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"Bioorganic Chemistry"
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The chemical basis of ferroptosis
Lipid peroxidation underlies the mechanism of oxidative cell death now known as ferroptosis. This modality, distinct from other forms of cell death, has been intensely researched in recent years owing to its relevance in both degenerative disease and cancer. The demonstration that it can be modulated by small molecules in multiple pathophysiological contexts offers exciting opportunities for novel pharmacological interventions. Herein, we introduce the salient features of lipid peroxidation, how it can be modulated by small molecules and what principal aspects require urgent investigation by researchers in the field. The central role of non-enzymatic reactions in the execution of ferroptosis will be emphasized, as these processes have hitherto not been generally considered ‘druggable’. Moreover, we provide a critical perspective on the biochemical mechanisms that contribute to cell vulnerability to ferroptosis and discuss how they can be exploited in the design of novel therapeutics.
This Perspective focuses on the chemical basis of ferroptotic cell death, discussing the prominent role of spontaneous chemical reactions, how they depend on enzyme-catalyzed processes and how to exploit this interplay for therapeutic benefit.
Journal Article
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.
Ferroptosis is a lipid-peroxide-driven cell death with promising therapeutic applications. Although peroxidation of various subcellular membranes can initiate ferroptosis, the authors found that the endoplasmic reticulum is an essential site.
Journal Article
How many human proteoforms are there?
Despite decades of accumulated knowledge about proteins and their post-translational modifications (PTMs), numerous questions remain regarding their molecular composition and biological function. One of the most fundamental queries is the extent to which the combinations of DNA-, RNA- and PTM-level variations explode the complexity of the human proteome. Here, we outline what we know from current databases and measurement strategies including mass spectrometry-based proteomics. In doing so, we examine prevailing notions about the number of modifications displayed on human proteins and how they combine to generate the protein diversity underlying health and disease. We frame central issues regarding determination of protein-level variation and PTMs, including some paradoxes present in the field today. We use this framework to assess existing data and to ask the question, \"How many distinct primary structures of proteins (proteoforms) are created from the 20,300 human genes?\" We also explore prospects for improving measurements to better regularize protein-level biology and efficiently associate PTMs to function and phenotype.
Journal Article
Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape
A fundamental feature of cellular plasma membranes (PMs) is an asymmetric lipid distribution between the bilayer leaflets. However, neither the detailed, comprehensive compositions of individual PM leaflets nor how these contribute to structural membrane asymmetries have been defined. We report the distinct lipidomes and biophysical properties of both monolayers in living mammalian PMs. Phospholipid unsaturation is dramatically asymmetric, with the cytoplasmic leaflet being approximately twofold more unsaturated than the exoplasmic leaflet. Atomistic simulations and spectroscopy of leaflet-selective fluorescent probes reveal that the outer PM leaflet is more packed and less diffusive than the inner leaflet, with this biophysical asymmetry maintained in the endocytic system. The structural asymmetry of the PM is reflected in the asymmetric structures of protein transmembrane domains. These structural asymmetries are conserved throughout Eukaryota, suggesting fundamental cellular design principles.
Lipidomics across the bilayer membrane plus biophysical and fluorescence approaches find asymmetry in phospholipid unsaturation and localization of protein transmembrane domains based on their ability to pack within the different membrane leaflets.
Journal Article
Deep learning-guided discovery of an antibiotic targeting Acinetobacter baumannii
Acinetobacter baumannii
is a nosocomial Gram-negative pathogen that often displays multidrug resistance. Discovering new antibiotics against
A. baumannii
has proven challenging through conventional screening approaches. Fortunately, machine learning methods allow for the rapid exploration of chemical space, increasing the probability of discovering new antibacterial molecules. Here we screened ~7,500 molecules for those that inhibited the growth of
A. baumannii
in vitro. We trained a neural network with this growth inhibition dataset and performed in silico predictions for structurally new molecules with activity against
A. baumannii
. Through this approach, we discovered abaucin, an antibacterial compound with narrow-spectrum activity against
A. baumannii
. Further investigations revealed that abaucin perturbs lipoprotein trafficking through a mechanism involving LolE. Moreover, abaucin could control an
A. baumannii
infection in a mouse wound model. This work highlights the utility of machine learning in antibiotic discovery and describes a promising lead with targeted activity against a challenging Gram-negative pathogen.
Using a neural network trained on bacterial growth inhibition data, in silico prediction of molecules with activity against
Acinetobacter baumannii
led to the identification of the narrow-spectrum abaucin, which perturbs lipoprotein trafficking.
Journal Article
Lysine l-lactylation is the dominant lactylation isomer induced by glycolysis
Lysine
l
-lactylation (K
l
-la
) is a novel protein posttranslational modification (PTM) driven by
l
-lactate. This PTM has three isomers: K
l
-la
,
N
-ε-(carboxyethyl)-lysine (K
ce
) and
d
-lactyl-lysine (K
d
-la
), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that K
l
-la
is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not K
d
-la
or K
ce
, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in
l
-lactylation, correlates positively with
K
l
-la
levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights K
l
-la
as the primary responder to glycolysis and the Warburg effect.
Using a combination of antibody- and LC–MS/MS-based methods, Zhang et al. reveal lysine
l
-lactylation as the key lactylation isomer in cellular histones, responding dynamically to glycolysis and positively correlating with lactyl-CoA levels, providing insights into the Warburg effect.
Journal Article
LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation
Selective protein degradation platforms have afforded new development opportunities for therapeutics and tools for biological inquiry. The first lysosome-targeting chimeras (LYTACs) targeted extracellular and membrane proteins for degradation by bridging a target protein to the cation-independent mannose-6-phosphate receptor (CI-M6PR). Here, we developed LYTACs that engage the asialoglycoprotein receptor (ASGPR), a liver-specific lysosome-targeting receptor, to degrade extracellular proteins in a cell-type-specific manner. We conjugated binders to a triantenerrary
N
-acetylgalactosamine (tri-GalNAc) motif that engages ASGPR to drive the downregulation of proteins. Degradation of epidermal growth factor receptor (EGFR) by GalNAc-LYTAC attenuated EGFR signaling compared to inhibition with an antibody. Furthermore, we demonstrated that a LYTAC consisting of a 3.4-kDa peptide binder linked to a tri-GalNAc ligand degrades integrins and reduces cancer cell proliferation. Degradation with a single tri-GalNAc ligand prompted site-specific conjugation on antibody scaffolds, which improved the pharmacokinetic profile of GalNAc-LYTACs in vivo. GalNAc-LYTACs thus represent an avenue for cell-type-restricted protein degradation.
Lysosome-targeting chimeras (LYTACs) based on glycan ligands of the asialoglycoprotein receptor facilitate the cell-specific targeting and turnover of proteins by lysosomal enzymes, expanding the scope of LYTAC-mediated targeted protein degradation.
Journal Article