Riboflavin biosynthetic and regulatory factors as potential novel anti-infective drug targets: Perspective

Chemical Biology and Drug Design

Volumn 75, Issue 4, 2010, Pages 339-347

  Long, Quanxin ^a   Ji, Lei ^a   Wang, Honghai ^b   Xie, Jianping ^a,b  

^a SOUTHWEST UNIVERSITY   (China)

^b FUDAN UNIVERSITY   (China)

Author keywords

Drug discovery; Drug lead; Riboflavin synthesis; Riboswitch

Indexed keywords

5 (1,3,7 TRIHYDRO 9 DEXTRO RIBITYL 2,4, 8 PURINETRIONE 7 YL) 1,1 DIFLUOROPENTANE 1 PHOSPHATE; 5 (6 DEXTRO RIBITYLAMINO 2,4 DIHYDROXYPYRIMIDINE 5 YL) 1 PENTYLPHOSPHONIC ACID; 5 AMINO 6 RIBITYLAMINO 2,4(1H,3H)PYRIMIDINEDIONE; 5 AMINO 6 RIBITYLAMINO 2,4(1H,3H)PYRIMIDINEDIONE DERIVATIVE; 5 NITRO 6 (DRIBITYLAMINO) 2,4(1H,3H)PYRIMIDINEDIONE; 6 (6 DEXTRO RIBITYLAMINO 2,4 DIHYDROXYPYRIMIDIN 5 YL) 1 HEXYLPHOSPHONIC ACID; 6 CARBOXYETHYL 7 OXO 8 RIBITYLLUMAZINE; 6,7 DIMETHYL 8 RIBITYLLUMAZINE; 6,7 DIMETHYL 8 RIBITYLLUMAZINE DERIVATIVE; 9-D-RIBITYL-1,3,7-TRIHYDRO-2,6,8 PURINETRIONE; [4 (6 CHLORO 2,4 DIOXO 1,2,3,4 TETRAHYDROPYRIMIDIN 5 YL)BUTYL] 1 PHOSPHATE; [5 (4 CHLOROPHENYL) 5 HYDROXY 3 (TRIFLUOROMETHYL) 4,5 DIHYDRO 1H PYRAZOL 1 YL] (3 TOLYL)METHANONE; ENZYME INHIBITOR; RIBOFLAVIN; RIBOFLAVIN SYNTHASE; TUBERCULOSTATIC AGENT; UNCLASSIFIED DRUG;

BACILLUS SUBTILIS; BIOSYNTHESIS; ENZYME INHIBITION; ESCHERICHIA COLI; GENE CONTROL; GENE TARGETING; HUMAN; MYCOBACTERIUM TUBERCULOSIS; NONHUMAN; OXIDATION REDUCTION REACTION; PRIORITY JOURNAL; PROTEIN TARGETING; REGULATORY MECHANISM; REVIEW; RIBOSWITCH; SCHIZOSACCHAROMYCES POMBE; TRANSCRIPTION INITIATION; TRANSLATION INITIATION; VITAMIN METABOLISM;

AMINO ACID SEQUENCE; ANTI-INFECTIVE AGENTS; ANTITUBERCULAR AGENTS; MOLECULAR SEQUENCE DATA; RIBOFLAVIN; RIBOFLAVIN SYNTHASE; SEQUENCE ALIGNMENT;

EID: 77449123790     PISSN: 17470277     EISSN: 17470285     Source Type: Journal    
DOI: 10.1111/j.1747-0285.2010.00946.x     Document Type: Review

References (54)

1. Norrby S.R., Nord C.E., Finch R. (2005) Lack of development of new antimicrobial drugs: a potential serious threat to public health. Lancet Infect Dis 5 : 115 119.
2. Lindsay M.A. (2003) Target discovery. Nat Rev Drug Discov 2 : 831 838.
3. Knowles J., Gromo G. (2003) A guide to drug discovery: target selection in drug discovery. Nat Rev Drug Discov 2 : 63 69.
4. Wang J., Zhu S., Xu C. (2002) Biochemistry, 3th edn. Beijing : higher education press.
5. Dahl S.G., Sylte I., Ravna A.W. (2004) Structures and models of transporter proteins. J Pharmacol Exp Ther 309 : 853 860.
6. Gelfand M.S., Mironov A.A., Jomantas J., Kozlov Y.I., Perumov D.A. (1999) A conserved RNA structure element involved in the regulation of bacterial riboflavin synthesis genes. Trends Genet 15 : 439 442.
7. Blount K.F., Breaker R.R. (2006) Riboswitches as antibacterial drug targets. Nat Biotechnol 24 : 1558 1564.
8. Lee E.R., Blount K.F., Breaker R.R. (2009) Roseoflavin is a natural antibacterial compound that binds to FMN riboswitches and regulates gene expression. RNA Biol 6 : 187 194.
9. Vitreschak A.G., Rodionov D.A., Mironov A.A., Gelfand M.S. (2002) Regulation of riboflavin biosynthesis and transport genes in bacteria by transcriptional and translational attenuation. Nucleic Acids Res 30 : 3141 3151.
10. Gusarov I.I., Kreneva R.A., Podcharniaev D.A., Iomantas Iu V., Abalakina E.G., Stoinova N.V., Perumov D.A., Kozlov Iu I. (1997) [Riboflavin biosynthetic genes in Bacillus amyloliquefaciens: primary structure, organization and regulation of activity]. Mol Biol (Mosk) 31 : 446 453.
11. Fuller T.E., Mulks M.H. (1995) Characterization of Actinobacillus pleuropneumoniae riboflavin biosynthesis genes. J Bacteriol 177 : 7265 7270.
12. Bereswill S., Hinkelmann S., Kist M., Sander A. (1999) Molecular analysis of riboflavin synthesis genes in Bartonella henselae and use of the ribC gene for differentiation of Bartonella species by PCR. J Clin Microbiol 37 : 3159 3166.
13. Morgunova E., Meining W., Illarionov B., Haase I., Jin G., Bacher A. et al. (2005) Crystal structure of lumazine synthase from Mycobacterium tuberculosis as a target for rational drug design: binding mode of a new class of purinetrione inhibitors. Biochemistry 44 : 2746 2758.
14. Mortl S., Fischer M., Richter G., Tack J., Weinkauf S., Bacher A. (1996) Biosynthesis of riboflavin. Lumazine synthase of Escherichia coli. J Biol Chem 271 : 33201 33207. (Pubitemid 27010126)
15. Zylberman V., Craig P.O., Klinke S., Braden B.C., Cauerhff A., Goldbaum F.A. (2004) High order quaternary arrangement confers increased structural stability to Brucella sp. lumazine synthase. J Biol Chem 279 : 8093 8101.
16. Klinke S., Zylberman V., Vega D.R., Guimaraes B.G., Braden B.C., Goldbaum F.A. (2005) Crystallographic studies on decameric Brucella spp. Lumazine synthase: a novel quaternary arrangement evolved for a new function? J Mol Biol 353 : 124 137.
17. Persson K., Schneider G., Jordan D.B., Viitanen P.V., Sandalova T. (1999) Crystal structure analysis of a pentameric fungal and an icosahedral plant lumazine synthase reveals the structural basis for differences in assembly. Protein Sci 8 : 2355 2365.
18. Meining W., Mortl S., Fischer M., Cushman M., Bacher A., Ladenstein R. (2000) The atomic structure of pentameric lumazine synthase from Saccharomyces cerevisiae at 1.85 A resolution reveals the binding mode of a phosphonate intermediate analogue. J Mol Biol 299 : 181 197.
19. Gerhardt S., Haase I., Steinbacher S., Kaiser J.T., Cushman M., Bacher A. et al. (2002) The structural basis of riboflavin binding to Schizosaccharomyces pombe 6,7-dimethyl-8-ribityllumazine synthase. J Mol Biol 318 : 1317 1329. (Pubitemid 34754000)
20. Gerhardt S., Schott A.K., Kairies N., Cushman M., Illarionov B., Eisenreich W. et al. (2002) Studies on the reaction mechanism of riboflavin synthase: X-ray crystal structure of a complex with 6-carboxyethyl-7-oxo-8- ribityllumazine. Structure 10 : 1371 1381.
21. Liao D.I., Wawrzak Z., Calabrese J.C., Viitanen P.V., Jordan D.B. (2001) Crystal structure of riboflavin synthase. Structure 9 : 399 408.
22. Beach R.L., Plaut G.W. (1970) Stereospecificity of the enzymatic synthesis of the o-xylene ring of riboflavin. J Am Chem Soc 92 : 2913 2916.
23. Fischer M., Schott A.K., Romisch W., Ramsperger A., Augustin M., Fidler A. et al. (2004) Evolution of vitamin B2 biosynthesis. A novel class of riboflavin synthase in Archaea. J Mol Biol 343 : 267 278.
24. Illarionov B., Eisenreich W., Bacher A. (2001) A pentacyclic reaction intermediate of riboflavin synthase. Proc Natl Acad Sci USA 98 : 7224 7229.
25. Illarionov B., Eisenreich W., Schramek N., Bacher A., Fischer M. (2005) Biosynthesis of vitamin B2: diastereomeric reaction intermediates of archaeal and non-archaeal riboflavin synthases. J Biol Chem 280 : 28541 28546.
26. Fischer M., Bacher A. (2008) Biosynthesis of vitamin B2: structure and mechanism of riboflavin synthase. Arch Biochem Biophys 474 : 252 265.
27. Eberhardt S., Zingler N., Kemter K., Richter G., Cushman M., Bacher A. (2001) Domain structure of riboflavin synthase. Eur J Biochem 268 : 4315 4323.
28. Vogl C., Grill S., Schilling O., Stulke J., Mack M., Stolz J. (2007) Characterization of riboflavin (vitamin B2) transport proteins from Bacillus subtilis and Corynebacterium glutamicum. J Bacteriol 189 : 7367 7375.
29. Winkler W.C., Cohen-Chalamish S., Breaker R.R. (2002) An mRNA structure that controls gene expression by binding FMN. Proc Natl Acad Sci USA 99 : 15908 15913.
30. Lee J.M., Zhang S., Saha S., Santa Anna S., Jiang C., Perkins J. (2001) RNA expression analysis using an antisense Bacillus subtilis genome array. J Bacteriol 183 : 7371 7380.
31. Burgess C.M., Slotboom D.J., Geertsma E.R., Duurkens R.H., Poolman B., van Sinderen D. (2006) The riboflavin transporter RibU in Lactococcus lactis: molecular characterization of gene expression and the transport mechanism. J Bacteriol 188 : 2752 2760.
32. Coquard D., Huecas M., Ott M., van Dijl J.M., van Loon A.P., Hohmann H.P. (1997) Molecular cloning and characterisation of the ribC gene from Bacillus subtilis: a point mutation in ribC results in riboflavin overproduction. Mol Gen Genet 254 : 81 84.
33. Kil Y.V., Mironov V.N., Gorishin I., Kreneva R.A., Perumov D.A. (1992) Riboflavin operon of Bacillus subtilis: unusual symmetric arrangement of the regulatory region. Mol Gen Genet 233 : 483 486.
34. Mack M., van Loon A.P., Hohmann H.P. (1998) Regulation of riboflavin biosynthesis in Bacillus subtilis is affected by the activity of the flavokinase/flavin adenine dinucleotide synthetase encoded by ribC. J Bacteriol 180 : 950 955.
35. Solovieva I.M., Kreneva R.A., Leak D.J., Perumov D.A. (1999) The ribR gene encodes a monofunctional riboflavin kinase which is involved in regulation of the Bacillus subtilis riboflavin operon. Microbiology 145 (Pt 1 67 73.
36. Mironov A.S., Gusarov I., Rafikov R., Lopez L.E., Shatalin K., Kreneva R.A. et al. (2002) Sensing small molecules by nascent RNA: a mechanism to control transcription in bacteria. Cell 111 : 747 756.
37. Serganov A., Huang L., Patel D.J. (2009) Coenzyme recognition and gene regulation by a flavin mononucleotide riboswitch. Nature 458 : 233 237.
38. Cushman M., Mihalic J.T., Kis K., Bacher A. (1999) Design and synthesis of 6-(6-D-ribitylamino-2,4-dihydroxypyrimidin-5-yl)-1-hexyl phosphonic acid, a potent inhibitor of lumazine synthase. Bioorg Med Chem Lett 9 : 39 42. (Pubitemid 29023294)
39. Cushman M., Yang D., Gerhardt S., Huber R., Fischer M., Kis K. et al. (2002) Design, synthesis, and evaluation of 6-carboxyalkyl and 6-phosphonoxyalkyl derivatives of 7-oxo-8-ribitylaminolumazines as inhibitors of riboflavin synthase and lumazine synthase. J Org Chem 67 : 5807 5816.
40. Zhang Y., Illarionov B., Morgunova E., Jin G., Bacher A., Fischer M. et al. (2008) 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. J Org Chem 73 : 2715 2724.
41. Morgunova E., Illarionov B., Sambaiah T., Haase I., Bacher A., Cushman M. et al. (2006) Structural and thermodynamic insights into the binding mode of five novel inhibitors of lumazine synthase from Mycobacterium tuberculosis. Febs J 273 : 4790 4804.
42. Cushman M., Yang D., Kis K., Bacher A. (2001) 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. J Org Chem 66 : 8320 8327.
43. Cushman M., Sambaiah T., Jin G., Illarionov B., Fischer M., Bacher A. (2004) 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. J Org Chem 69 : 601 612.
44. Zhao Y., Bacher A., Illarionov B., Fischer M., Georg G., Ye Q.Z. al. (2009) Discovery and development of the covalent hydrates of trifluoromethylated pyrazoles as riboflavin synthase inhibitors with antibiotic activity against Mycobacterium tuberculosis. J Org Chem 74 : 5297 5303.
45. Philipp W.J., Poulet S., Eiglmeier K., Pascopella L., Balasubramanian V., Heym B. et al. (1996) An integrated map of the genome of the tubercle bacillus, Mycobacterium tuberculosis H37Rv, and comparison with Mycobacterium leprae. Proc Natl Acad Sci USA 93 : 3132 3137.
46. Cole S.T., Eiglmeier K., Parkhill J., James K.D., Thomson N.R., Wheeler P.R. et al. (2001) Massive gene decay in the leprosy bacillus. Nature 409 : 1007 1011.
47. Pal C., Papp B., Lercher M.J., Csermely P., Oliver S.G., Hurst L.D. (2006) Chance and necessity in the evolution of minimal metabolic networks. Nature 440 : 667 670.
48. Anishetty S., Pulimi M., Pennathur G. (2005) Potential drug targets in Mycobacterium tuberculosis through metabolic pathway analysis. Comput Biol Chem 29 : 368 378.
49. Bardos T.J. (1974) Antimetabolites: molecular design and mode of action. Top Curr Chem 52 : 63 98.
50. Mack M., Grill S. (2006) Riboflavin analogs and inhibitors of riboflavin biosynthesis. Appl Microbiol Biotechnol 71 : 265 275.
51. Montange R.K., Batey R.T. (2006) Structure of the S-adenosylmethionine riboswitch regulatory mRNA element. Nature 441 : 1172 1175.
52. Serganov A., Polonskaia A., Phan A.T., Breaker R.R., Patel D.J. (2006) Structural basis for gene regulation by a thiamine pyrophosphate-sensing riboswitch. Nature 441 : 1167 1171.
53. Chen J., Illarionov B., Bacher A., Fischer M., Haase I., Georg G. et al. (2005) A high-throughput screen utilizing the fluorescence of riboflavin for identification of lumazine synthase inhibitors. Anal Biochem 338 : 124 130.
54. Kaiser J., Illarionov B., Rohdich F., Eisenreich W., Saller S., den Brulle J.V. et al. (2007) A high-throughput screening platform for inhibitors of the riboflavin biosynthesis pathway. Anal Biochem 365 : 52 61.