Team
MycoMet
Presentation
The MycoMet team is seeking to characterize the metalloproteome essential for the survival of pathogenic mycoplasmas, and is particularly interested in the mechanisms by which these minimalist bacteria acquire and use transition metals. The team is developing an integrative, multidisciplinary approach combining biochemistry, structural biology, molecular biology, microbiology, enzymology, proteomics and bioinformatics.
Project 1
Transition metals are required by all life forms to carry out central functions necessary for survival. Moreover, they are at the heart of the host-pathogen battle as the host immune system sequesters essential metals from pathogens. In order to acquire metals and maintain their metal homeostasis, microbial pathogens have developed vital mechanisms involving a range of proteins that constitute their metalloproteome. Mycoplasmas are bacteria that have amongst the smallest genomes known for an autonomously replicating cell. Through evolution, genomes of mycoplasmas underwent drastic reduction to select a minimal set of essential genes. As such, the metalloproteome of mycoplasmas might represent a minimal metalloproteome required to perform some of the most fundamental functions supporting life. Many mycoplasmas are pathogens of vertebrates that are alarming in the raise of antimicrobial resistance, e.g., the avian pathogen Mycoplasma gallisepticum and the human pathogen Mycoplasma pneumoniae causing respiratory diseases. An attractive way to design drugs against these pathogens is to target essential components of their metalloproteome. However, microbial metalloproteomes are largely uncharacterized, especially in mycoplasmas. The MycoMet team aims to decipher the mechanisms of metal acquisition and utilization in the minimalist mycoplasma organisms through a multidisciplinary approach combining biochemistry, structural biology, biophysics and bioinformatics. The project will unravel new biochemical mechanisms and answer fundamental questions regarding the metal homeostasis and metalloenzyme chemistry essential to minimal microbial pathogens. Ultimately, the project will identify key components in the survival of mycoplasmas, thereby uncovering putative new drug targets in order to combat antimicrobial resistance.
Link to the ANR website: here
Project 2
In this project, we aim to study catalytic intermediates in two metal dependent oxidoreductases that both utilize dioxygen (O2) to catalyze reactions essential to various human pathogens. To capture intermediates, we want to employ a novel technique where we perform in situ enzyme activation with O2 gas at room temperature, and use time resolved X-ray crystallography coupled with X-ray spectroscopy at an X-ray free electron laser. Using this approach, we will obtain detailed information about changes in the geometry and in the electronic structure of the metal site, and therefore, we will gain further mechanistic understanding of these important enzymes with the long-term goal to open up ways for novel antimicrobial treatments.
Link to the France-Berkeley Fund website: here
Link to the SLAC website: here
– Hugo Lebrette*, Vivek Srinivas, Juliane John, Oskar Aurelius, Rohit Kumar, Daniel Lundin, Aaron S Brewster, Asmit Bhowmick, Abhishek Sirohiwal, In-Sik Kim, Sheraz Gul, Cindy Pham, Kyle D Sutherlin, Philipp Simon, Agata Butryn, Pierre Aller, Allen M Orville, Franklin D Fuller, Roberto Alonso-Mori, Alexander Batyuk, Nicholas K Sauter, Vittal K Yachandra, Junko Yano, Ville R I Kaila, Britt-Marie Sjöberg, Jan Kern*, Katarina Roos, Martin Högbom*. (*corresponding authors)
Structure of a ribonucleotide reductase R2 protein radical
Science.
2023 Oct 6;382(6666):109-113.
doi: 10.1126/science.adh8160.
– Juliane John, Oskar Aurelius, Vivek Srinivas, Patricia Saura, In-Sik Kim, Asmit Bhowmick, Philipp S Simon, Medhanjali Dasgupta, Cindy Pham, Sheraz Gul, Kyle D Sutherlin, Pierre Aller, Agata Butryn, Allen M Orville, Mun Hon Cheah, Shigeki Owada, Kensuke Tono, Franklin D Fuller, Alexander Batyuk, Aaron S Brewster, Nicholas K Sauter, Vittal K Yachandra, Junko Yano, Ville RI Kaila, Jan Kern, Hugo Lebrette, Martin Högbom.
Redox-controlled reorganization and flavin strain within the ribonucleotide reductase R2b–NrdI complex monitored by serial femtosecond crystallography
eLife.
2022 Sep 9:11:e79226.
doi: 10.7554/eLife.79226.
– Rahul Banerjee, Vivek Srinivas, Hugo Lebrette.
Ferritin-Like Proteins: A Conserved Core for a Myriad of Enzyme Complexes
Subcellular Biochemistry.
2022:99:109-153.
doi: 10.1007/978-3-031-00793-4_4.
– Riccardo Diamanti, Vivek Srinivas, Annika I Johansson, Anders Nordström, Julia J Griese, Hugo Lebrette, Martin Högbom.
Comparative structural analysis provides new insights into the function of R2-like ligand-binding oxidase
FEBS Letters.
2022 Jun;596(12):1600-1610.
doi: 10.1002/1873-3468.14319.
– Alex Perálvarez-Marín, Eric Baranowski, Paula Bierge, Oscar Q Pich, Hugo Lebrette. Metal utilization in genome-reduced bacteria: Do human mycoplasmas rely on iron? Computational and Structural Biotechnology Journal.
2021 Oct 18:19:5752-5761.
doi: 10.1016/j.csbj.2021.10.022.
– Vivek Srinivas #, Hugo Lebrette #, Daniel Lundin, Yuri Kutin, Margareta Sahlin, Michael Lerche, Jürgen Eirich, Rui M M Branca, Nicholas Cox, Britt-Marie Sjöberg, Martin Högbom. (# equal contributions)
Metal-free ribonucleotide reduction powered by a DOPA radical in Mycoplasma pathogens
Nature.
2018 Nov;563(7731):416-420.
doi: 10.1038/s41586-018-0653-6.
Affiliation
