016\/s0021-9258(18)54753-0","article-title":"Biosynthesis of riboflavin. Studies on the mechanism of L-3,4-dihydroxy-2-butanone 4-phosphate synthase","volume":"266","author":"Volk","year":"1991","journal-title":"J. Biol. Chem."},{"key":"B95","doi-asserted-by":"publisher","first-page":"19479","DOI":"10.1016\/s0021-9258(17)45398-1","article-title":"Studies on the 4-carbon precursor in the biosynthesis of riboflavin. Purification and properties of L-3,4-dihydroxy-2-butanone-4-phosphate synthase","volume":"265","author":"Volk","year":"1990","journal-title":"J. Biol. Chem."},{"key":"B96","first-page":"362","article-title":"Isolation of vitamin B2 auxotroph and preliminary genetic mapping in Salmonella typhimurium","volume":"19","author":"Wang","year":"1992","journal-title":"Yi Chuan Xue Bao"},{"key":"B97","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1146\/annurev.genet.40.110405.090603","article-title":"Interplay of circadian clocks and metabolic rhythms","volume":"40","author":"Wijnen","year":"2006","journal-title":"Annu. Rev. Genet."},{"key":"B98","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.jsb.2015.08.004","article-title":"Structural and biochemical characterization of GTP cyclohydrolase II from Helicobacter pylori reveals its redox dependent catalytic activity","volume":"192","author":"Yadav","year":"2015","journal-title":"J. Struct. Biol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/s0022-2836(03)00186-4","article-title":"A structure-based model of the reaction catalyzed by lumazine synthase from Aquifex aeolicus","volume":"328","author":"Zhang","year":"2003","journal-title":"J. Mol. Biol."},{"key":"B100","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1006\/jmbi.2000.4435","article-title":"X-Ray structure analysis and crystallographic refinement of lumazine synthase from the hyperthermophile aquifex aeolicus at 1.6 A resolution: Determinants of thermostability revealed from structural comparisons","volume":"306","author":"Zhang","year":"2001","journal-title":"J. Mol. Biol."},{"key":"B101","doi-asserted-by":"publisher","first-page":"2715","DOI":"10.1021\/jo702631a","article-title":"A new series of N-[2,4-dioxo-6-d-ribitylamino-1,2,3,4-tetrahydropyrimidin-5-yl]oxalamic acid derivatives as inhibitors of lumazine synthase and riboflavin synthase: Design, synthesis, biochemical evaluation, crystallography, and mechanistic implications","volume":"73","author":"Zhang","year":"2008","journal-title":"J. Org. Chem."},{"key":"B102","doi-asserted-by":"publisher","first-page":"7176","DOI":"10.1021\/jo070982r","article-title":"A new series of 3-alkyl phosphate derivatives of 4,5,6,7-tetrahydro-1-D-ribityl-1H-pyrazolo[3,4-d]pyrimidinedione as inhibitors of lumazine synthase: Design, synthesis, and evaluation","volume":"72","author":"Zhang","year":"2007","journal-title":"J. Org. Chem."},{"key":"B103","doi-asserted-by":"publisher","first-page":"5297","DOI":"10.1021\/jo900768c","article-title":"Discovery and development of the covalent hydrates of trifluoromethylated Pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis","volume":"74","author":"Zhao","year":"2009","journal-title":"J. Org. Chem."},{"key":"B104","doi-asserted-by":"publisher","first-page":"8093","DOI":"10.1074\/jbc.M312035200","article-title":"High order quaternary arrangement confers increased structural stability to Brucella sp. lumazine synthase","volume":"279","author":"Zylberman","year":"2004","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2023.1228763\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T04:37:30Z","timestamp":1689050250000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2023.1228763\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,11]]},"references-count":104,"alternative-id":["10.3389\/fmolb.2023.1228763"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2023.1228763","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,11]]},"article-number":"1228763"}}