Current Opinion in Chemical Biology最新文献

Chemogenetic approaches have been developed to define the mechanisms whereby the intracellular oxidant hydrogen peroxide (H₂O₂) modulates both physiological and pathological responses. Recombinant yeast D-amino acid oxidase (DAAO) can be exploited to modulate H₂O₂ in target cells and tissues. In vitro studies using cultured cells expressing recombinant DAAO have provided critical new information on the intracellular transport and metabolism of H₂O₂ with great temporal and spatial resolution. In contrast, in vivo studies using chemogenetic/transgenic animal models have explored the pathological effects of chronically elevated H₂O₂ in tissues. Coupled with transcriptomic, proteomic, and metabolomic methods, in vivo chemogenetic approaches are providing new insights into the adaptations to oxidative stress. This review of chemogenetic applications focuses on new models of heart failure and neurodegeneration that leverage in vivo chemogenetic modulation of oxidative stress in target tissues to identify new therapeutic targets.

Cysteines are amenable to a diverse set of modifications that exhibit critical regulatory functions over the proteome and thereby control a wide range of cellular processes. Proteomic technologies have emerged as a powerful strategy to interrogate cysteine modifications across the proteome. Recent advancements in enrichment strategies, multiplexing capabilities and increased analytical sensitivity have enabled deeper quantitative cysteine profiling, capturing a substantial proportion of the cysteine proteome. This is complemented by a rapidly growing repertoire of analytical strategies illuminating the diverse landscape of cysteine modifications. Cysteine chemoproteomics technologies have evolved into a powerful strategy to facilitate the development of covalent drugs, opening unprecedented opportunities to target the extensive undrugged proteome. Herein we review recent technological and scientific advances that shape the cysteine proteomics field.

The hypoxia-inducible factors are α,β-heterodimeric transcription factors that mediate the chronic response to hypoxia in humans and other animals. Protein hydroxylases belonging to two different structural subfamilies of the Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenase superfamily modify HIFα. HIFα prolyl-hydroxylation, as catalysed by the PHDs, regulates HIFα levels and, consequently, α,β-HIF levels. HIFα asparaginyl-hydroxylation, as catalysed by factor inhibiting HIF (FIH), regulates the transcriptional activity of α,β-HIF. The activities of the PHDs and FIH are regulated by O₂ availability, enabling them to act as hypoxia sensors. We provide an overview of the biochemistry of the HIF hydroxylases, discussing evidence that their kinetic and structural properties may be tuned to their roles in the HIF system. Avenues for future research and therapeutic modulation are discussed.

In the rhizosphere, plants and microbes communicate chemically, especially under environmental stress. Over millions of years, plants and their microbiome have coevolved, sharing various chemicals, including signaling molecules. This mutual exchange impacts bacterial communication and influences plant metabolism. Inter-kingdom signal crosstalk affects bacterial colonization and plant fitness. Beneficial microbes and their metabolomes offer eco-friendly ways to enhance plant resilience and agriculture. Plant metabolites are pivotal in this dynamic interaction between host plants and their interacting beneficial microbes. Understanding these associations is key to engineering a robust microbiome for stress mitigation and improved plant growth. This review explores mechanisms behind plant-microbe interactions, the role of beneficial microbes and metabolomics, and the practical applications for addressing climate change's impact on agriculture. Integrating beneficial microbes' activities and metabolomics' application to study metabolome-driven interaction between host plants and their corresponding beneficial microbes holds promise for enhancing crop resilience and productivity.

Numerous electrophilic metabolites are formed during cellular activity, particularly under conditions of oxidative, inflammatory and metabolic stress. Among them are lipid oxidation and nitration products, and compounds derived from amino acid and central carbon metabolism. Here we focus on one cellular target of electrophiles, the Kelch-like ECH associated protein 1 (KEAP1)/nuclear factor erythroid 2 p45-related factor 2 (NRF2) partnership. Many of these reactive compounds modify C151, C273 and/or C288 within KEAP1. Other types of modifications include S-lactoylation of C273, N-succinylation of K131, and formation of methylimidazole intermolecular crosslink between two KEAP1 monomers. Modified KEAP1 relays the initial signal to transcription factor NRF2 and its downstream targets, the ultimate effectors that provide means for detoxification, adaptation and survival. Thus, by non-enzymatically covalently modifying KEAP1, the electrophilic metabolites discussed here serve as chemical signals connecting metabolism with stress responses.

Hydrogen peroxide (H₂O₂), a natural metabolite commonly found in aerobic organisms, plays a crucial role in numerous cellular signaling processes. One of the key organelles involved in the cell's metabolism of H₂O₂ is the peroxisome. In this review, we first provide a concise overview of the current understanding of H₂O₂ as a molecular messenger in thiol redox signaling, along with the role of peroxisomes as guardians and modulators of cellular H₂O₂ balance. Next, we direct our focus toward the recently identified primary protein targets of H₂O₂ originating from peroxisomes, emphasizing their importance in unraveling the complex interplay between peroxisomal H₂O₂ and cell signaling. We specifically focus on three areas: signaling through peroxiredoxin redox relay complexes, calcium signaling, and phospho-signaling. Finally, we highlight key research directions that warrant further investigation to enhance our comprehension of the molecular and biochemical mechanisms linking alterations in peroxisomal H₂O₂ metabolism with disease.

Antimicrobial resistance is an increasing phenomenon that is threatening global health. Tuberculosis causative bacteria and several resistant and multidrug-resistant bacteria are widely spread and listed by the World Health Organization as global priorities for research and development. Hence, new antibacterial agents with new modes of action are urgently required. In this context, carbohydrate-based drugs have been extensively studied and used, presenting several benefits for therapeutical purposes. In this review, the latest efforts done in the carbohydrate-based antibacterial agents research field, reported from 2021 to 2023, are summarized. Carbohydrate-based prodrugs, drugs, and delivery systems are covered, highlighting derivatization of existing antibiotics, use of nanotechnology, and repurposing of available therapeutical agents as the most popular strategies used in antibacterial agents’ development.

To accelerate the biological study and application of the diverse functions of glycosphingolipids (GSLs), the production of structurally defined GSLs has been greatly demanded. In this review, we focus on the recent developments in the chemical and chemoenzymatic synthesis of GSLs. In the chemical synthesis section, the syntheses based on glucosyl ceramide cassette, late-stage sialylation, and diversity-oriented strategies for GSLs or ganglioside synthesis are highlighted, which delivered terpioside B, fluorescent sialyl lactotetraosyl ceramide, and analogs of lacto-ganglio-series GSLs, respectively. In the chemoenzymatic synthesis section, the synthesis of ganglioside GM1 by multistep one-pot multienzyme method and the total synthesis of highly complex ganglioside LLG-5 using a water-soluble lactosyl ceramide as a key substrate for enzymatic sialylation are described.

Glycosylphosphatidylinositol (GPI) attachment to the C-terminus of proteins is a prevalent posttranslational modification in eukaryotic species, and GPIs help anchor proteins to the cell surface. GPI-anchored proteins (GPI-APs) play a key role in various biological events. However, GPI-APs are difficult to access and investigate. To tackle the problem, chemical and chemoenzymatic methods have been explored for the preparation of GPI-APs, as well as GPI probes that facilitate the study of GPIs on live cells. Substantial progress has also been made regarding GPI-AP biosynthesis, which is helpful for developing new synthetic methods for GPI-APs. This article reviews the recent advancements in the study of GPI-AP biosynthesis, GPI-AP synthesis, and GPI interaction with the cell membrane utilizing synthetic probes.