Identification of essential sites of lipid peroxidation in ferroptosis.

Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, provides a potential treatment avenue for drug-resistant cancers and may play a role in the pathology of some degenerative diseases. Identifying the subcellular membranes essential for ferroptosis and the sequence of their peroxidation will illuminate drug discovery strategies and ferroptosis-relevant disease mechanisms. In this study, we employed fluorescence and stimulated Raman scattering imaging to examine the structure-activity-distribution relationship of ferroptosis-modulating compounds. We found that, although lipid peroxidation in various subcellular membranes can induce ferroptosis, the endoplasmic reticulum (ER) membrane is a key site of lipid peroxidation. Our results suggest an ordered progression model of membrane peroxidation during ferroptosis that accumulates initially in the ER membrane and later in the plasma membrane. Thus, the design of ER-targeted inhibitors and inducers of ferroptosis may be used to optimally control the dynamics of lipid peroxidation in cells undergoing ferroptosis.

Probing the selectivity of ß-hydroxylation reactions in non-ribosomal peptide synthesis using analytical ultracentrifugation.

Bacteria and fungi use non-ribosomal peptide synthetases (NRPSs) to produce peptides of broad structural diversity and biological activity, many of which have proven to be of great importance for human health. The impressive diversity of non-ribosomal peptides originates in part from the action of tailoring enzymes that modify the structures of single amino acids and/or the mature peptide. Studying the interplay between tailoring enzymes and the peptidyl carrier proteins (PCPs) that anchor the substrates is challenging owing to the transient and complex nature of the protein-protein interactions. Using sedimentation velocity (SV) methods, we studied the collaboration between the PCPs and cytochrome P450 enzyme that results in the installation of ß-hydroxylated amino acid precursors in the biosynthesis of the depsipeptide skyllamycin. We show that SV methods developed for the analytical ultracentrifuge are ideally suited for a quantitative exploration of PCP-enzyme equilibrium interactions. Our results suggest that the PCP itself and the presence of substrate covalently tethered to the PCP together facilitate productive PCP-P450 interactions, thereby revealing one of nature's intricate strategies for installing interesting functionalities using natural product synthetases.

Malaria-Induced B Cell Genomic Instability.

Nussenzweig and colleagues evaluate genomic instability and germinal center derived lymphomagenesis in mice infected with Plasmodium to recreate some of the hallmark characteristics of Burkitt lymphoma, a form of cancer more common in parts of Africa where malaria is endemic.