Staff Profile:Professor Simon Andrews

Name:

Professor Simon Andrews

Job Title:

Academic, AMS Building

Responsibilities:

Areas of Interest:

Iron-regulation and virulence in E. coli and Salmonella. Iron is an essential trace element and an important factor in pathogenicity. E. coli and Salmonella possess multiple iron storage and acquisition systems. Our studies are focused on the roles and mechanisms of the iron-storage proteins of these organisms, and their contribution to pathogenicity. áWe have used DNA arrays to identify iron-controlled genes, and are currently investigating the roles of a number of novel potential iron transport systems.

DcuS-DcuR - a two-component sensor-regulator. DcuS-DcuR of E. coli is an interesting two-component sensor-regulator under study in our laboratory. It appears to possess two sensory input domains, one in the periplasm that senses external C4-dicarboxylates (e.g. fumarate and succinate), and another 'PAS' domain in the cytosol that is of unknown function. We are studying the function of the PAS domain, the extent of the DcuSR regulon, and the role of DcuSR in regulating transport. á

Hydrogenase-4. Hydrogenases interconvert H₂ and H⁺ and are used to produce energy in many microorganisms. Our work led to the discovery of a 4th hydrogenase (Hydrogenase-4 or Hyd-4) in E. coli. This enzyme appears to be composed of 10 subunits and multiple metal-containing redox centres. It is encoded by a 12-gene operon (hyfABCDEFGHIJR-focB) that also encodes a sigma54-dependent transcriptional activator (HyfR) and a potential foramate transporter (FocB). Our studies are aimed at determining the function of Hyd-4, and the associated regulator and transporter. á

Functional genomics in E. coli. The E. coli genome contains 4,288 protein-encoding genes of which ~33% (1,400) are of unknown function. We are studying the functions of ~60 highly conserved Unidentified Open-Reading Frames (cURFs) in E. coli through a programme of gene-knockout and phenotypic analysis. Many of these genes are likely to have important and possibly novel functions. á

The di-Mn catalase of Thermus thermophilus. T. thermophilus is a thermophilic bacterium that grows optimally at 60-70^oC. It possesses an unusual di-Mn containing catalase that is highly abundant and appears to be required for normal growth. The structure of the enzyme has been solved at high resolution and we are involved in investigating the structural-functional properties of the enzyme through protein engineering, and we are also interested in further examining redox-stress resistance in T. thermophilus.

Research groups / Centres:

Bacterial Iron Homeostasis

Bacteriology Research in Biomedical Sciences

Publications:

1. Williams, J.M., Andrews, S.C., Treffry, A. & Harrison, P.M. (1986) The relationship between ferritin and haemosiderin. Hyperfine Interactions 29, 1447-1450.

2. Andrews, S.C., Treffry, A. & Harrison, P.M. (1987) Siderosomal ferritin - the missing link between ferritin and haemosiderin. Biochem. J. 245, 439-446.

3. Andrews, S.C., Treffry, A. & Harrison, P.M. (1987) A new form of ferritin heterogeneity explained. Isolation and identification of a nineteen-amino-acid-residue fragment from siderosomal ferritin of rat liver. Biochem. J. 245, 447-453.

4. Harrison, P.M., Andrews, S.C., Ford, G.C., Smith, J.M.A., Treffry, A. & White, J.L. (1987) Ferritin and bacterioferritin: iron sequestering molecules from man to microbe. Iron Transport in Microbes, Plants and Animals, eds. G.Winkelmann, D.van der Helm and J.B.Neilands, VCH Publishers, pp 445-476.

5. Andrews, S.C. and Guest, J.R. (1988) Nucleotide sequence of the gene encoding the GMP reductase of Escherichia coli K-12. Biochem. J. 255, 35-43.

6. Andrews, S.C., Brady, M.C., Treffry, A., Williams, J.M., Mann, S., Cleton, M.I., Bruijn, W. & Harrison, P.M. (1988) Studies on haemosiderin and ferritin from iron-loaded rat liver. Biol. Metals 1, 33-42.

7. Andrews, S.C., Smith, J.M.A., Guest, J.R. and Harrison, P.M. (1989) Genetic and structural studies on the bacterioferritin of Escherichia coli. J. Inorg. Biochem., 36, 342.

8. Bell, P.J., Andrews, S.C., Sivak, M.N. and Guest, J.R. (1989) Nucleotide sequence of the FNR-regulated fumarase gene (fumB) of Escherichia coli K-12. J. Bacteriol.171, 3494-3503.

9. Dean, B., Andrews, S.C., Treffry, A., Harrison, P.M., Keen, J.N. & Findlay, J.B.C. (1989) Ferritin subunits in livers of siderotic mice. Biol. Metals 2, 77-82.

10. Andrews, S.C., Smith, J.M.A., Harrison, P.M. & Guest, J.R. (1989) Amino acid sequence of the bacterioferritin (cytochrome b1) of Escherichia coli. Biochem. Biophys. Res. Commun. 158, 489-496.

11. Andrews, S.C., Harrison, P.M. & Guest, J.R. (1989) Cloning, sequencing, and mapping of the bacterioferritin gene (bfr) of Escherichia coli K-12. J. Bacteriol. 171, 3940-3947.

12. Harrison, P.M., Andrews, S.C., Artymiuk, P.J., Ford, G.C., Lawson, D.M., Smith, J.M.A., Treffry, A., White, J.L. (1990) Ferritin. Iron Transport and Storage, eds P. Ponka, H.M. Schulman and R.C. Woodworth, CRC Press, pp. 83-101.

13. Andrews, S.C., Findlay, J.B.C., Guest, J.R., Harrison, P.M., Keen, J.N., & Smith, J.M.A. (1991) Physical, chemical and immunological properties of the bacterioferritins of Escherichia coli, Pseudomonas aeruginosa and Azotobacter vinelandii. Biochim. Biophys. Acta 1078, 111-116.

14. Andrews, S.C., Harrison, P.M. & Guest, J.R. (1991) A molecular analysis of the 53.3 minutes region of the Escherichia coli linkage map. J. Gen. Microbiol. 137, 361-367.

15. Harrison, P.M., Andrews, S.C., Artymiuk, P.J., Ford, G.C., Guest, J.R., Hirzmann, J., Lawson, D.M., Livingstone, J.C., Smith, J.M.A., Treffry, A. & Yewdall, S.J. (1991) Probing structure-function relations in ferritin and bacterioferritin. Adv. Inorg. Chem. 36, 449-486.

16. Smith, J.M.A., Andrews, S.C., Guest, J.R. and Harrison, P.M. (1991) Bacterioferritin: A microbial iron-storage protein? Iron Biominerals, eds. R.B. Frankel and R.P. Blakemore, Plenum Press, NY, pp. 325-337.

17. Andrews, S.C., Guest, J.R., Smith, J.M.A., Yewdall, S.J., and Harrison, P.M. (1991) Bacterioferritin and ferritin are distantly related in evolution: conservation of ferroxidase-centre residues. FEBS Letters 293, 164-168.

18. Andrews, S.C., Shipley, D., Keen, J.N., Findlay, J.B.C., Harrison, P.M. & Guest, J.R. (1992) The haemoglobin-like protein (HMP) of Escherichia coli has ferrisiderophore reductase activity and its C-terminal domain shares homology with ferredoxin NADP+ reductases. FEBS Letters 302, 247-252.

19. Andrews, S.C., Arosio, P., Bottke, W., Briat, J-F., Darl, M. V., Harrison, P.M., Laulhere, J-P., Levi, S., Lobreaux, S. & Yewdall, S.J. (1992) Structure, function and evolution of ferritins. J. Inorg. Biochem. 47, 161-174.

20. Mielczarek, E.V., Andrews, S.C., & Bauminger, R. (1992) M?ssbauer spectroscopy and electron paramagnetic resonance studies of iron metabolites in pseudomonas aeruginosa: Fe²⁺ and Fe³⁺ ferritin in ⁵⁷ferripyoverdine incubated cells and ⁵⁷ferric citrate fed cells. NioMetals 5, 87-93.

21. Rocha, E.R., Andrews, S.C., Keen, J.N. & Brock, J.H. (1992) Isolation of a ferritin from Bacteroides fragilis. FEMS Micro. Letters 95, 207-212.

22. Andrews, S.C., Smith, J.M.A., Hawkins, C., Williams, J.M., Harrison, P.M. & Guest, P.M. (1993) Overproduction, purification and characterization of bacterioferritin (BFR) from Escherichia coliand a C-terminally extended variant. Eur. J. Biochem. 213, 329-338.

23. Cheesman, M.R., Le Brun, N.E., Kadir, F.H.A., Thomson, A.J., Moore, G.R., Andrews, S.C., Guest, J.R., Harrison, P.M., Smith, J.M.A. & Yewdall, S.J. (1993) Haem and non-haem iron sites in Escherichia coli bacterioferritin: spectroscopic and model building studies. Biochem. J. 292, 47-56.

24. Le Brun, N.E., Cheesman, M.R., Thomson, A.J., Moore, G.R., Andrews, S.C., Guest, J.R., & Harrison, P.M. (1993) An EPR investigation of non-haem iron sites in Escherichia coli bacterioferritin and their interaction with phosphate. FEBS Letters 323, 261-266.

25. Le Brun, N.E., Wilson, M.T., Andrews, S.C., Guest, J.R., Harrison, P.M., Thomson, A.J. & Moore, G.R. (1993) Kinetic and structural characterization of an intermediate in the biomineralization of bacterioferritin. FEBS Lett. 333, 197-202.

26. Hudson, A.J., Andrews, S.C., Hawkins, C., Williams, J.M., Izuhara, M., Meldrum, F.C., Mann, S., Harrison, P.M. & Guest, J.R. (1993) Overproduction, purification and characterization of the Escherichia coli ferritin. Eur. J. Biochem. 218, 985-995.

27. Bauminger, E.R., Treffry, A., Hudson, A.J., Hechel, D., Hodson, N.W., Andrews, S.C., Levi, S., Nowik, I., Arosio, P., Guest, J.R. & Harrison, P.M. (1994) Iron incorporation into ferritins. Evidence for the transfer of monomeric Fe(III) between ferritin molecules and for the formation of an unusual mineral in the ferritin of Escherichia coli. Biochem. J. 302, 813-820.

28. Hempstead, P.D., Hudson, A.J., Artymiuk, P.J., Andrews, S.C., Banfield, M.J., Guest, J.R. & Harrison, P.M. (1994) First direct observation of the iron-binding sites in ferritin. FEBS Lett. 350, 258-262.

29. Six, S., Andrews, S.C., Unden, R.E. & Guest, J.R. (1994) Escherichia coli possesses two homologous anaerobic C4-dicarboxylate membrane transporters (DcuA and DcuB) distinct from the aerobic dicarboxylate transport system (Dct). J. Bacteriol. 176, 6470-6478.

30. Hawkins, C., Williams, J.M., Hudson, A.J., Andrews, S.C., & Treffry, A. (1994) M?ssbauer studies of the ultrafineantiferromagnetic cores of ferritin. Hyperfine Interactions, 91, 827-833.

31. Andrews, S.C., Le Brun, N.E., Barynin, V., Thomson, A.J., Moore, G.R., Guest, J.R., & Harrison, P.M. (1995) Site-directed replacement of the coaxial-haem ligands of bacterioferritin generates haem-free variants. J. Biol. Chem. 270, 23268-23274.

32. Le Brun, N.E., Andrews, S.C., Guest, J.R., Harrison, P.M., Moore, G.R. & Thomson, A.J. (1995) Identification of the ferroxidase centre of Escherichia coli bacterioferritin. Biochem. J. 312, 385-392.

33. Hawkins, C., Treffry, A., Mackey, J.B., Williams, J.M., Andrews, S.C., Guest, J.R. & Harrison, P.M. (1996) Iron(III) species formed during iron(II) oxidation and iron-core formation in the bacterioferritin of Escherichia coli. Condensed Matter Atomic Molecular & Chemical Physics Fluids Plasmas Biophysics. 18, 347-352.

34. Quail, M.A., Jordan, P., Grogan, J.M., Butt, J.N., Lutz, M., Thomson, A.J., Andrews, S.C. & Guest, J.R. (1996) Spectroscopic and voltammetric characterisation of the bacterioferritin-associated ferredoxin of Escherichiacoli. Biochem. Biophys. Res. Commun. 229, 635-642.

35. Le Brun, N.E., Keech, A.M., Mauk, M.R., Mauk, A.G., Andrews, S.C., Thomson, A.J. & Moore, G.R. (1996) Charge compensated binding of divalent metals to bacterioferritin: H⁺ release associated with colbalt(II) and zinc(II) binding at dinuclear metal sites. FEBS Letters 397, 159-163.

36. Le Brun, N.E., Andrews, S.C., Moore, G.R. & Thomson, A.J. (1997) Interaction of NO with bacterioferritin. Biochem. J., 326, 173-179.

37. Keech, A.M., LeBrun, N.E., Wilson, M.T., Andrews, S.C., Moore, G.R. & Thomson, A.J. (1997) Spectroscopic studies of cobalt(II) binding to Escherichia coli bacterioferritin. J. Biol. Chem. 272,.422-429.

38. Andrews, S.C., Berks, B.C., McClay, J., Ambler, A., Quail, M.A., Golby, P. & Guest, J.R. Nucleotide sequence of a twelve-cistron Escherichia coli operon (hyf) encoding a putative proton-translocating formate hydrogenlyase system. (1997) Microbiology, 143, 3633-3647.

39. Mackey, J.B., Hawkins, C., Treffry, A., Quail, M.A., Williams, J.M., Andrews, S.C., Guest, J.R. and Harrison, P.M. (1997) The importance of the ferroxidase centre in the catalysis of iron(II) oxidation in the bacterioferritin of E. coli. XXXIII Xakopane School of Physisc Conference Proceedings.

40. Harrison, P.M., Hempstead, P.D., Artymiuk, P.J. & Andrews, S.C. (1998) in "Iron Transport and Storage in Microorganisms, Plants, and Animals" Volume 35 of 'Metal Ions in Biological Systems', A. Sigel and H. Sigel, Eds., Marcel Dekker, Inc., New York, 435-477.

41. Andrews, S.C. (1998) Iron storage in bacteria, in ÔAdvances in Microbial PhysiologyÕ, Vol. 40, 281-351.

42. Golby, P., Kelly, D.J., Guest, J.R. & Andrews, S.C. (1998) Topological analysis of DcuA, an anaerobic C₄-dicarboxylate transporter of Escherichia coli, J. Bacteriol. 180, 4821-4827.

43. Golby, P., Kelly, D. J., Guest, J. R. & Andrews, S. C. (1998) Transcriptional regulation and organization of the dcuA and dcuB genes encoding homologous anaerobic C₄-dicarboxylate transporters in Escherichia coli. J. Bacteriol. 180, 6586-6596.

44. Golby, P., Davies, S., Kelly, D. J., Guest, J. R. & Andrews, S. C. (1999) Identification and characterization of a two-component sensor-kinase and response-regulator system (DcuS-DcuR) controlling gene expression in response to C₄-dicarboxylates in Escherichia coli. J. Bacteriol. 181, 1238-1248

45. Abdul-Tehrani, H., Hudson, A. J., Chang, Y-S., Timms, A. R., Hawkins, C., Williams, J. M.,. Harrison, P. M, Guest J. R. & Andrews, S. C. (1999) Ferritin mutants of Escherichia coli are iron deficient and growth impaired; fur mutants are iron deficient. J. Bacteriol. 181, 1415-1428

46. Davies, S.J., Golby, P., Omrani, D., Guest, J.R., Kelly, D.J. & Andrews, S.C. (1999) Inactivation and regulation of the aerobic C₄-dicarboxylate transport (dctA) gene of Escherichia coli. J. Bacteriol. 181, 5624-5635.

47. Velayudhan, J., Hughes, N.J., Andrews, S.C., Clayton, C.L. & Kelly, D.J. (1999) Functional characterisation of Helicobacter pylori iron assimilation genes. Gut 45, A17

48. Velayudhan, J., Hughes, N.J., McColm, A.A., Bagshaw, J., Clayton, C.L., Andrews, S.C. & Kelly, D.J. (2000) Iron acquisition and virulence in Helicobacter pylori: a major role for FocB, a high-affinity ferrous iron transporter. Mol. Microbiol. 37, 274-286.

49. Wyborn, N.R., Alderson, J., Andrews, S.C. & Kelly, D.J. (2000) Topological analysis of DctQ, the small integral-membrane protein of the C4-dicarboxylate TRAP transporter of Rhodobacter capsulatus. FEMS Micro Letters, 194, 13-17.

50. Stillman, T.J., Hempstead, P.D., Artymiuk, P.J., Andrews, S.C., Hudson, A.J., Treffry, A., Guest, J.R. & Harrison, P.M. The high-resolution X-ray crystallographic structure of the ferritin (EcFtnA) of Escherichia coli; Comparison with human H ferritin (HuHF) and the structures of the Fe³⁺ and Zn²⁺ derivatives. (2001) J. Mol. Biol. 307, 587-603.

51. Waidner, B., Greiner, S., Odenbreit, S., Kavermann, H., Velayudhan, J., Stahler, F., Guhl, J., Bisse, E., van Vliet, A.H.M., Andrews, S.C., Kusters, J.G., Kelly, D.J., Haas, R., Kist, M. & Bereswill, S. (2002) Essential role of ferritin Pfr in Helicobacter pylori iron metabolism and gastric colonization. Infect. Immun. 70 3923-3929

52. Skibinski, D.A.G., Golby, P., Chang, Y.S., Sargent, F., Hoffman, R., Harper, R., Guest, J.R., Attwood, M.M., Berks, B.C. & Andrews, S.C. (2002) Regulation of the hydrogenase-4 operon of Escherichia coli by the s⁵⁴-dependent transcriptional activators FhlA and HyfR J. Bacteriol. 184, 6642-6653

53. Andrews, S.C., Robinson, A.K. & Rodr'guez-Qui¯ones, F. (2003) Iron homeostasis in bacteria. FEMS Microbiol. Rev. 27, 215-237

54. Timothy J. Stillman, Paul P. Connolly, Charlotte L. Latimer, Andrew F. Morland, Michael A. Quail, Simon C. Andrews, Amyra Treffry, John R. Guest, Peter J. Artymiuk, and Pauline M. Harrison (2003) Insights into the Effects on Metal Binding of the Systematic Substitution of Five Key Glutamate Ligands in the Ferritin of Escherichia coli J. Biol. Chem.278 26275-26286

55. McHugh, J.P., Rodriguez-Quinones, F., Abdul-Tehrani, H., Svistunenko, D.A., Poole, R.K., Cooper, C.E. & Andrews, S.C. (2003) Global iron-dependent gene regulation in escherichia coli, a new mechanism for iron homeostasis. J. Biol. Chem , in press