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Targeting Mycobacterium Tuberculosis Proteins: Structure and Function Studies of Five Essential Proteins

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Targeting Mycobacterium Tuberculosis Proteins: Structure and Function Studies of Five Essential Proteins Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 411 Targeting Mycobacterium tuberculosis Proteins: Structure and Function Studies of Five Essential Proteins ADRIAN SUAREZ COVARRUBIAS ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 UPPSALA ISBN 978-91-554-7134-7 2008 urn:nbn:se:uu:diva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ist of publications This thesis consists of a comprehensive summary based on the following papers. In the text, the papers will be referred to by their roman numerals. I Covarrubias, A. S., Larsson, A. M., Högbom, M., Lindberg, J., Bergfors, T., Björkelid, C., Mowbray, S. L., Unge, T., and Jones, T. A. (2005). Structure and function of carbonic anhydrases from Mycobacterium tuberculosis, J. Biol. Chem. 280: 18782-89. II Covarrubias, A. S., Bergfors, T., Jones, T. A., and Högbom, M. (2006). Structural mechanics of the pH-dependent activity of beta-carbonic anhydrase from Mycobacterium tuberculosis. J. Biol. Chem. 281: 4993-4999. III Sacco, E.*, Covarrubias, A. S.*, O’Hare, H., Carroll, P., Eynard, N., Jones, T. A., Parish, T., Daffé, M., Bäckbro, K., and Quémard, A. (2007). The missing piece of the type II Fatty Acid Synthase system from Mycobacterium tuberculosis. PNAS. 104: 14628-14633. IV Covarrubias, A. S., Högbom, M., Bergfors, T., Carroll, P., Mannerstedt. K., Oscarson, S., Parish, T., Jones, T. A., and Mowbray, S. L. (2008). Structural, biochemical and in vivo investigations of the threonine synthase from Mycobacterium tuberculosis. J. Mol. Biol. Submitted. V Covarrubias, A. S., Larsson, A. M., Bergfors, T., Jones, T. A., Mowbray, S., and Unge, T. (2008). Structure and biochemical function studies of Mycobacterium tuberculosis essential protein Rv3778c*. Manuscript. * Sharing first authorship Articles I- III have been reproduced with permission from the respective copyright holders. Contents Introduction.....................................................................................................9 Aim and outline of thesis ..............................................................................11 General Methods...........................................................................................12 Target selection ........................................................................................12 Cloning.....................................................................................................15 Expression ................................................................................................16 Purification...............................................................................................18 Crystallization ..........................................................................................18 Solving the three-dimensional structure...................................................19 Biochemical function ...............................................................................19 Future perspectives...................................................................................20 Carbonic anhydrases .....................................................................................21 Background ..............................................................................................21 Rv1284 (Paper I) ......................................................................................22 Active site and enzymatic characterization .........................................23 Rv3588c (Paper I and II)..........................................................................25 Active site and enzymatic characterization .........................................25 Rv3273 .....................................................................................................28 Future perspectives...................................................................................29 FAS II proteins (Paper III)............................................................................30 Background ..............................................................................................30 Rv0636 co-expression and enzymatic characterization ...........................31 Future perspectives...................................................................................34 Threonine Synthase (Paper IV).....................................................................35 Background ..............................................................................................35 Active site and enzymatic characterization ..............................................36 Reaction mechanism ................................................................................37 Essentiality studies ...................................................................................39 Future perspectives...................................................................................40 Rv3778c (Paper V) .......................................................................................41 Background ..............................................................................................41 Structure solution .....................................................................................41 We have the structure, but what does Rv3778c do?.................................42 Known structures with a similar fold have a different active site........42 Proteins identified by BLASTp searches have a similar active site ....44 Investigation of Rv3778c’s function ...................................................46 Rv3778c does not seem to be an aminotransferase .............................47 Other information that could be significant.........................................47 The enzymatic activities assayed.........................................................49 Future perspectives...................................................................................50 Concluding remarks......................................................................................52 Summary in Swedish ....................................................................................53 Acknowledgements.......................................................................................55 References.....................................................................................................57 Abbreviations AP5 2-amino-5-phosphonopentanoic acid CoA Coenzyme A CSA Catalytic Site Atlas FAD Riboflavin adenine dinucleotide FAS Fatty acid synthase FMN Riboflavin mononucleotide FT Freeze thaw method HK Homoserine kinase LB Luria-Bertani medium MR Molecular replacement Mtb Mycobacterium tuberculosis MtTS Mycobacterium tuberculosis Threonine synthase NAD Nicotine adenine dinucleotide Ni-NTA Nickel-nitrilotriacetic acid-agarose OPH (2S)-O-phospho-L-homoserine PDB Protein Data Bank PLP Pyridoxal phosphate RAPID Rational Approaches to Pathogen Inhibitor Discovery RBS Ribosome binding site rmsd Root mean square distance SEC Size exclusion chromatography SSC Sodium chloride sodium citrate buffer TB Tuberculosis TBSGC TB Structure Genomics Consortium THF Tetrahydrofolate TraSH Transposon site hybridization TS Threonine synthase TtTS Thermus thermophilus Threonine synthase WHO World Health Organization -, -, -CA Alpha-, beta-, gamma carbonic anhydrase Introduction In my country, Cuba, there is a small town named Rincón not so far away from the capital. Every 17th of December many people arrive in this town to pray and ask for health from San Lázaro. My mother has explained to me that in this place, before the Cuban revolution, there was a hospital that treated people suffering from leprosy. I was a child and I had never met any person suffering from that traumatic disease. I was also very far away from linking leprosy with tuberculosis (TB), another disease “eradicated” by the huge vaccination campaign that every child has a right to in my country. Tuberculosis first became known to me as the name of a disease that had killed a three year old sister of my mother. I do not like that any family in the world suffers the loss of a dear person, even less when it is caused by a disease that most people still think of as “curable”. Despite all the efforts that have been made to eradicate TB, the World Health Organization (WHO) statistics about the disease are still frightening. One third of the world’s population is infected with Mycobacterium tuberculosis, mostly in highly populated third world countries in South-East Asia and Africa, but other world regions do not escape the problem. (http://www.who.org; Kochi 2001; Ducati, Ruffino-Netto et al. 2006). HIV infection is seen as the main cause for the increase in new TB cases in Africa. According to WHO estimates,
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