Research interests
Professor Edith Sim is the Dean Designate for the newly formed Faculty of Science, Engineering and Computing at Kingston University, London. Edith took up this new appointment in January 2011, having spent most of her career at Oxford University. She has a BSc in Biochemistry from Edinburgh and a D. Phil. from the University of Oxford. Her D. Phil. was a combination of chemistry and biochemistry applied to understanding of biological membrane structure using the then new technique of 31P nuclear magnetic resonance and the combination of techniques from multiple disciplines is still a key theme of her research. She held a Royal Society European Exchange Fellowship to study hydrogenase from Paracoccus denitrificans before returning to Oxford as a demonstrator in the Biochemistry Department and was a visitor in the MRC Immunochemistry Unity working on proteins of the innate immune system. Her particular contributions were understanding the covalent binding mechanism and reactivities of the proteins C3 and C4 of the complement system along with Bob Sim with whom she is again collaborating on the interaction of complement with mycobacteria.
She took up a Wellcome Senior Lectureship in the Pharmacology Department at Oxford and initially worked on understanding immune mediated toxicity associated with hydralazine and isoniazid. Through these studies on understanding polymorphism in the human NAT enzymes which metabolise isoniazid her group identified and characterised an expressed nat gene in many mycobacterial strains. The NAT enzyme metabolises and inactivates isoniazid, is active in M. tuberculosis and contributes slightly to isoniazid resistance. There are specific clinical isolates in which mutations in the nat gene have been found. The activity of the NAT protein involves the hydrolysis of acetylCoA and also propionylCoA which are central to the synthesis of the cell wall in M. tuberculosis.
Edith's work on the nat gene and identification of inhibitors of the protein, has led to identification of an associated operon which is now known to be involved in cholesterol degradation in M. tuberculosis and to be under control of a stress response.
Her work involves a combination of structural studies on the NAT enzyme and related enzymes of the operon, in particular an enzyme known as HsaD as well as studies looking at inhibitors of these enzymes using a chemical biology approach. As a result of TBDUK a project on fragment based drug discovery of HsaD has been developed.
She has wide experience in gradate education and in post-doctoral training.
She has been on the Molecular and Cellular Medicine Board of the MRC, chaired the Biology panel of the Norwegian Research Council and also sits on the Norwegian National Research Assessment Panel on Biology.
Publications
A selection of publications enclosed below:
Abuhammad, A, Lack, N, Schweichler, J, Staunton, D, Sim, RB and Sim, E (2011) Improvement of the expression and purification of Mycobacterium tuberculosis arylamine N-acetyltransferase (TBNAT) a potential target for novel anti-tubercular agents. Protein Expression and Purification, 80(2), pp. 246-252. ISSN (print) 1046-5928
Ryan, Ali, Kaplan, Elise, Laurieri, Nicola, Lowe, Edward and Sim, Edith (2011) Activation of nitrofurazone by azoreductases: multiple activities in one enzyme. Scientific Reports, 1, Article number: 63 (online only). ISSN (online) 2045-2322
Fullam, Elizabeth, Abuhammad, Areej, Wilson, David L., Anderton, Matthew C., Davies, Steve G., Russell, Angela J. and Sim, Edith (2011) Analysis of beta-amino alcohols as inhibitors of the potential anti-tubercular target N-acetyltransferase. Bioorganic & Medicinal Chemistry Letters, 21(4), pp. 1185-1190. ISSN (print) 0960-894X
Westwood, I. M., Kawamura, A, Russell, A. J., Sandy, J, Davies, S. G. and Sim, E (2011) Novel Small-Molecule Inhibitors of Arylamine N-Acetyltransferases: Drug Discovery by High Throughput Screening. Combinatorial Chemistry & High Throughput Screening, 14(2), pp. 117-124. ISSN (print) 1386-2073
Abuhammad, Areej M., Lowe, Edward D., Fullam, Elizabeth, Noble, Martin, Schweichler, Judith, Garman, Elspeth F. and Sim, Edith (2010) Structural Studies on the Mycobacterial Arylamine N-Acetyltransferases. Drug Metabolism Reviews - Official Journal of the International Society for the Study of Xenobiotics (ISSX), 42(Suppl. 1), pp. 111-112.
Laurieri, Nicola, Crawford, Matthew H. J., Kawamura, Akane, Westwood, Isaac M., Robinson, James, Fletcher, Ai M., Davies, Stephen G., Sim, Edith and Russell, Angela J. (2010) Small Molecule Colorimetric Probes for Specific Detection of Human Arylamine N-Acetyltransferase 1, a Potential Breast Cancer Biomarker. Journal of the American Chemical Society, 132(10), pp. 3238-3239.
Lack, Nathan A.; Yam, Katherine C.; Lowe, Edward D.; Horsman, Geoff P.; Owen, Robin L.; Sim, Edith; Eltis, Lindsay D. Characterization of a Carbon-Carbon Hydrolase from Mycobaterium tuberculosis involved in Cholesterol Metabolisim. Journal of Biological Chemistry (2010), 285(1), 434-443. CODEN: JBCHA3 ISSN: 0021-9258. CAN 152:281289 AN 2009: 1609408 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Carroll, Maria V.; Lack, Nathan; Sim, Edith; Krarup, Anders; Sim, Robert B. Multipe routes of complement activation by Mycobacterium bovis BCG. Molecular Immunology (2009), 46(16), 3367-3378. CODEN: MOIMD5 ISSN: 0161- 5890. CAN 151:548492 AN 2009:1212709 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Carroll, Maria V.; Krarup, Anders; Sim, Edith; Sim, Robert B. Complement activation by Mycobacterium bovis BCG. Molecular Immunology (2009), 46(14),2834. CODEN: MOIMD5 ISSN: 0161- 5890 CAN 151:286788 AN 2009:955254 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Fullam, Elizabeth; Kawamura, Akane; Wilkinson, Helen; Abuhammad, Areej; Westwood, Isaac; Sim, Edith. Comprison of theArylamine N-Acetyltransferase from Mycobacterium marium and Mycobacterium tuberculosis. Protein Journal (2009), 28(6), 281-293. CODEN: PJROAH ISSN: 1572-3887. CAN 151:330904 AN 2009:905944 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Ayers, Benjamin; Long, Hilary; Sim, Edith; Smellie, Iain A.; Wilkinson, Brendan L,; Fairbanks, Antony J. Stereoselective synthesis of ?- arabino glycosyl sulfones as potential inhibitors of mycobacterial cell wall biosynthesis. Carbohydrate Research (2009), 344(6), 739 -746. CODEN: CRBRAT ISSN:0008-6215. CAN 151:8813 AN 2009:442423 CAPLUS 9Copyright (C) 2010 ACS on SciFinder (R))
Lack, Nathan A,; Kawamura, Akane; Fullam, Elizabeth; Laurieri, Nicola; Bread, Stacey; Russell, Angela J.; Evangelopoulos, Dimitrios; Westwood, Isaac; Sim, edith. Temperature sability of proteins essential for the intracellular survival of Mycobacterium tuberculosis. Biochemical Journal (2009), 418 (2), 369 - 378. CODEN:BIJOAK ISSN .CAN 150:232257 AN 2009:167403 CAPLUS (Copyright (C) 2010 ACS on SciFinder (R))
Sim, Edith, Sandy, James, Evangelopoulos, Dimitrios, Fullam, Elizabeth, Bhakta, Sanjib, Westwood, Isaac, Krylova, Anna, Lack, Nathan and Noble, Martin (2008) Arylamine N-acetyltransferases in mycobacteria. Current Drug Metabolism, 9(6), pp. 510-519. ISSN (print) 1389-2002
Sim, E. (2008) Abstract: Pharmacogenomics: from drug metabolism to disease susceptibility and beyond. Febs Journal, 275(Suppl. 1), p. 12. ISSN (print) 1742-464X
Hein, David W., Boukouvala, Sotiria, Grant, Denis M., Minchin, Rodney F. and Sim, Edith (2008) Changes in consensus arylamine N-acetyltransferase gene nomenclature. Pharmacogenetics And Genomics, 18(4), pp. 367-368. ISSN (print) 1744-6872
Lack, N., Lowe, E.D., Liu, J., Eltis, L.D., M.E.M., Edith Sim, E., and Westwood, I.M. (2008) Structure of HsaD, a steroid-degrading hydrolase, from Mycobacterium tuberculosis. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 64: 2-7.
Fullam, F., Westwood, I.M., Anderton, M.C, Lowe, E.D., Sim, E., Noble, M.E. (2008) Divergence of co-factor recognition across evolution: Coenzyme A binding in a prokaryotic Arylamine N-acetyltransferase. J. Mol. Biol. 375: 178-191
Smellie, I.A., Bhakta, S., Sim E., and Fairbanks, A.J. (2007) Synthesis of putative chain terminators of mycobacterial arabinan biosynthesis. Org. Biomol. Chem. 5: 2257 - 2266
Madikane, E., Bhakta, S., Russell, A., Campbell, W., Claridge, T., Elisha, G., Davies, S., Smith, P., & Sim, E. (2007) Inhibition of mycobacterial arylamine N-acetyltransferase contributes to anti-mycobacterial activity of Warburgia salutaris Bioorganic & Medicinal Chemistry 15: 3579-3586
Van der Geize, R., Heuser, T., Yam, K., Wilbrink, M, Hara, H, Anderton, M, Sim, E., Dijkhuizen, L.,Davies, J, Mohn, W., and Eltis, L. (2007) A gene cluster encoding cholesterol catabolism in a soil actinomycete provides insight into Mycobacterium tuberculosis survival in macrophages. PNAS 104: 1947-1952
Anderton MC, Bhakta S, Besra GS, Jeavons P, Eltis LD, Sim E. Characterization of the putative operon containing arylamine N-acetyltransferase (nat) in Mycobacterium bovis BCG. (2006) Mol Microbiol. 59:181-92.
Sholto-Douglas-Vernon, C., Sandy, J., Victor, T.C., Sim, E & van Helden, P.D. (2005) Mutational and expression analysis of tbnat and its response to isoniazid. Journal of Medical Microbiology 54: 1189-1197.
Sandy, J., Mushtaq, A., Holton, S.J., Schartau, P., Noble, M.E.M., & Sim, E. (2005) Investigation of the catalytic triad of arylamine N-acetyltransferases: essential residues required for acetyl transfer to arylamines. The Biochemical Journal. 390: 115-123.
Sandy, J., Holton, S., Fullam, E., Sim, E., & Noble, M. (2005) Binding of the anti-tubercular drug isoniazid to the arylamine N-acetyltransferase protein from Mycobacterium smegmatis. Protein Science 14: 775-782.
Bhakta, S., Besra, G.S., Upton, A.M., Parish, T., Sholto-Douglas-Vernon, C., Gibson, K.J.C., Knutton, S., Gordon, S., P.daSilva, R, Anderton, M.C., & Sim, E. (2004) Arylamine N-Acetyltransferase Is Required for Synthesis of Mycolic Acids and Complex Lipids in Mycobacterium bovis BCG and Represents a Novel Drug Target J. Exp. Med. 199: 1191-1199.
Brooke, E.W., Davies, S.G., Mulvaney, A.W., Okada, M., Pompeo, F., Sim, E., Vickers, R.J. & Westwood, I.M. (2003) Synthesis and in vitro evaluation of novel small molecule inhibitors of bacterial Arylamine N-Acetyltransferases. Bioorganic & Med Chem Letts 13: 2527-2530.
Brooke, E.W., Davies, S.G., Mulvaney, A.W., Pompeo, F., Sim, E. and Vickers, R.J. (2003) An approach to identifying novel substrates of bacterial arylamine N-acetyltransferases. Bioorganic & Medicinal Chemistry. 11: 1227-1234.
Sandy, J., Mushtaq, A., Kawamura, A., Sinclair, J., Sim, E. and Noble, M. (2002) The structure of Arylamine N-acetyltransferase from Mycobacteria smegmatis - An Enzyme which Inactivates the Anti-tubercular Drug, Isoniazid. The Journal of Molecular Biology 318: 1071-1083.
Mushtaq, A., Payton, M. and Sim, E. (2002) The COOH terminus of arylamine N-acetyltransferase from Salmonella typhimurium controls enzymic activity. Journal of Biological Chemistry 277: 12175-12181.
Payton, M., Mushtaq, A., Yu, T., Wu, L., Sinclair, J. and Sim, E. (2001) Eubacterial arylamine N-acetyltransferases - identification and comparison of 18 members of the protein family with conserved active site cysteine, histidine and aspartate residues. Microbiology 147: 1137-1147.
Payton, M., Gifford, C., Schartau, P., Hagemeier, C., Mushtaq, A., Lucas, S., Pinter, K. and E. Sim. (2001) Evidence towards the role of arylamine N-acetyltransferase in Mycobacterium smegmatis and development of a specific antiserum against the homologous enzyme of Mycobacterium tuberculosis. Microbiology 147: 3295-3302
Upton, A., Everett, M., Mushtaq, A., van Helden, P., Victor, T., Wagner, R. and Sim, E. (2001) Arylamine N-acetyltransferase of Mycobacterium tuberculosis is a polymorphic enzyme and a site of isoniazid metabolism. Molecular Microbiology 42: 309-319.
Sinclair, J.C., Sandy, J., Delgoda, R., Sim, E. and Noble, M.E.M. (2000) Structure of arylamine N-acetyltransferase reveals a catalytic triad. Nature (Struct. Biol.) 7: 560-564.
Payton, M., Auty, R., Delgoda, R., Everett, M. and Sim, E. (1999) Cloning and Characterisation of Arylamine N-acetyltransferase Genes from Mycobacterium smegmatis and M. tuberculosis: Increased Expression Results in Isoniazid Resistance. Journal of Bacteriology 181: 1343-1347.
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