Mowbray lab
We study how proteins look at the atomic level, and try to understand how that allows them to carry out their many different functions in biology. The overall goal is to apply this information to do useful and interesting things. For example, in many projects we look for small molecules that bind to and block the activity of enzymes important for particular pathogens, and which might be developed into drugs to kill those pathogens. In other projects, we are looking at the details of how enzymes bind to their substrates, and carry out the chemistry they do, in hopes of applying that information to make new and better enzymes. There are so many possibilities!
Popular science presentation
Disease-causing microorganisms place a huge burden on the people of the world. One example is Plasmodium falciparum, the parasite that causes malaria. The World Health Organization (WHO) estimates that a million people, mostly small children in Africa, die of malaria each year, and that half of the world’s population lives in areas where the risk of contracting the disease is high. Another striking example is Mycobacterium tuberculosis, which is thought to infect one-third of world’s population, albeit in an inactive form. When activated, these bacteria cause tuberculosis, which kills approximately 1.4 million people every year. These two diseases are important causes of poverty and suffering in the third world, and the increasing resistance of the relevant pathogens to the available drugs worsens the situation considerably. New drugs are urgently needed, yet there is little incentive for pharmaceutical companies to invest in developing drugs from which they can expect little or no profit. It is therefore important for academic laboratories to take on some of the burden; projects carried out in collaboration with industrial partners seem to offer the best way forward.
More interesting for big pharma, and a more tangible threat for those living in industrialized countries, are the so-called ESKAPE pathogens. These antibiotic-resistant bacteria cause the majority of infections acquired by patients in conjunction with hospital care. Such infections are particularly sinister, since admission to a hospital is intended to cure the patient, not give them an even worse illness than they had upon arrival!
In our lab, we focus on enzymes (catalytic proteins) that pathogens require, but which are not found in humans. We clone, express and purify sufficient quantities of the chosen proteins, and study how they look using a method called X-ray crystallography. In parallel, we try to identify small molecules (inhibitors) that block the function of the pathogen’s enzymes, without harmful effects on the human host. We also design completely new inhibitor molecules, using our knowledge about how the enzymes look, and seek others using high-throughput screening.
Research projects
STOPping pathogens in their tracks
We study enzymes from various pathogens, most often Mycobacterium tuberculosis (tuberculosis), Plasmodium falciparum (malaria) and ESKAPE bacteria (causing antibiotic resistant hospital-acquired infections), using a STOP approach (Same-Target-Other-Pathogen). By studying the structure of particular enzymes, and how small molecules bind to them and thereby affect their function, we are able to identify compounds that are leads in the antimicrobial drug-discovery process.
Some of the enzymes belong to the MEP pathway for isoprenoid biosynthesis (e.g. IspC, IspD and IspE). The terpenoid (isoprenoid) precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) are universally essential because they are required for the production of a vast number of vital biological compounds, including ones needed for steroid biosynthesis, N-glycosylation and numerous other key cellular functions. For many years, the mevalonate or HMG-CoA reductase pathway was believed to be the only way of providing these precursors, which is indeed the case in most eukaryotes, archaea, a few eubacteria, fungi and protozoa such as Trypanosoma, Leishmania and Giardia; statins, for instance, target this pathway. It is now known that most bacteria (including important pathogens such as M. tuberculosis and almost all ESKAPE bacteria), and apicomplexan protozoa (such as malaria parasites), produce their terpenoids via an alternate route called the methylerythritol phosphate (MEP) or non-mevalonate pathway. Inhibition of enzymes of this pathway thus offer good opportunities to injure the pathogens, while leaving the host unharmed.
Additional work focuses on the type II NADH-dehydrogenase (NDH-2) from NAD metabolism. Again, this type of enzyme is essential to many bacteria, but absent from the human host, and is a good target for selectively killing the pathogen.
A typical project involves cloning, expression, purification, assay, crystallization and X-ray structure determination of the relevant protein, with and without bound substrates or inhibitors. And of course, figuring out what it all means, so that we can work with chemists to design and synthesize new molecules with even better properties.
Group members
Publications
Part of Bioorganic & Medicinal Chemistry Letters, 2024
Bacterial type I signal peptidase inhibitors-Optimized hits from nature
Part of European Journal of Medicinal Chemistry, 2022
Part of ACS - Infectious Diseases, p. 482-498, 2022
Part of European Journal of Medicinal Chemistry, 2021
Part of European Journal of Medicinal Chemistry, p. 1346-1360, 2018
Part of Bioorganic & Medicinal Chemistry, p. 897-911, 2017
Part of Molecular Microbiology, p. 13-25, 2017
Part of ChemMedChem, p. 2024-2036, 2016
- DOI for Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with -Arylpropyl Analogues of Fosmidomycin
- Download full text (pdf) of Targeting an Aromatic Hotspot in Plasmodium falciparum 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase with -Arylpropyl Analogues of Fosmidomycin
Expanding the catalytic triad in epoxide hydrolases and related enzymes
Part of ACS Catalysis, p. 5702-5713, 2015
Part of ChemistryOpen, p. 342-362, 2015
- DOI for Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
- Download full text (pdf) of Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents
Part of Journal of Medicinal Chemistry, p. 2988-3001, 2015
Part of Bioscience Reports, p. 865-877, 2014
DXR Inhibition by Potent Mono- and Disubstituted Fosmidomycin Analogues
Part of Journal of Medicinal Chemistry, p. 6190-6199, 2013
Structural studies on Mycobacterium tuberculosis DXR in complex with the antibiotic FR-900098
Part of Acta Crystallographica Section D, p. 134-143, 2012
Part of MedChemComm, p. 620-626, 2012
Trisubstituted Imidazoles as Mycobacterium tuberculosis Glutamine Synthetase Inhibitors
Part of Journal of Medicinal Chemistry, p. 2894-2898, 2012
Part of Journal of Medicinal Chemistry, p. 4964-4976, 2011
- DOI for Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
- Download full text (pdf) of Design, Synthesis, and X-ray Crystallographic Studies of alpha-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-D-xylulose 5-Phosphate Reductoisomerase
Part of Plant Molecular Biology, p. 33-45, 2011
Structural and functional studies of mycobacterial IspD enzymes
Part of Acta Crystallographica Section D, p. 403-414, 2011
Part of The FEBS Journal, p. 793-808, 2011
- DOI for Structures of type B ribose 5-phosphate isomerase from Trypanosoma cruzi shed light on the determinants of sugar specificity in the structural family
- Download full text (pdf) of Structures of type B ribose 5-phosphate isomerase from Trypanosoma cruzi shed light on the determinants of sugar specificity in the structural family
Part of Journal of Organic Chemistry, p. 8986-8998, 2011
- DOI for Synthesis of Functionalized Cinnamaldehyde Derivatives by an Oxidative Heck Reaction and Their Use as Starting Materials for Preparation of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Inhibitors
- Download full text (pdf) of Synthesis of Functionalized Cinnamaldehyde Derivatives by an Oxidative Heck Reaction and Their Use as Starting Materials for Preparation of Mycobacterium tuberculosis 1-Deoxy-D-xylulose-5-phosphate Reductoisomerase Inhibitors
Conformational Changes and Ligand Recognition of Escherichia coli d-Xylose Binding Protein Revealed
Part of Journal of Molecular Biology, p. 657-668, 2010
Zinc ions bind to and inhibit activated protein C
Part of Thrombosis and Haemostasis, p. 544-553, 2010
Part of Bioorganic & Medicinal Chemistry Letters, p. 6649-6654, 2009
Part of Carbohydrate Research, p. 869-880, 2009
Part of Journal of Molecular Biology, p. 504-513, 2009
The first crystal structures of a family 19 class IV chitinase: the enzyme from Norway spruce
Part of Plant Molecular Biology, p. 277-289, 2009
Part of The FEBS Journal, p. 2116-2124, 2009
Part of Journal of Molecular Biology, p. 217-228, 2008
- DOI for Crystal Structures of Mammalian Glutamine Synthetases Illustrate Substrate-Induced Conformational Changes and Provide Opportunities for Drug and Herbicide Design
- Download full text (pdf) of Crystal Structures of Mammalian Glutamine Synthetases Illustrate Substrate-Induced Conformational Changes and Provide Opportunities for Drug and Herbicide Design
Part of Journal of Molecular Biology, p. 667-679, 2008
- DOI for D-ribose-5-phosphate isomerase B from Escherichia coli is also a functional D-allose-6-phosphate isomerase, while the Mycobacterium tuberculosis enzyme is not
- Download full text (pdf) of D-ribose-5-phosphate isomerase B from Escherichia coli is also a functional D-allose-6-phosphate isomerase, while the Mycobacterium tuberculosis enzyme is not
Part of Bioorganic & Medicinal Chemistry, p. 5501-5513, 2008
Part of Protein Science, p. 1275-1284, 2008
- DOI for Removal of distal protein-water hydrogen bonds in a plant epoxide hydrolase increases catalytic turnover but decreases thermostability
- Download full text (pdf) of Removal of distal protein-water hydrogen bonds in a plant epoxide hydrolase increases catalytic turnover but decreases thermostability
Part of Journal of Molecular Biology, p. 622-633, 2008
Part of Journal of Molecular Biology, p. 109-119, 2008
Part of The FEBS Journal, p. 3695-3703, 2007
Part of Combinatorial chemistry & high throughput screening, p. 783-789, 2007
Part of Journal of Biological Chemistry, p. 19905-19916, 2007
Part of Acta Crystallogr D Biol Crystallogr, p. 807-13, 2006
Part of Acta Crystallogr. Section D Biol. Crystallogr., p. 807-813, 2006
X-ray structure of potato epoxide hydrolase sheds light on its substrate specificity
Part of Protein Science, p. 1628-1637, 2006
Competitive inhibitors of Mycobacterium tuberculosis ribose-5-phosphate isomerase
Part of J Biol Chem, p. 6416-22, 2005
Structure and function of carbonic anhydrases from Mycobacterium tuberculosis.
Part of J Biol Chem, p. 18782-9, 2005
Structure of an atypical epoxide hydrolase from Mycobacterium tuberculosis
Part of J Mol Biol, p. 1048-56, 2005
Part of Proc. Natl. Acad. Sci. USA, p. 10499-10504, 2005
Part of Proceedings of the National Academy of Sciences of the United States of America, p. 10499-10504, 2005
Part of Tetrahedron letters, p. 3691-3694, 2005
Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site
Part of Journal of Molecular Biology, p. 799-809, 2004
Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site.
Part of J Mol Biol, p. 799-809, 2004
X-ray structure of peptidyl-prolyl cis-trans isomerase A from Mycobacterium tuberculosis.
Part of Eur J Biochem, p. 4107-13, 2004
Part of J Biol Chem, p. 8747-52, 2004
People
Sherry Mowbray, Professor
sherry.mowbray@icm.uu.se
Lu Lu, PhD student
lu.lu@icm.uu.se, +46-18-471 4018
Adrian Suarez Covarrubias, post-doctoral fellow
Adrian.Suarez@icm.uu.se
Sanjeewani Sooriyaarachchi, post-doctoral fellow
sanjee.soori@icm.uu.se, +46-18-471 4018
Annette Roos SciLife
annette.roos@icm.uu.se, +46-18-471 4984