Annual review of biochemistry最新文献

Axon degeneration is a tightly regulated process that plays a central role in the pathogenesis of many neurodegenerative diseases. Three core mediators, DLK (dual leucine zipper kinase), NMNAT2 (nicotinamide mononucleotide adenylyltransferase 2), and SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) form a molecular axis that orchestrates axonal self-destruction. Upon stress, DLK initiates mitogen-activated protein kinase signaling, which triggers the expression of prodegenerative genes. NMNAT2, an essential nicotinamide adenine dinucleotide biosynthetic enzyme, is rapidly depleted following injury. Loss of NMNAT2 leads to the accumulation of its substrate, nicotinamide mononucleotide, which in turn activates SARM1, a central executioner of axon degeneration. Together, these proteins constitute a coordinated signaling axis that monitors cellular stress and metabolic cues to regulate axonal integrity. In this review, we provide an overview of the biochemical and cellular mechanisms of DLK, NMNAT2, and SARM1 signaling and discuss how targeting these factors offers opportunities for therapeutic intervention in a broad range of neurodegenerative disorders.

Radical chemistry, once deemed too reactive for biological systems, is delicately controlled within metalloenzymes to catalyze challenging chemical transformations under physiological conditions. This review explores the diverse strategies employed by metalloenzymes to generate, stabilize, and utilize highly reactive radical intermediates. We discuss amino acid-based radicals (tyrosyl, tryptophan, cysteinyl, glycyl, and DOPA), radicals derived from molecular oxygen (in heme, manganese, copper, and nonheme iron enzymes), and cofactor-based radicals (specifically adenosylcobalamin and radical S-adenosylmethionine enzymes). We devote special attention to ribonucleotide reductases as a prime example of evolutionary convergence of radical mechanisms. The interplay among redox-active cofactors, metal ions, and protein scaffolds highlights nature's ingenuity in generating, controlling, and utilizing radicals. We also discuss emerging themes and open questions, emphasizing how advances in structural and spectroscopic techniques continue to deepen our understanding of these complex and vital enzymatic processes.

The human oral microbiome is a densely populated and chemically dynamic ecosystem where interspecies competition and cooperation shape community structure and influence host health. Metagenomic analyses reveal the immense biosynthetic potential of oral microbes to encode biosynthetic gene clusters (BGCs) and produce natural products. These metabolites are increasingly recognized as key mediators of microbial interactions, with many oral BGCs linked to health and disease. This review focuses on natural products in the oral microbiome derived from nonribosomal peptide synthetases and polyketide synthases, which are notable for their large size, modular machinery, and ecological relevance. We review the biosynthetic origins and bioactivities of these specialized metabolites in oral bacteria and discuss their biosynthetic regulation within the broader microbial community. Continued investment in whole-genome sequencing, integrative omics, and natural product discovery pipelines is essential for elucidating the microbial biochemical drivers of disease and advancing strategies to promote oral health.

Our double-stranded DNA (dsDNA) genomes are famously compacted by proteins in the nuclei of our cells, resulting in meters of dsDNA being confined in micron-sized volumes. The most prevalent form of viral genomes, however, is single-stranded RNA (ssRNA), which is compacted at significantly higher density in protective protein shells with nanometer dimensions. In this review, we discuss the special nature of ssRNA that allows it to be spontaneously packaged in this way by co-self-assembly with viral capsid protein (CP). We focus on the few viruses whose nucleocapsids can be reconstituted from their purified CP and ssRNA genomes and whose CPs can spontaneously package heterologous RNA into virus-like particles (VLPs). These VLPs are then compared with their cell-synthesized versions, with lentivirus and adeno-associated virus vector particles, and with nucleocapsids formed by nonviral proteins whose messenger RNAs are put under directed evolutionary pressure to be packaged by them in cellulo.

To protect their delicate, carefully curated contents from the world, bacteria encase themselves within a protective envelope made up of sugars, lipids, and proteins. Cell envelopes give bacteria their characteristic shapes, provide rigidity and mechanical stability, and form a selective antechamber-granting access only to a desirable subset of environmental substances. Yet this protective layer is a double-edged sword: Its effectiveness at keeping things out also makes it difficult for things to leave, including the proteins required to interface with the outside world and form the envelope itself. Bacteria have solved this problem by constructing an array of proteinaceous nanomachines that expend energy to selectively shuttle proteins and other building blocks to their intended destinations. Here, we present an overview of our current understanding of how these transporters work, focusing on the major, conserved machines that ferry proteins across the cell envelope throughout the domain Bacteria. The emphasis is on recent discoveries and open questions, with the hope that answering these will provide new avenues to help combat the rising threat of antimicrobial resistance and the rapidly expanding list of diseases linked to human microbiome composition.

The assembly of newly synthesized proteins into functionally active oligomers has long been regarded as a posttranslational process driven by random collision of subunits. However, growing evidence indicates that, for many proteins, assembly occurs cotranslationally, tightly coupling synthesis, folding, and subunit assembly. This fundamentally different mechanism enables the spatial and temporal coordination of assembly, promotes the hierarchical formation of multisubunit assemblies, enhances the stability of involved subunits, enlarges the space of feasible protein structures including complexes with intertwined subunits, and has profound effects on protein evolution and function. In this review, we describe the molecular mechanisms, cellular requirements, and functional implications of cotranslational assembly and discuss its relevance to human disease, its evolutionary significance, and its transformative potential in synthetic biology and recombinant protein production.

Cancer cells acquire hallmark behaviors through adaptations that extend beyond genetic and epigenetic changes. Proteostasis-the biochemical network governing protein synthesis, folding, trafficking, and degradation-is a fundamental, yet underappreciated, mediator of these adaptations that merits consideration as a hallmark-enabling mechanism. Metabolic alterations impose proteotoxic stress, globally rewire protein homeostasis, and selectively modulate key oncogenic and tumor suppressive proteins. A unifying framework is proposed wherein metabolic deregulation of proteostasis operates throughout carcinogenesis: early, by enhancing accumulation of premalignant clones bearing cancer-driving somatic mutations in response to environmental and systemic metabolic stress, and later, by buffering proteotoxic stress to sustain malignant growth in hostile tissue environments. This perspective connects cancer risk with genetic background, diet, microbiome-derived metabolites, and metabolic disease, introduces metabolic bypass of tumor suppression as an alternative to classical genetic models, and highlights the metabolism-proteostasis interface as a promising target for cancer prevention and therapy.

The ability of cells to transmit information encoded in the genome, and its organization into chromatin across cell generations, is a cornerstone of eukaryotic life. Chromatin replication, the copying of the mammalian genome in its structural and functional chromatin context to maintain cell identity and fate, is fundamental to lifelong health and has important implications for cancer and aging. Here, we review the major breakthroughs in our understanding of chromatin dynamics during DNA replication, critical for genome and epigenome inheritance. We discuss how chromatin is disrupted at the replication fork and how the replication machinery ensures transmission of parental histones with their modifications to daughter DNA strands with high fidelity. We highlight how incorporation of new histones is integrated into this process to maintain chromatin integrity and functionality. Finally, we consider how these processes maintain gene expression programs and thus cellular identity and function across cell division throughout the organismal life span.

Protein aging, stress, or metabolism can lead to the accumulation of numerous nonenzymatic chemical alterations that can threaten protein stability and function, particularly in long-lived proteins. Eukaryotic cells recognize these protein-damage events through repair and removal pathways, whose loss can lead to adverse effects and contribute to age-related disease pathogenesis. Here, we review recent advances in understanding the formation, repair, and removal mechanisms of posttranslational modifications arising from protein damage, including dehydroamino acids, early-stage glycation, isoaspartate, C-terminal cyclic imides, and C-terminal amides. We emphasize the emerging role of E3 ubiquitin ligases in facilitating the degradation of proteins bearing these modifications, highlight the approaches used to make these discoveries, and discuss the potential functions of these modifications beyond protein damage. Mounting evidence that protein-damage events influence cellular signaling and metabolism suggests the existence of vast undiscovered regulatory networks, creating opportunities to uncover tissue-specific repair mechanisms and their roles in development, aging, and stress responses across diverse biological contexts.

Lactate's role in biochemistry and physiology has attracted considerable biochemical interest for over a century. Beyond its classical description as a glycolytic byproduct, lactate is now recognized as a central energy metabolite, a redox shuttle, and a signaling molecule. Modern advances in mass spectrometry have uncovered yet another dimension of lactate biology: lactate as a chemical modification on proteins and metabolites. Covalent conjugation of lactate to the ε-amine of a protein lysine side chain generates a posttranslational modification (lysine lactylation); in a related reaction on metabolites, conjugation of lactate to the α-amine of free amino acids produces a class of bioactive lactate-modified amino acids (the N-lactoyl amino acids). These lactate modifications represent a fundamental mechanism by which transient increases in glycolytic flux are translated into durable downstream effectors. Here, we review the detection, regulation, and function of these lactate-derived modifications in cellular and organismal homeostasis.