Nick Le Brun graduated in 1990 with a first class degree in Chemistry from UEA. Supported through a Wellcome Trust Prize Studentship, he remained at UEA to begin his research career in the area of bioinorganic chemistry under the guidance of Prof Andrew Thomson, FRS OBE and Prof Geoff Moore. He gained his PhD in 1993, and continued his research in the School through a Wellcome Trust Fellowship. In 1996, he moved to the Department of Microbiology, Lund University, Sweden to take up an EMBO Fellowship, in the laboratory of Prof Lars Hederstedt. In 1999 Nick was appointed as Lecturer in biological chemistry at UEA,  and subsequently appointed as Senior Lecturer (2006-2009), Reader (2009-2011), and Professor (2011 - ).

Proteins that contain metal ions (metalloproteins) constitute a diverse and hugely important group. By utilising and fine-tuning the wide range of physical and chemical properties exhibited by metal ions, they fulfil many essential roles in many cellular processes. Nick's research interests lie in understanding how bacterial cells handle essential metal ions (particularly iron and copper), the pathways by which metal-containing proteins are assembled, and the reactivities associated with metalloproteins.

Nick’s research has been funded over the past few years by BBSRC, The Wellcome Trust and EPRSC. He was a member of the BBSRC Pool of Experts (2009-2010) and served as a core member of BBSRC Committee D: Molecules, Cells and Industrial biotechnology from 2010-13. Since 2010, Nick has been Director of the UEA Centre for Molecular and Structural Biochemistry, and from 2014-22 he was Chair of the UK's Inorganic Biochemistry Discussion Group (IBDG, an Interest Group of the RSC).  In 2015-16 he was a member of RSC Dalton Council and was the Chair of the organising committee for the Dalton 2016 meeting.  Nick was on the editorial board of Journal of Biological Inorganic Chemistry (JBIC) from 2014-2017 and an Associate Editor for Microbiology 2012-2020. He is currently on the Editorial Board of Journal of Inorganic Biochemistry (2022-).

In 2018 Nick was the recipient of the RSC's Joseph Chatt Award, in recognition of his contributions to the understanding of molecular mechanisms of bacterial gene regulation by environmental levels of oxygen, nitric oxide and iron employing iron-sulfur clusters.

Nick was Head of the School of Chemistry at UEA from September 2019 to July 2024, when the School merged with Pharmacy to create the new School of Chemistry, Pharmacy and Pharmacology. He is currently deputy Head of the School.

Selected Publications

Human mitochondrial ferritin exhibits highly unusual iron-O₂ chemistry distinct from that of cytosolic ferritins.
Bradley, J. M., Bugg, Z., Pullin, J., Moore, G. R., Svistunenko, D. A. and Le Brun, N. E.
Nat. Commun., 2025, 16, 4695.
DOI:10.1038/s41467-025-59463-1.

Observation of the assembly of the nascent mineral core at the nucleation site of human mitochondrial ferritin.
Bradley, J. M., Bugg, Z., Moore, G. R., Hemmings, A. M. and Le Brun, N. E.
J. Am. Chem. Soc., 2025, 147, 13699-13710.
DOI: 10.1021/jacs.5c01337.

Iron-sensing and redox properties of the hemerythrin-like domains of Arabidopsis BRUTUS and BRUTUS-LIKE2 proteins.
Pullin, J., Rodríguez-Celma, J., Franceschetti, M. Mundy, J. E. A., Svistunenko, D. A., Bradley, J. M., Le Brun, N. E. and Balk, J.
Nat. Commun., 2025, 16, 3865.
DOI: 10.1038/s41467-025-58853-9.

The ferroxidase centre of Escherichia coli bacterioferritin plays a key role in the reductive mobilisation of the mineral iron core.
Bradley, J. M., Bugg, Z., Sackey, A., Andrews, S. C., Wilson, M. T. and Svistunenko, D. A., Moore, G. R., Le Brun, N. E.
Angew. Chem. Int. Ed., 2024, 63, e202401379.
DOI: 10.1002/anie.202401379.

Binding of a single nitric oxide molecule is sufficient to disrupt DNA binding of the nitrosative stress regulator NsrR.
Crack, J. C. and Le Brun, N. E.
Chem. Sci., 2024, 15, 18920-18932.
DOI: 10.1039/D4SC04618H

Stabilisation of the RirA [4Fe–4S] cluster results in loss of iron-sensing function.
Gray, E., Stewart, M. Y. Y., Hanwell, L., Crack, J. C., Devine, R., Stevenson, C. E. M., Volbeda, A, Johnston, A. W. B., Fontecilla-Camps, J.-C., Hutchings, M. I., Todd, J. D. and Le Brun, N. E.
Chem. Sci., 2023, 14, 9744-9758.
DOI: 10.1039/d3sc03020b.

Native mass spectrometric studies of IscSU reveal a concerted, sulfur-initiated mechanism of iron-sulfur cluster assembly.
Bennett, S. P., Crack, J. C., Puglisi, R. Pastore, A. and Le Brun, N. E.
Chem. Sci., 2023, 14, 78-95.
DOI: 10.1039/d2sc04169c.

The diiron protein YtfE is a nitric oxide-generating nitrite reductase involved in management of nitrosative stress.
Crack, J. C., Balasiny, B. K. Bennett, S. P., Rolfe, M. D., Froes, A. MacMillian, F., Green, J., Cole, J. C. and Le Brun, N. E.
J. Am. Chem. Soc., 2022, 144, 7129-7145.
DOI: 10.1021/jacs.1c12407.

Insights into methionine S-methylation in diverse organisms.
Peng, M., Li, C. Y., Chen, X. L., Williams, B. T., Li, K., Gao, Y. N., Wang, P., Wang, N., Gao, C., Zhang, S., Schoelmerich, M. C., Banfield, J. F., Miller, J. B., Le Brun, N. E., Todd, J. D.and Zhang, Y. Z.
Nat. Commun. 2022, 13, 2947
DOI: 10.1038/s41467-022-30491-5.

Electron transfer from haem to the di-iron ferroxidase centre in bacterioferritin
Pullin, J., Bradley, J. M., Moore, G. R., Le Brun, N. E., Wilson, M. T. and Svistunenko, D. A.
Angew. Chem. Int. Ed., 2021, 60, 8376-8379.
DOI: 10.1002/anie.202015965.

Electron and proton transfers modulate DNA binding by the transcription regulator RsrR
Crack, J. C., Amara, P., Volbeda, A., Mouesca, J.-M., Rohac, R., Pellicer Martinez, M. T., Huang, C.-Y., Gigarel, O., Rinaldi, C.; Le Brun, N. E. and Fontecilla-Camps, J. C.
J. Am. Chem. Soc., 2020, 142, 5104 – 5116.
DOI:10.1021/jacs.9b12250.

PhD studentships

I am also always interested to hear from prospective students who can bring their own funding! Please get in touch.

• 1987 to 1990 BSc Chemistry at UEA, first class
• 1990 to 1993 Wellcome Trust PhD Prize Studentship at UEA
• 1993 to 1995 Wellcome Trust Prize Fellowship at UEA
• 1996 to 1998 EMBO Long Term Fellowship, Department of Microbiology, Lund University, Sweden
• 1998 to 1999 Senior Research Associate at UEA
• 1999 – 2006 Lecturer in Biological Chemistry at UEA.
• 2006 – 2009 Senior Lecturer in Biological Chemistry at UEA
• 2009 – 2011 Reader in Biological Chemistry at UEA
• 2011 to present, Professor of Biological Chemistry at UEA

Nick's research interests lie in understanding how bacterial cells handle essential metal ions, the pathways by which metal-containing proteins are assembled, and the reactivities associated with metalloproteins.  Specifically, these are in the following areas:

• Iron-sulfur cluster-containing transcriptional regulators
• Iron-sulfur cluster biogenesis in bacteria
• Iron sensing, storage and detoxification in bacteria, animals and plants
• Bacterial iron-dependent transcriptional regulators
• Copper trafficking pathways, including in the assembly of nitrous oxide reductase

Iron-sulfur cluster-containing transcriptional regulators

Collaborators:
Prof Matt Hutchings (UEA), Prof Yvain Nicolet, Prof Jon Todd (UEA).

Researchers:
Dr Jason Crack
Miaomiao Gao

Funding:
BBSRC

In terms of survival, bacteria are extremely adaptable.  For example, many, including the model Gram-negative bacterium Escherichia coli, can grow in the presence and absence of oxygen.  The cellular machineries that enable it to do this are distinct under the two sets of conditions and so the cell must have a mechanism of sensing the oxygen concentration such that, when it drops, genes encoding anaerobic respiratory enzymes can be switched on (and vice versa).  In E. coli and many other bacteria, oxygen is sensed through the transcription regulatory protein FNR.  In the absence of oxygen the protein is dimeric, contains a [4Fe-4S] cluster in each monomer, and adopts a conformation that enables it to bind to specific operator sequences of DNA, and thus regulates the transcription of many genes.  Exposure to oxygen causes the conversion of the [4Fe-4S] cluster into a [2Fe-2S] cluster, inducing a conformational change that results in dissociation of the protein into monomers and unable to bind specifically to DNA. 
We are using kinetic and spectroscopic methods to understand the mechanism by which the reaction with oxygen proceeds.

Nitric oxide is a poisonous molecule that is generated by soil and other bacteria, and in our bodies as a defence against pathogenic organisms trying to establish infection. One of the major ways by which nitric oxide exerts its toxic effects is through reaction with a widespread group of proteins that contain a type of cofactor made from both iron and sulfur (called an iron-sulfur (FeS) cluster). Members of this group play crucial roles in a very wide range of cellular processes. To avoid nitric oxide toxicity, disease-causing (as well as benign) bacteria have evolved protective systems that function to detoxify nitric oxide by removing it through chemical reaction. The fact that iron-sulfur cofactors are particularly sensitive to nitric oxide has been exploited in Nature, through the evolution of a number of regulatory proteins that themselves contain an iron-sulfur cluster and which function as biological switches, turning on the cellular nitric oxide detoxification response in the presence of nitric oxide. Despite the importance and widespread nature of the reaction of iron-sulfur clusters with NO, very little is known about this reaction process. We are interested in understanding how NO-responsive iron-sulfur cluster-containing regulators function.

We are working on a number of regulators. Some of these are members of the WhiB-like (or Wbl) family of proteins that are found only in a small number of bacteria (which includes Mycobacterium tuberculosis, the causative agent of tuberculosis, one of the world's major killers, and Streptomyces coelicolor, the source of many of the antibiotics currently in use in the clinic). Wbl proteins are known to play key roles in these bacteria in cell developmental processes associated with stress response, and are crucial for the ability of M. tuberculosis to survive in the inhospitable environment of a human host for years, in a dormant state that is highly resistant to antibiotics. Another regulator that we work on, NsrR from S. coelicolor, is a member of a widely distributed but largely unstudied family of regulators. It functions as a primary NO sensor by controlling the cellular response to NO toxicity. Our recent work has revealed important new insight into the nature of these regulatory proteins, including, for the first time, detailed mechanistic information about the reaction of a protein-bound iron-sulfur cluster with nitric oxide, leading to the formation of previously unreported products, and, most recently, the structures of cluster-bound and cluster-free NsrR.

Our interests now extend to other FeS regulatory proteins that sense, for example, iron levels and redox stress.

• Pellicer Martinez, M. T., Crack, J. C., Stewart, M. Y. Y., Bradley, J. M., Svistunenko, D. A., Johnston, A. W. B., Cheesman, M. R., Todd, J. D., and Le Brun, N. E. (2019)
  Mechanism of iron- and O2-sensing by the [4Fe-4S] cluster of the global iron regulator RirA. eLife. 8, e47804. DOI: 10.7554/eLife.47804.

• Volbeda, A., Pellicer Martinez, M. T., Crack, J. C., Amara, P., Gigarel, O., Munnoch, J. T., Huttchings, M. I., Darnault, C., Le Brun, N. E. and Fontecilla-Camps, J. C. (2019)
  The crystal structure of the transcription regulator RsrR reveals a [2Fe-2S] cluster coordinated by Cys, Glu and His residues. J. Am. Chem. Soc. 141, 2367-2375. DOI: 10.1021/jacs.8b10823.

• Crack, J. C. and Le Brun, N. E. (2019)
  Mass spectrometric identification of [4Fe-4S](NO)x intermediates of nitric oxide sensing by regulatory iron-sulfur cluster proteins. Chem. Eur. J., 25, 3675-3684. DOI: 10.1002/chem.201806113.

• Crack, J. C., Stewart, M. Y. Y. and Le Brun, N. E. (2019)
  Generation of 34S-substituted protein-bound [4Fe-4S] clusters using 34S-L-cysteine. Biol. Meth. Prot. Accepted. doi.org/10.1093/biomethods/bpy015.

• Child, S. A., Bradley, J. M., Pukala, T. L., Svistunenko, D. A., Le Brun, N. E. and Bell, S. G. (2018)
  Electron transfer ferredoxins with unusual cluster binding motifs support secondary metabolism in many bacteria. Chem. Sci. 9, 7948-7957. DOI: 10.1039/C8SC01286E.

• Crack, J. C., Hamilton, C. and Le Brun, N. E. (2018)
  Mass spectrometric detection of iron nitrosyls, sulfide oxidation and mycothiolation during nitrosylation of the NO sensor [4Fe–4S] NsrR. Chem. Commun. 54, 5992-5995. DOI: 10.1039/c8cc01339j

• Crack, J. C. and Le Brun, N. E. (2018)
  Redox sensing iron-sulfur cluster regulators. Antiox. Red. Signal. 29, 1809-1829. doi: 10.1089/ars.2017.7361

• Volbeda, A., Dodd, E. L., Darnault, C., Crack, J. C., Renoux, O., Hutchings, M. I., Le Brun, N. E. and Fontecilla-Camps, J. C. (2017)
  Crystal structures of apo and holo forms of the nitric oxide sensor regulator NsrR reveal the role of the [4Fe-4S] cluster in modulating DNA binding. Nat. Commum. 8, 15052. doi: 10.1038/ncomms15052.

• Crack, J. C., Thomson, A. J. and Le Brun, N. E. (2017)
  Mass spectrometric identification of intermediates in the O2 driven [4Fe-4S] to [2Fe-2S] cluster conversion in FNR. Proc. Natl. Acad. Sci. U.S.A. 114, E3215-E3223. doi: 10.1073/pnas.1620987114.

• Serrano, P. N., Wang, H., Crack, J. C., Prior, C., Hutchings, M. I., Thomson, A. J., Kamali, S., Yoda, Y., Zhao, J., Hu, M. Y., Alp, E. E., Oganesyan, V. S., Le Brun, N. E. and Cramer, S. P. (2016)
  Nitrosylation of nitric oxide-sensing regulatory proteins containing [4Fe-4S] clusters gives rise to multiple iron-nitrosyl complexes. Angew. Chem. Int. Ed. 55, 14575-14579. doi: 10.1002/anie.201607033.

• Bastow, E., Bych, K., Crack, J. C., Le Brun, N. E., Balk, J. (2016)
  NBP35 interacts with DRE2 in the maturation of cytosolic iron-sulfur proteins in Arabidopsis thaliana. Plant J. 89, 590-600. doi: 10.1111/tpj.13409.

• Munnoch, J., Pellicer Martinez, M.T., Svistunenko, D. A., Crack, J. C., Le Brun, N. E., and Hutchings, M. I. (2016)
  Characterization of a putative NsrR homologue in Streptomyces venezuelae reveals a new member of the Rrf2 superfamily. Sci. Reports, 6, 31597. doi: 10.1038/srep31597

• Crack, J. C., Svistunenko, D. A., Munnoch., J., Thomson, A. J., Hutchings, M. I., and Le Brun, N. E. (2016)
  Differentiated, promoter-specific response of [4Fe-4S] NsrR DNA-binding to reaction with nitric oxide. J. Biol. Chem. 291, 8663-8672. doi: 10.1074/jbc.M115.693192

• Crack J. C., Hutchings, M. I., M. K., Thomson, A. J., and Le Brun, N. E. (2016)
  Biochemical properties of Paracoccus denitrificans FnrP: Reactions with molecular oxygen and nitric oxide. J. Biol. Inorg. Chem. 21, 71-82. doi: 10.1007/s00775-015-1326-7

• Ibrahim, S. A., Crack, J. C., Rolfe, M. D., Borrero-de Acuňa, J. M., Thomson, A. J., Le Brun, N. E., Schobert, M., Stapleton, M. R., and Green, J. (2015)
  Three Pseudomonas putida FNR family proteins with different sensitivities to O2. J. Biol. Chem., 290,16812-16823.

• Crack J. C., Munnoch, J. Dodd, E. L., Knowles, F. Al Bassam, M. M., Kamali, S., Holland, A. A., Cramer, S. P., Hamilton, C. J., Johnson, M. K., Thomson, A. J., Hutchings, M. I., and Le Brun, N. E. (2015)
  NsrR from Streptomyces coelicolor is a nitric oxide-sensing [4Fe-4S] cluster protein with a specialized regulatory function. J. Biol. Chem. 290,12689-12704

• Crack, J. C., Stapleton, M. R. Green, J., Thomson, A. J., Le Brun, N. E. (2014)
  Influence of association state and DNA binding on the O2-reactivity of [4Fe-4S] fumarate and nitrate reduction (FNR) regulator. Biochem. J. 463, 83-92.

• Crack, J. C., Green, J., Thomson, A. J., Le Brun, N. E. (2014)
  Iron-sulfur clusters as biological sensors: the chemistry of reactions with molecular oxygen and nitric oxide. Acc. Chem. Res. 47, 3196-3205

• Crack, J. C., Stapleton, M. R. Green, J., Thomson, A. J., Le Brun, N. E. (2013)
  Mechanism of [4Fe-4S](Cys)4 cluster nitrosylation is conserved amongst NO-responsive regulators. J. Biol. Chem. 288, 11492-11502.

• Crack, J. C., Green, J., Thomson, A. J. and Le Brun, N. E. (2012)
  Iron-sulfur sensor-regulators. Curr. Opin. Chem. Biol. 16, 35-44.

• Crack, J. C., Green, J., Hutchings, M. I., Thomson, A. J. and Le Brun, N. E. (2012)
  Bacterial iron-sulfur regulatory proteins as biological sensor-switches. Antiox Red Signal. 17, 1215-1231.

• Crack, J. C., Smith, L. J., Stapleton, M. R., Peck, J., Watmough, N. J., Buttner, M. J., Buxton, R. S., Green, J., Oganesyan, V. S., Thomson, A. J., and Le Brun, N. E. (2011)
  Mechanistic insight into the nitrosylation of the [4Fe-4S] cluster of WhiB-like proteins. J. Am. Chem. Soc. 133, 1112-1121.

• Tucker, N. P., Le Brun, N. E., Dixon, R and Hutchings, M. I. (2010)
  There’s NO stopping NsrR, a global regulator of the bacterial NO stress response. Trends Microbiol., 18, 149-156

• Smith, L. J., Stapleton, M. R., Fullstone, G. J. M., Crack, J. C., Thomson, A. J., Le Brun, N. E., Hunt, D. M., Harvey, E., Adinolfi, S., Buxton, R. S. and Green, J. (2010)
  Mycobacterium tuberculosis WhiB1 is an essential DNA-binding protein with a nitric oxide sensitive iron-sulphur cluster. Biochem. J. 432, 417-427.

• Crack, J.C., den Hengst, C. D., Jakimowicz, P., Subramanian, S., Johnson, M. K., Buttner, M. J., Thomson, A. J. and Le Brun, N. E. (2009)
  Characterization of [4Fe-4S]-containing and cluster-free forms of Streptomyces WhiD. Biochemistry, 48, 12252-12264

• Tucker, N. P., Hicks, M. G., Clarke T. A., Crack, J. C., Chandra, G. C., Le Brun, N. E., Dixon, R and Hutchings, M. I. (2008)
  The transcriptional repressor protein NsrR senses nitric oxide directly via a [2Fe-2S] cluster. PLoS One, 3, e3623.

Iron sensing, storage and detoxification

Collaborators:
Dr Janneke Balk (John Innes Centre), , Dr Dima Svistunenko (Essex), Prof. Andrew Hemmings (UEA), Prof. Geoff Moore (UEA), Prof Simon Andrews (Reading).

Researchers:
Dr Justin Bradley
Dr Jacob Pullin
Zinnia Bugg

Funding:
BBSRC

Iron is essential for virtually all cells where it plays an important role in many processes, e.g. DNA synthesis, respiration and oxygen transport.  The importance of iron for pathogens is such that they often do not become virulent unless they have a supply of iron.

Iron presents organisms with two major problems that must be overcome for the useful properties of the metal ion to be exploited.  Firstly, at neutral pH and normal oxygen pressure, it is most stable in the +3 oxidation state which is extremely insoluble.  Secondly, it is potentially extremely toxic because of its ability to catalyse formation of reactive free radicals via Fenton and Haber-Weiss chemistry.

Organisms have developed strategies to overcome these problems.  A common one is to store iron within the cell in a form that is safe, i.e. away from molecules with which it can react to produce toxic free radicals.  This is achieved by iron-storage proteins called ferritins, which consist of 24 subunits that pack together to form an approximately spherical molecule with a central cavity in which iron is safely stored as an inorganic ferric iron oxy-hydroxide mineral.

We are studying a number of ferritin proteins, including those from bacteria and a simple marine eukaryote.  Our aim is to understand how the protein catalyses the formation of its iron core, and how this promotes detoxification of iron and reactive oxygen species. We are also interested in the question of how and under what circumstances the protein releases its iron into the cell.

• Bradley, J. M., Pullin, J., Moore, G. R., Svistunenko, D. A., Hemmings, A. M. and Le Brun, N. E. (2019)
  Routes of iron entry into, and exit from, the catalytic ferroxidase sites of the prokaryotic ferritin SynFtn. Dalton Trans., Accepted.

• Bradley, J. M., Svistunenko, D. A., Pullin, J., Hill, N., Stuart, R. K., Palenik, B., Wilson, M. T., Hemmings, A. M., Moore, G. R. and Le Brun, N. E. (2019)
  Reaction of O₂ with a di-iron protein generates a mixed valent Fe²⁺/Fe³⁺ center and peroxide. Proc. Natl. Acad. Sci. U.S.A., 116, 2058 - 2067, DOI: 10.1073/pnas.1809913116.

• Bradley, J. M., Moore, G. R. and Le Brun, N. E. (2017)
  Diversity of Fe2+ entry and oxidation in ferritins. Curr. Opin. Chem. Biol. 37, 122-128. doi: 10.1016/j.cbpa.2017.02.027.

• Bradley, J. M., Le Brun, N. E., and Moore, G. R. (2016)
  Ferritins: Furnishing proteins with iron. J. Biol. Inorg. Chem. 21, 13-28. doi: 10.1007/s00775-016-1336-0

• Bradley, J. M., Svistunenko, D. A., Lawson, T. L., Hemmings, A. M., Moore, G. R. and Le Brun, N. E. (2015)
  Three Aromatic Residues are required for electron transfer during iron mineralization in bacterioferritin. Angew. Chem. Int. Ed., 54, 14763 - 14767.

• Pfaffen, S., Bradley, J. M., Abdulqadir, R., Firme, M. R., Moore, G. R., E. Le Brun, N. E., and Murphy, M. E. P. (2015)
  A diatom ferritin optimized for iron oxidation but not iron storage. J. Biol. Chem. 290, 28416-28427.

• Wong, S. G., Grigg, J. C. Le Brun, N. E., Moore, G. R. Murphy, M. E. P., and Mauk, A. G. (2015)
  The B-type channel is a major route for iron entry into the ferroxidase center and central cavity of bacterioferritin. J. Biol. Chem. 290, 3732-3739.

• Bradley, J. M., Moore, G. R., and Le Brun, N. E. (2014)
  Mechanisms of iron mineralization in ferritins: one size does not fit all. J Biol Inorg Chem. 19, 775-785.

• Pfaffen, S., Abdulqadir, R. LeBrun, N. E. and Murphy, M. E. P (2013)
  Mechanism of ferrous iron binding and oxidation by ferritin from a pennate diatom.  J. Biol. Chem. 288, 14917-14925.
• Wong, S. G., Abdulqadir, R., Le Brun, N. E., Moore, G. R. and Mauk, A. G. (2012)
  Fe-heme bound to Escherichia coli bacterioferritin accelerates iron core formation by an electron transfer mechanism.  Biochem. J. 444, 553-560.
• Yasmin, S., Andrews, S. C., Moore, G. R. and Le Brun, N. E. (2011)
  A new role for heme: facilitating release of iron from the bacterioferritin iron biomineral.  J. Biol. Chem. 286, 3473-3483.
• Le Brun, N. E., Crow, A., Murphy, M. E. P., Mauk, A. G. and Moore, G. R. (2010)
  Iron core mineralisation in prokaryotic ferritins.  Biochim. Biophys. Acta, 1800, 732-744.
• Lawson, T. L., Crow, A., Lewin, A., Yasmin, S., Moore, G. R. and Le Brun, N. E. (2009)
  Monitoring the iron status of the ferroxidase center of Escherichia coli bacterioferritin using fluorescence spectroscopy.  Biochemistry 48, 9031-9039
• Crow, A., Lawson, T. L., Lewin, A., Moore, G. R. and Le Brun, N. E. (2009)
  The structural basis for iron mineralization by bacterioferritin.  J. Am. Chem. Soc. 131, 6808-6813
• Wong, S. G., Tom-Yew, S. A. L., Lewin, A., Le Brun, N. E., Moore, G. R., Murphy, M. E. P. and Mauk, A. G. (2009)
  Structural and mechanistic studies of a stabilized subunit dimer variant of Escherichia coli bacterioferritin identify residues required for core formation. J. Biol. Chem. 284, 18873-18881.

Iron-sulfur cluster biogenesis and sulfur utilisation in bacteria

Collaborators:
Prof Silke Leimkuehler

Researchers:
Dr Jason Crack
Miaomiao Gao

Funding:
BBSRC

We are applying native mass spectrometry to understand the assembly of iron-sulfur clusters in the Isc pathway of bacteria, focussing on the proteins from E. coli.

• Adinolfi, S., Puglisi, R., Crack, J. C., Iannuzzi, C., Dal Piaz, F., Konarev, P. V., Svergun, D. I., Martin, S., Le Brun, N. E. and Pastore, A. (2018)
  The molecular bases of the dual regulation of bacterial iron sulfur cluster biogenesis by CyaY and IscX. Front. Mol. Biosci. 4, 97. doi: 10.3389/fmolb.2017.00097.

Copper trafficking pathways, including in assembly of nitrous oxide reductase

Collaborators:
Dr Andy Gates (UEA), Prof David Richardson (UEA), Prof Andrew Hemmings (UEA), Prof Geoff Moore (UEA)

Researchers:


Funding:

Copper plays an essential role in many cellular processes (eg respiration and photosynthesis). One example of copper enzymes in action that we are all familiar with it fruit browning. When you expose the flesh of a fruit to air, it quickly becomes brown. This is due to a copper enzyme called tyrosinase which oxidises tyrosine to eventually form pigments.  As with iron, copper is also potentially extremely toxic. This is due to its ability to redox cycle and catalyse the formation of hydroxyl radicals via Haber-Weiss like chemistry, and its ability to displace native metals from protein sites.
As well as there being conditions such as Menkes' and Wilson's diseases that result from a breakdown in copper transport, it is becoming clear that copper is an important factor in the development of a wide range of neurological disorders in humans, including Alzheimer’s and Parkinson’s diseases.  Amyloid precursor proteins from a variety of species have been shown to bind copper and this may promote aggregation leading to plaque formation.  The human prion protein is a copper-binding protein in its normal conformation, suggesting that it may have a role in brain copper metabolism.  In diseases such as Alzheimer’s, Parkinson’s and CJD it appears, therefore, that copper trafficking has gone wrong, and to understand such processes it is essential to understand how copper is  handled in normally functioning cells.

We are studying copper trafficking proteins of the Gram-positive model bacterium Bacillus subtilis, and the assembly of the Cu centres of the key dentrification enzyme nitrous oxide reductase. We are using a combination of genetic, spectroscopic, bioanalytical and structural methods to understand how these proteins bind/assemble copper.
 

• Bennett, S. P., Soriano-Laguna, M. J., Bradley, J. M., Svistunenko, D. A., Richardson, D. J., Gates, A. J. and Le Brun, N. E. (2019)
  NosL is a dedicated copper chaperone for assembly of the Cuz center of nitrous oxide reductase. Chem. Sci. 10, 4985-4993. DOI: 10.1039/c9sc01053j.

• Kay, K. L., Hamilton, C. J. and Le Brun, N. E. (2018)
  Mass spectrometric studies of Cu(I)-binding to the N-terminal domains of B. subtilis CopA and influence of bacillithiol. J. Inorg. Biochem. 190, 24-30. doi: 10.1016/j.jinorgbio.2018.10.004.

• Zhou, L., Kay, K. L., Hecht, O., Moore, G. R., and Le Brun, N. E. (2017)
  The N-terminal domains of Bacillus subtilis CopA do not form a stable complex in the absence of their inter-domain linker. Biochim. Biophys. Acta. 1866, 275-282. DOI 10.1016/j.bbapap.2017.11.008.

• Kay, K. L., Zhou, L., Tenori, L., Bradley, J. M., Singleton, C., Kihlken, M. A., Ciofi-Baffoni, S. and Le Brun, N. E. (2017)
  Kinetic analysis of copper transfer from a chaperone to its target protein mediated by complex formation. Chem. Comm. 53, 1397-1400. doi: 10.1039/C6CC08966F.

• Kay, K. L., Hamilton, C. J. and Le Brun, N. E. (2016)
  Mass spectrometry of B. subtilis CopZ: Cu(I)-binding and interactions with bacillithiol. Metallomics 8, 709-719. doi: 10.1039/c6mt00036c

• Le Brun, N. E. (2013)
  Binding, Transport and Storage of Copper in Prokaryotes, in ‘Binding, Transport and Storage of Metal Ions in Biological Cells’, Maret, W. and Wedd, A. G. Eds. RSC Publishing, pp 461 - 499.

• Zhou, L., Singleton, C. and Le Brun, N. E. (2012) 
• CopAb, the second N-terminal soluble domain of Bacillus subtilis CopA, dominates the Cu(I)-binding properties of CopAab. Dalton Trans. 41, 5939-5948.
• Zhou, L., Singleton, C., Hecht, O., Moore, G. R. and Le Brun, N. E. (2012)
  Cu(I)- and proton-binding properties of the first N-terminal soluble domain of Bacillus subtilis CopA.  FEBS J. 279, 285-298.
• Singleton, C., Hearnshaw, S., Zhou, L., Le Brun, N. E., Hemmings, A. M. (2009)
  Mechanistic insights into Cu(I) cluster transfer between the chaperone CopZ and its cognate Cu(I)-transporting P-type ATPase, CopA.  Biochem. J. 424, 347-356
• Hearnshaw, S., West, C., Singleton, C., Zhou, L., Kihlken, M. A. Strange, R. W., Le Brun, N. E., Hemmings, A. M. (2009)
  A tetranuclear Cu(I) cluster in the metallochaperone protein CopZ.  Biochemistry. (rapid communication), 48, 9324-9326
• Singleton, C. and Le Brun, N. E. (2009)
  The N-terminal soluble domains of Bacillus subtilis CopA exhibit a high affinity and capacity for Cu(I) ions. Dalton Trans., 688 - 696.
• Kihlken, M. A. Singleton, C. and Le Brun, N. E. (2008)
  Distinct characteristics of Ag+- and Cd2+-binding to CopZ from Bacillus subtilis. J. Biol. Inorg. Chem. 13, 1011-1023.
• Zhou, L., Singleton, C. and Le Brun, N. E. (2008)
  High Cu(I) and low proton affinities of the CXXC motif of Bacillus subtilis CopZ.  Biochem. J.  413, 459-465.
• Singleton, C., Banci, L., Ciofi-Baffoni, S., Tenori, L., Kihlken, M. A., Boetzel, R. and Le Brun, N. E. (2008)
  Structure and Cu(I)-binding properties of the N-terminal soluble domains of Bacillus subtilis CopA. Biochem. J.  411, 571-579.

Nick has many years’ experience of teaching across a range of subjects at the chemistry-biology interface, including the areas of biophysical chemistry, bioinorganic chemistry and DNA forensics.

PDRA

Dr Jason Crack (funded by the BBSRC to work on mechanisms of NO sensing by iiron-sulfur cluster regulators.

Dr Justin Bradley (funded by the BBSRC to work on ELEMENTAL Engineering Biology of technology-important metal ion biorecovery

Dr Jacob Pullin (funded by the BBSRC to work on plant iron sensor-regulators in collaboration with Dr Janneke Balk (John Innes Centre)

PhD students

Zinnia Bugg (working on iron storage and detoxification proteins)

Miaomiao Gao (working on iron-sulfur cluster regulators and biogenesis)

Recent PhD students

Lizzy Gray (worked on iron-sulfur cluster regulators). Graduated 2024

Leanne Sims (supervised jointly with Prof Colin Murrell (ENV), worked on isoprene monooxygenase, a key enzyme in the bacterial utilisation of the important environmental volatile isoprene). Graduated 2021

Melissa Stewart (worked on iron-sulfur cluster regulatory proteins). Graduated 2021

Sophie Bennett (working on the assembly of nitrous oxide reductase, a key enzyme in denitrification and climate change). Graduated 2019

Maria Pellicer Martinez (worked on mechanisms of sensing by iron-sulfur cluster regulators). Graduated 2018

Krissy Kay (working on copper trafficking proteins and the application of mass spec to metalloprotein studies).  Graduated 2017

Technicians