Trends in Biochemical Sciences最新文献

Peptides are a powerful drug modality with potential to access difficult targets. This recognition underlies their growth in the global pharmaceutical market, with peptides representing ~8% of drugs approved by the FDA over the past decade. Currently, the peptide therapeutic landscape is evolving, with high-throughput display technologies driving the identification of peptide leads with enhanced diversity. Yet, chemical modifications remain essential for improving the 'drug-like' properties of peptides and ultimately translating leads to market. In this review, we explore two recent therapeutic candidates (semaglutide, a peptide hormone analogue, and MK-0616, an mRNA display-derived candidate) as case studies that highlight general approaches to improving pharmacokinetics (PK) and potency. We also emphasize the critical link between advances in medicinal chemistry and the optimisation of highly efficacious peptide therapeutics.

A recent report by Makasewicz et al. delineates how α-synuclein (αSyn) membrane-binding modes drive amyloid formation. Their in vitro data reveal a lipid-to-protein (L/P) ratio tipping point influencing fibril formation. Preliminary validation from existing literature supports that these findings are also relevant in cellular contexts, informing potential new disease-modulating strategies.

Elucidating plant biosynthetic pathways is key to advancing a sustainable bioeconomy by enabling access to complex natural products through synthetic biology. Despite progress from genomic, transcriptomic, and metabolomic approaches, much multiomics data remain underutilized. This review highlights state-of-the-art multiomics strategies for discovering plant biosynthetic pathways, addressing challenges in data acquisition and interpretation with emerging computational tools. We propose an integrated workflow combining molecular networking, reaction pair analysis, and gene expression patterns to enhance data utilization. Additionally, artificial intelligence (AI)-driven approaches promise to revolutionize pathway discovery by streamlining data analysis and validation. Integrating multiomics data, chemical insights, and advanced algorithms can accelerate understanding of plant metabolism and bioengineering valuable natural products efficiently.

Recent studies emphasize that lipid synthesis, metabolism, and transport are crucial in modulating lipid function, underscoring the significance of lipid localization within the cell, in addition to their chemical structure. Ceramides stand out in this context because of their multifaceted roles in cellular processes. Here, we focus on the role of ceramides in apoptosis, senescence, and autophagy as these processes offer unique and contrasting perspectives on how ceramides function and can be intricately linked to their subcellular localization, providing critical insights into their complex biological interactions. Additionally, we highlight recent advancements in tools and techniques that have boosted our understanding of ceramide dynamics and different mechanisms of lipid functioning.

Advances in small RNA sequencing have revealed diverse small noncoding RNAs (sncRNAs) beyond microRNAs (miRNAs), derived from transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs), and Y RNAs, carrying distinct RNA modifications. These emerging sncRNAs can function beyond RNA interference (RNAi), adopting aptamer-like roles by interacting with Toll-like receptors 7 and 8 (TLR7 and TLR8) via specific sequences, modifications, and structures. We propose a Sequential Activation Hypothesis where initial abnormal sncRNAs - triggered by infections or stresses - activate TLR7/8, leading to autoantibody production against autoantigens like RNA-binding proteins La and Ro. These autoantibody-antigen complexes further promote secondary immunogenic sncRNA production and repetitive TLR7/8 activation, perpetuating a vicious cycle sustaining autoimmunity. TLR7/8's X chromosome location and sex-biased expression contribute to female-dominant autoimmune diseases. Understanding sncRNA-TLR interactions is essential for designing novel therapeutic strategies.

For new laboratories, maintaining pricing within a budget while obtaining the necessary supplies and reagents for experiments can feel daunting. In this article, we highlight a practical guide to negotiating the best pricing for your laboratory. Using these approaches enables scientists to be fiscally responsible stewards of grant funding.

Biological timing mechanisms are intrinsic to all organisms, orchestrating the temporal coordination of biological events through complex genetic networks. Circadian rhythms and developmental timers utilize distinct timekeeping mechanisms. This review summarizes the molecular basis for circadian rhythms in mammals and Drosophila, and recent work leveraging these clocks to understand temporal regulation in Caenorhabditis elegans development. We describe the evolutionary connections between distinct timing mechanisms and discuss recent insights into the rewiring of core clock components in development. By integrating findings from circadian and developmental studies with biochemical and structural analyses of conserved components, we aim to illuminate the molecular basis of nematode timing mechanisms and highlight broader insights into biological timing across species.

Lignin is an attractive alternative to fossil fuels as a feedstock for the sustainable manufacture of chemicals. Emergent strategies for lignin valorization include tandem processes whereby thermochemical fractionation of the biomass yields a mixture of lignin-derived aromatic compounds (LDACs), which are then transformed into target compounds by a microbial cell factory. Identifying LDAC-degrading pathways is critical to optimize carbon yield from diverse depolymerization mixtures. Characterizing enzymes - especially those that catalyze the rate-limiting steps of O-demethylation, hydroxylation, and decarboxylation - informs and enables biocatalyst design. Rational, structure-based engineering of key enzymes, as well as untargeted, evolution-based approaches, further optimize biocatalysis. In this review we outline recent advances in these fields which are critical in developing biocatalysts to efficiently synthesize lignin-based bioproducts.

Post-translational modifications of nucleocytoplasmic proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) and O-linked fucose (O-fucose) are emerging as key signaling mechanisms in plants. O-fucosylation and O-GlcNAcylation are catalyzed by SPINDLY (SPY) and SECRET AGENT (SEC), respectively, which are redundantly essential for viability and growth yet function antagonistically or independently in specific developmental contexts. Proteomic studies have identified hundreds of O-GlcNAcylated and O-fucosylated nucleocytoplasmic proteins, revealing their regulatory roles and intersections with phosphorylation pathways that mediate nutrient and hormone signaling. Functional studies on O-glycosylated proteins demonstrate diverse impacts on protein activity and biological processes. Together, O-fucosylation, O-GlcNAcylation, and phosphorylation form a regulatory network that controls plant growth, development, and acclimation. This review highlights recent progress and outlines future directions in studying O-fucosylation and O-GlcNAcylation in plants.