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 TIR 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.

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.

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 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.

A signature feature of transcription on most genes in multicellular animals is that RNA polymerase II (RNAPII) piles up approximately 50 bases downstream of the start site at the promoter-proximal pause (PPP). Promoter-proximal pausing is controlled by positive and negative elongation factors that associate with RNAPII. There are two major outcomes for promoter-proximally paused RNAPII complexes: release into the gene body and premature termination. Here we discuss how RNAPII dynamics at the PPP function in a quality control checkpoint and in regulation of RNAPII flux through genes. We propose a pause release-attenuation model to describe RNAPII dynamics at the PPP.

The eleven known zinc-dependent histone deacetylases (HDACs) catalyze the deacetylation or deacylation of myriad protein and small molecule substrates throughout the cell. The biological functions of HDACs are much more diverse than the name HDAC implies, but this name is nonetheless retained for historical purposes. The chemical mechanism of catalysis is generally conserved among HDAC isozymes: Electrophilic activation of the substrate is achieved by zinc coordination and hydrogen bonding, and nucleophilic activation of a zinc-bound water molecule is enhanced by a general base. Since aberrant activity is observed for specific HDAC isozymes in certain diseases, the development of isozyme-selective inhibitors is a current priority in worldwide medicinal chemistry campaigns. In this review, the biological functions and chemical mechanisms of the HDACs are discussed to establish the molecular context of catalysis and inhibition, particularly as the chemistry of catalysis is harnessed in the development of mechanism-based inhibitors.

Coronaviruses (family Coronaviridae, order Nidovirales) include major human and animal pathogens. They have exceptionally large RNA genomes and use complex strategies to replicate and express these genomes. Intensive research activities in recent years have significantly advanced our knowledge of the molecular mechanisms involved in coronavirus RNA synthesis. Here, we briefly review these mechanisms and focus in particular on the structures and functions of the core replication-transcription complex (RTC) and other enzyme functions that can be recruited to this complex to fulfil additional functions, for example, in the context of 5' capping of viral mRNAs or in the context of mechanisms that control the processivity, replication fidelity, and backtracking of RTCs. Some of these recent studies provided fundamentally new insight into specific roles of previously identified genetic markers of coronaviruses and other nidoviruses, including specific functions in an unconventional RNA capping mechanism and potential roles in proofreading and discontinuous negative-strand RNA synthesis.

Damage to mitochondria imparts multifaceted cellular stress that extends beyond bioenergetic deficit. One newly emerged example is mitochondrial precursor overaccumulation stress (mPOS). mPOS is marked by impaired mitochondrial protein import, causing the toxic accumulation and aggregation of unimported mitochondrial precursor proteins in the cytosol. Analogous to the well-studied endoplasmic reticulum stress, which blocks proteins from leaving the cell, mPOS can impose a drastic proteostatic burden in the cytosol and closely interconnects with cell signaling pathways. Here, we review how researchers discovered mPOS and discuss its central importance in several major mitochondria-induced stress signaling pathways. We then focus on the emerging field of mPOS in cell demise and human disease, and we present recent evidence that mPOS can affect cell fitness and survival independent of bioenergetics. Looking forward, mPOS may provide a complementary or alternative pathogenic mechanism to bioenergetic deficit for classic mitochondriopathy and many aging-associated degenerative diseases involving mitochondrial stress.

Three fundamental classes of gene regulatory elements were identified in Escherichia coli in the 1960s: operators bound by repressor proteins, promoters bound by the basic transcription machinery, and enhancers bound by activator proteins. Promoters mediate constitutive gene expression, whereas operators and enhancers regulate expression in response to physiological conditions. As discovered in the 1980s, interactions between proteins associated with spatially separated elements can loop out the intervening DNA and regulate transcription. Eukaryotic gene regulation is mediated by the same three classes of genetic elements, but due to semantic confusion, it is often believed the eukaryotic enhancers activate transcription from long distances via enhancer-promoter loops. However, eukaryotic enhancers mediate only local changes in chromatin, and they stimulate transcription via directional and short-range interactions with the basic Pol II machinery at promoters. Enhancer action at a distance is mediated by loops between proximal and distal enhancers that bring activator proteins associated with distal enhancers in proximity to promoters. Thus, Jacques Monod's 1954 conjecture that "what is true for E. coli is true for the elephant, only more so" has proven correct.

AlphaFold, a groundbreaking artificial intelligence model developed by DeepMind, has transformed the field of structural biology by predicting protein structures with unprecedented accuracy. Despite its widespread recognition and application across academia and industry, comprehensive reviews detailing AlphaFold's unexpected applications within the molecular sciences remain scarce. In this review, we critically examine AlphaFold's emerging roles across diverse molecular scientific disciplines. Specifically, we highlight its applications in enzyme engineering and drug development, nucleic acid modeling and vaccine design, the development of protein-based materials and targeted drug delivery systems, and modeling of complex systems and biological networks. To conclude, the review outlines potential future developments and enduring challenges within the application of AlphaFold to molecular sciences. Overall, this review aims to systematically analyze the most recent advances; explore novel interdisciplinary applications of AlphaFold within the realms of biology, chemistry, and materials science; and offer insights into future directions for research and application.