Biochemistry and Metabolic Regulation


Our laboratory studies the role of fatty acid synthesis and enzyme cofactors in the cell biology and physiology of microorganisms and animals. The implications of this topic extend from the search for antimicrobials that act by interfering with fatty acid synthesis and derived metabolites, to the elucidation of regulatory pathways involved in neurodegenerative diseases and obesity in animals.

Research Lines

Use of Caenorhabditis elegans to study lipid metabolism disorders

The roundworm C. elegans is a powerful model organism for elucidating fundamental biological processes. The quick generation time and easy lab maintenance of C. elegans provides a high-throughput way to address research questions that may be too complex to approach in higher order organisms. Many genes in C. elegans are conserved from worms to humans, thus nematodes provide a way to address questions in the context of a whole organism that otherwise must be done in vitro or in isolated cell culture systems. These aspects of C. elegans biology, together with conserved lipid biosynthesis pathway, make C. elegans an attractive model for study the role of lipid in neurodegenerative diseases. We use this nematode to address 1) How endocannabinoids prevent or recover the dysfunction of cholesterol homeostasis associated to Alzheimer and Niemann-Pick diseases, 2) How malonyl-CoA, a key intermediate of fatty acid biosynthesis, controls feeding behavior, and 3) How unsaturated fatty acids regulates metabolic disorders and the cellular aggregation of amyloid proteins.  To tackle this last aim, we collaborate with the group of Dr. Andres Binolfi using NMR methodologies in vitro, e in vivo combined with microscopy and metabolomic approaches.

Search for new targets for the development of bioactive compounds against Gram positive bacteria and unicellular parasites

The emergence and spread of antimicrobial resistance among bacteria and the lack of effective and low-toxicity drugs to combat parasitic protozoa has intensified the need for the discovery of compounds directed against hitherto unexploited targets. Organic and inorganic cofactors, such as vitamins or metal ions, play a fundamental role in the survival of both eukaryotes and bacteria. Therefore, interfering with biosynthetic pathways or their acquisition through diet presents interesting pharmacological possibilities. One of the objectives of our working group is to understand how microorganisms post-translationally modify their proteins with lipoic acid, and to validate the underlying molecular processes as targets for the design of new antimicrobials. Through an inter and multidisciplinary strategy, including genetics, biochemistry, structural biology and combinatorial chemistry techniques, we propose to identify and test the effect of bioactive compounds, with structures and mechanisms of action different from those currently used, that block protein lipoylation in Trypanosoma, Plasmodium, Staphylococcus aureus and other pathogenic Gram positive bacteria.

Role of the synthesis of unsaturated fatty acids in adaptation to cold, production of virulence factors and pathogenesis of Bacillus cereus

The Bacillus cereus group comprises bacteria of economic importance and of different degrees of pathogenicity. They are Gram-positive bacteria with extraordinary ecological diversity that adapt to different stress conditions and can grow between 4° and 50°C. At low temperatures, bacteria undergo changes in their cell physiology, the most important being the decrease in membrane fluidity. In bacteria, the content of unsaturated fatty acids (UFAs) in membrane lipids plays an essential role in increasing the fluidity and functioning of biological membranes at low temperatures. UFAs are synthesized by enzymes called desaturases, which introduce double bonds in the acyl chains of fatty acids (FA) in membrane lipids, thus playing an important role during the adaptation process. Bioinformatic studies carried out with the genomes of B. cereus showed a variable number of putative membrane desaturases and Acyl-ACP-desaturases (soluble) in the same organism, this being the first time that the presence of Acyl-ACP-desaturases has been reported in Bacillus. In this project we intend to establish the role of these desaturases in the adaptation to low temperatures and in the production and excretion of virulence factors, decisive elements in the establishment of pathogenesis.


Selected Publications

  • Endocannabinoids in Caenorhabditis elegans are essential for the mobilization of cholesterol from internal reserves. Sci. Reports. Galles, C., Prez, G. Penkov, S. Boland, S. Porta, E. Altabe, S., Labadie, G., Schmidt, U., Knölker, H.J., Kurzchalia, T. and de Mendoza, D (2018) doi: 10.1038/s41598-018-24925-8
  • Structural determinant of functionality in acyl lipid desaturases. J. Lipid Res. Sastre, D.E,  Saita, E., Uttaro, A.,  de Mendoza D.Altabe, S. (2018) doi: 10.1194/jlr.M085258.
  • Unravelling the lipoyl-relay of exogenous lipoate utilization in Bacillus subtilis. Mol. Microbiol. Rasetto N, Lavatelli A, Martin N. Mansilla MC (2019) ISSN: 0950-382X.
  • Transmembrane prolines mediate signal sensing and decoding in Bacillus subtilis DesK histidine kinase. mBio. Fernández P, Porrini L, Albanesi D, Abriata L, Dal Peraro M, de Mendoza D, Mansilla MC. (2019). https://doi: 10.1128/mBio.02564-19.
  • Defining Caenorhabditis elegans as a model system to investigate lipoic acid metabolism. J. Biol. Chem. Lavatelli, A., de Mendoza, D. and Mansilla, M.C. (2020) DOI: 10.1074/jbc.RA120.013760
  • Cannabinoids Activate the Insulin Pathway to Modulate Mobilization of Cholesterol in C. elegans. Plos Genetics. Hernandez-Cravero, Gallino, S.   Florman,J Vranych, C., Diaz, P, Elgoyhen, A.B., Alkema, M.J and  de Mendoza (2022) doi: 10.1371/journal.pgen.1010346. 022
  • The role of cell-envelope synthesis for envelope growth and cytoplasmic density in Bacillus subtilis PNAS Nexus Kitahara, Y. Oldewurtel, E.R.,  Wilson, S.,   Sun, Y.,  Altabe, S., de Mendoza,D.  Garner, E.C.,   van Teeffelen, S. (2022)
  • Unsaturated fatty acids profiling in live C. elegans using real-time NMR spectroscopy. bioRxiv. Hernandez-Cravero, B., Prez, G., Lombardo, V. Binolfi, A. and de Mendoza, D. 2023
  • Impaired cholesterol transport from aged astrocytes to neurons can be rescued by cannabinoids. bioRxiv. Allende, LG,  Natalí, L,  Cragnolini, A.B, Musri, MM,  de Mendoza, and Martín, M.G. doi: