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. 2011 Oct 6;2(9):691–695. doi: 10.1007/s13238-011-1100-8

Biotin biosynthesis in Mycobacterium tuberculosis: physiology, biochemistry and molecular intervention

Wanisa Salaemae 1, Al Azhar 1, Grant W Booker 1, Steven W Polyak 1,✉
PMCID: PMC4875270  PMID: 21976058

Abstract

Biotin is an important micronutrient that serves as an essential enzyme cofactor. Bacteria obtain biotin either through de novo synthesis or by active uptake from exogenous sources. Mycobacteria are unusual amongst bacteria in that their primary source of biotin is through de novo synthesis. Here we review the importance of biotin biosynthesis in the lifecycle of Mycobacteria. Genetic screens designed to identify key metabolic processes have highlighted a role for the biotin biosynthesis in bacilli growth, infection and survival during the latency phase. These studies help to establish the biotin biosynthetic pathway as a potential drug target for new anti-tuberculosis agents.

References

  1. Abdel-Hamid A.M., Cronan J.E. In vivo resolution of conflicting in vitro results: synthesis of biotin from dethiobiotin does not require pyridoxal phosphate. Chem Biol. 2007;14:1215–1220. doi: 10.1016/j.chembiol.2007.10.009. [DOI] [PubMed] [Google Scholar]
  2. Ahmad S. Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection. Clin Dev Immunol. 2011;2011:814943. doi: 10.1155/2011/814943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Arabolaza A., Shillito M.E., Lin T.W., Diacovich L., Melgar M., Pham H., Amick D., Gramajo H., Tsai S.C. Crystal structures and mutational analyses of acyl-CoA carboxylase beta subunit of Streptomyces coelicolor. Biochemistry. 2010;49:7367–7376. doi: 10.1021/bi1005305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baek S.H., Li A.H., Sassetti C.M. Metabolic regulation of mycobacterial growth and antibiotic sensitivity. PLoS Biol. 2011;9:e1001065. doi: 10.1371/journal.pbio.1001065. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berkovitch F., Nicolet Y., Wan J.T., Jarrett J.T., Drennan C.L. Crystal structure of biotin synthase, an S-adenosylmethionine-dependent radical enzyme. Science. 2004;303:76–79. doi: 10.1126/science.1088493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Chan D.I., Vogel H.J. Current understanding of fatty acid biosynthesis and the acyl carrier protein. Biochem J. 2010;430:1–19. doi: 10.1042/BJ20100462. [DOI] [PubMed] [Google Scholar]
  7. Cronan J.E., Lin S. Synthesis of the α,ω-dicarboxylic acid precursor of biotin by the canonical fatty acid biosynthetic pathway. Curr Opin Chem Biol. 2011;15:407–413. doi: 10.1016/j.cbpa.2011.03.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dey S., Lane J.M., Lee R.E., Rubin E.J., Sacchettini J.C. Structural characterization of the Mycobacterium tuberculosis biotin biosynthesis enzymes 7,8-diaminopelargonic acid synthase and dethiobiotin synthetase. Biochemistry. 2010;49:6746–6760. doi: 10.1021/bi902097j. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dye C., Williams B.G. The population dynamics and control of tuberculosis. Science. 2010;328:856–861. doi: 10.1126/science.1185449. [DOI] [PubMed] [Google Scholar]
  10. Eisenreich W., Dandekar T., Heesemann J., Goebel W. Carbon metabolism of intracellular bacterial pathogens and possible links to virulence. Nat Rev Microbiol. 2010;8:401–412. doi: 10.1038/nrmicro2351. [DOI] [PubMed] [Google Scholar]
  11. Gago G., Diacovich L., Arabolaza A., Tsai S.C., Gramajo H. Fatty acid biosynthesis in actinomycetes. FEMS Microbiol Rev. 2011;35:475–497. doi: 10.1111/j.1574-6976.2010.00259.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hebbeln P., Rodionov D.A., Alfandega A., Eitinger T. Biotin uptake in prokaryotes by solute transporters with an optional ATP-binding cassette-containing module. Proc Natl Acad Sci U S A. 2007;104:2909–2914. doi: 10.1073/pnas.0609905104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Joshi S.M., Pandey A.K., Capite N., Fortune S.M., Rubin E.J., Sassetti C.M. Characterization of mycobacterial virulence genes through genetic interaction mapping. Proc Natl Acad Sci U S A. 2006;103:11760–11765. doi: 10.1073/pnas.0603179103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Keer J., Smeulders M.J., Gray K.M., Williams H.D. Mutants of Mycobacterium smegmatis impaired in stationaryphase survival. Microbiology. 2000;146:2209–2217. doi: 10.1099/00221287-146-9-2209. [DOI] [PubMed] [Google Scholar]
  15. Kitahara T., Hotta K., Yoshida M., Okami Y. Biological studies of amiclenomycin. J Antibiot (Tokyo) 1975;28:215–221. doi: 10.7164/antibiotics.28.215. [DOI] [PubMed] [Google Scholar]
  16. Koul A., Arnoult E., Lounis N., Guillemont J., Andries K. The challenge of new drug discovery for tuberculosis. Nature. 2011;469:483–490. doi: 10.1038/nature09657. [DOI] [PubMed] [Google Scholar]
  17. Kwan C.K., Ernst J.D. HIV and tuberculosis: a deadly human syndemic. Clin Microbiol Rev. 2011;24:351–376. doi: 10.1128/CMR.00042-10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lawn S.D., Zumla A.I. Tuberculosis. Lancet. 2011;378:57–72. doi: 10.1016/S0140-6736(10)62173-3. [DOI] [PubMed] [Google Scholar]
  19. Lin S., Hanson R.E., Cronan J.E. Biotin synthesis begins by hijacking the fatty acid synthetic pathway. Nat Chem Biol. 2010;6:682–688. doi: 10.1038/nchembio.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Lu H., Tonge P.J. Inhibitors of FabI, an enzyme drug target in the bacterial fatty acid biosynthesis pathway. Acc Chem Res. 2008;41:11–20. doi: 10.1021/ar700156e. [DOI] [PubMed] [Google Scholar]
  21. Mann S., Colliandre L., Labesse G., Ploux O. Inhibition of 7,8-diaminopelargonic acid aminotransferase from Mycobacterium tuberculosis by chiral and achiral anologs of its substrate: biological implications. Biochimie. 2009;91:826–834. doi: 10.1016/j.biochi.2009.03.019. [DOI] [PubMed] [Google Scholar]
  22. Mann S., Marquet A., Ploux O. Inhibition of 7,8-diaminopelargonic acid aminotransferase by amiclenomycin and analogues. Biochem Soc Trans. 2005;33:802–805. doi: 10.1042/BST0330802. [DOI] [PubMed] [Google Scholar]
  23. Minnikin D.E., Kremer L., Dover L.G., Besra G.S. The methyl-branched fortifications of Mycobacterium tuberculosis. Chem Biol. 2002;9:545–553. doi: 10.1016/S1074-5521(02)00142-4. [DOI] [PubMed] [Google Scholar]
  24. Mock D.M., Malik M.I. Distribution of biotin in human plasma: most of the biotin is not bound to protein. Am J Clin Nutr. 1992;56:427–432. doi: 10.1093/ajcn/56.2.427. [DOI] [PubMed] [Google Scholar]
  25. Niederweis M., Danilchanka O., Huff J., Hoffmann C., Engelhardt H. Mycobacterial outer membranes: in search of proteins. Trends Microbiol. 2010;18:109–116. doi: 10.1016/j.tim.2009.12.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ogata K., Izumi Y., Tani Y. The controlling action of actithiazic acid on the biosynthesis of biotin-vitamers by various microorganisms Agr. Biol Chem. 1973;37:1079–1085. [Google Scholar]
  27. Okami Y., Kitahara T., Hamada M., Naganawa H., Kondo S. Studies on a new amino acid antibiotic, amiclenomycin. J Antibiot (Tokyo) 1974;27:656–664. doi: 10.7164/antibiotics.27.656. [DOI] [PubMed] [Google Scholar]
  28. Parsons, J.B., and Rock, C.O. (2011). Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery? Curr Opin Microbiol Aug 20. [Epub ahead of print]. [DOI] [PMC free article] [PubMed]
  29. Rengarajan J., Bloom B.R., Rubin E.J. Genome-wide requirements for Mycobacterium tuberculosis adaptation and survival in macrophages. Proc Natl Acad Sci U S A. 2005;102:8327–8332. doi: 10.1073/pnas.0503272102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rodionov D.A., Hebbeln P., Eudes A., ter Beek J., Rodionova I.A., Erkens G.B., Slotboom D.J., Gelfand M.S., Osterman A.L., Hanson A.D., et al. A novel class of modular transporters for vitamins in prokaryotes. J Bacteriol. 2009;191:42–51. doi: 10.1128/JB.01208-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Rodionov D.A., Mironov A.A., Gelfand M.S. Conservation of the biotin regulon and the BirA regulatory signal in Eubacteria and Archaea. Genome Res. 2002;12:1507–1516. doi: 10.1101/gr.314502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Russell D.G. Mycobacterium tuberculosis: here today, and here tomorrow. Nat Rev Mol Cell Biol. 2001;2:569–577. doi: 10.1038/35085034. [DOI] [PubMed] [Google Scholar]
  33. Russell D.G., Barry C.E., 3rd, Flynn J.L. Tuberculosis: what we don’t know can, and does, hurt us. Science. 2010;328:852–856. doi: 10.1126/science.1184784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Said H.M. Cell and molecular aspects of human intestinal biotin absorption. J Nutr. 2009;139:158–162. doi: 10.3945/jn.108.092023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Sandmark J., Mann S., Marquet A., Schneider G. Structural basis for the inhibition of the biosynthesis of biotin by the antibiotic amiclenomycin. J Biol Chem. 2002;277:43352–43358. doi: 10.1074/jbc.M207239200. [DOI] [PubMed] [Google Scholar]
  36. Sassetti C.M., Boyd D.H., Rubin E.J. Comprehensive identification of conditionally essential genes in mycobacteria. Proc Natl Acad Sci U S A. 2001;98:12712–12717. doi: 10.1073/pnas.231275498. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Sassetti C.M., Boyd D.H., Rubin E.J. Genes required for mycobacterial growth defined by high density mutagenesis. Mol Microbiol. 2003;48:77–84. doi: 10.1046/j.1365-2958.2003.03425.x. [DOI] [PubMed] [Google Scholar]
  38. Sassetti C.M., Rubin E.J. Genetic requirements for mycobacterial survival during infection. Proc Natl Acad Sci U S A. 2003;100:12989–12994. doi: 10.1073/pnas.2134250100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Seki M. Biological significance and development of practical synthesis of biotin. Med Res Rev. 2006;26:434–482. doi: 10.1002/med.20058. [DOI] [PubMed] [Google Scholar]
  40. Takayama K., Wang C., Besra G.S. Pathway to synthesis and processing of mycolic acids in Mycobacterium tuberculosis. Clin Microbiol Rev. 2005;18:81–101. doi: 10.1128/CMR.18.1.81-101.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Wright H.T., Reynolds K.A. Antibacterial targets in fatty acid biosynthesis. Curr Opin Microbiol. 2007;10:447–453. doi: 10.1016/j.mib.2007.07.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Yu J., Niu C., Wang D., Li M., Teo W., Sun G., Wang J., Liu J., Gao Q. MMAR_2770, a new enzyme involved in biotin biosynthesis, is essential for the growth of Mycobacterium marinum in macrophages and zebrafish. Microbes Infect. 2011;13:33–41. doi: 10.1016/j.micinf.2010.08.010. [DOI] [PubMed] [Google Scholar]

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