Oeiras, 26.10.2015

One never knows where innovation will come from. Even strange microorganisms living in hot springs can hold solutions for fighting infections.  A new study involving researchers from the Cell Physiology and NMR Lab shows how looking into the biosynthesis of stress metabolites in hyperthermophiles may lead to novel drug targets against tuberculosis. The work is published in Nature Communications.

One of the tricks to identifying antibiotic targets is to find an essential protein that is present in pathogenic bacteria and absent, or different, in humans. The enzyme catalyzing the synthesis of phosphatidylinositol is one such protein. In some bacteria, phosphatidylinositol is required for the biosynthesis of key components of the cell wall and in Mycobacterium tuberculosis these lipids also function as important virulence factors and modulators of the host immune response.  Unlike eukaryotes, synthesis of phosphatidylinositol in bacteria occurs in two steps; the first step is catalyzed by PIP synthase (short for phosphatidylinositol-phosphate synthase). Previous studies have shown that removal of mycobacterial PIP synthase is lethal for the bacteria.

In this study, researchers combine the structural analysis of Renibacterium salmoninarum PIP synthase, 40% identical to the protein of Mycobacterium tuberculosis, with functional assays of point mutants to determine the location of the acceptor site, and the molecular determinants of substrate specificity and catalysis. This work unfolded from the discovery by the Cell Physiology and NMR Lab of the enzyme involved in the synthesis of di-myo-inositol phosphate, a compound restricted to organisms thriving in hydrothermal vents and hot springs. The link between DIP synthase and mycobacteria became apparent from an early study of the same Lab that identified PIP synthase as the closest evolutionary relative of DIP synthase.  

By providing a structural and functional framework to understand the mechanism of PIP synthase, this study is an important contribution to exploring this enzyme as target for the development of novel antituberculosis therapeutics.

The work involved researchers from ITQB, Columbia University, and Cornell University. David Turner is the PI of the FCT project that supported this study at ITQB and Carla Jorge from ITQB shares first authorship of the paper.

Original article

Nature Communications (2015) DOI: 10.1038/ncomms9505

Structural basis for phosphatidylinositol-phosphate biosynthesis

Oliver B. Clarke¹,*, David Tomasek²,*, Carla D. Jorge³,*, Meagan Belcher Dufrisne², Minah Kim², Surajit Banerjee⁴, Kanagalaghatta R. Rajashankar⁴, Lawrence Shapiro¹, Wayne A. Hendrickson¹, Helena Santos³ & Filippo Mancia²

1 Columbia University (USA)
2. Columbia University(USA)
3 ITQB-NOVA
4 Cornell University (USA)

* These authors contributed equally to this work