Critical Reviews in Biochemistry and Molecular Biology最新文献

Breast cancer is the most frequent malignancy and the most common cause of cancer-related death in women worldwide. Despite remarkable improvements in therapy, the prognosis of advanced breast cancer remains poor. Further investigations are mandatory to explore the molecular pathophysiology. Recent studies provide evidence that B-cell lymphoma 6 (BCL6) may play important roles in breast cancer progression. BCL6, a transcriptional suppressor, is critical in the initiation and maintenance of the germinal centers by regulating the formation and function of germinal center B cells, follicular helper T cells and follicular regulatory T cells. It is a well-known key oncogene in lymphomagenesis. In this narrative review, we have summarized the current knowledge of its expression levels in primary breast cancers, analyzed its pathophysiological functions in breast cancer cells, and discussed the underlying molecular mechanisms. The data highlight that elevated BCL6 is significantly related to malignant properties of breast cancer, including tumor size, grade, invasion, metastasis, recurrence, therapy resistance, and poor prognosis. Moreover, elevated BCL6 is tightly associated with cancerous cellular features, such as increased proliferation and survival, poor differentiation, augmented migration, and formation of cancer stem cells, through diverse molecular pathways. In particular, enhanced BCL6 is observed in triple negative breast cancer and linked to decreased progression-free survival of patients. These findings strongly suggest that BCL6 plays a key role in breast cancer development and that targeting BCL6 may be a novel strategy for the treatment of breast cancer.

Autophagy, a highly conserved catabolic pathway in eukaryotes, is essential for cellular survival during starvation and for maintaining cellular homeostasis. Central to autophagy is the de novo formation of double-membrane autophagosomes, which requires the orchestrated action of a set of autophagy-related (ATG) proteins. ATG16L1 is a core autophagy protein involved in distinct phases of autophagosome biogenesis, including membrane remodeling and the formation of phagophore-like membrane cups. It interacts with the ATG12-ATG5 conjugate to form the ATG12-ATG5-ATG16L1 complex, which functions as an E3-like enzyme to catalyze LC3 lipidation. The membrane targeting of the ATG12-ATG5-ATG16L1 complex is crucial for regulating autophagy and preventing ectopic membrane engagement. In this review, we summarize and discuss the potential mechanisms underlying ATG16L1 membrane recruitment, focusing on its intrinsic membrane-binding properties and partner-mediated recruitment pathways. We critically explore how these multiple mechanisms collectively ensure the proper localization and function of ATG16L1, thereby regulating the initiation of autophagy, LC3 lipidation, and the sequestration of bacteria during xenophagy.

In 1926, James B. Sumner crystallized jack bean urease-the first enzyme to be obtained in crystalline form-thus demonstrating that enzymes are proteinaceous. To honor the 100-year anniversary of that momentous event, this review highlights critical findings leading up to Sumner's efforts, explains the significance of his results, and describes subsequent experimental findings related to urease. For example, nearly five decades after crystals became available Burt Zerner and colleagues identified urease as the first known nickel-containing enzyme. The surprising discovery of nickel in urease raised questions about the structure of the metal-containing active site, the enzyme mechanism, and pathway by which the catalytic center is synthesized - each of which is addressed here. Finally, I reflect on remaining open questions related to this remarkable enzyme and potential experimental directions that could be employed to provide corresponding insights.

The endoplasmic reticulum (ER) serves as a central hub for protein production and sorting in eukaryotic cells, processing approximately one-third of the cellular proteome. Protein targeting to the ER occurs through multiple pathways that operate both during and independent of translation. The classical translation-dependent pathway, mediated by cytosolic factors like signal recognition particle, recognizes signal peptides or transmembrane helices in nascent proteins, while translation-independent mechanisms utilize RNA-based targeting through specific sequence elements and RNA-binding proteins. At the core of these processes lies the Sec61 complex, which undergoes dynamic conformational changes and coordinates with numerous accessory factors to facilitate protein translocation and membrane insertion across and into the endoplasmic reticulum membrane. This review focuses on the molecular mechanisms of protein targeting to the ER, from the initial recognition of targeting signals to the dynamics of the translocation machinery, highlighting recent discoveries that have revealed unprecedented complexity in these cellular trafficking pathways.

Mycobacterium tuberculosis (Mtb) depends on the bifunctional enzyme catalase-peroxidase (KatG) for survival within the host. KatG exhibits both catalase and peroxidase activities, serving distinct yet critical roles. While its peroxidase activity is essential for activating the frontline tuberculosis drug isoniazid, its catalase activity protects Mtb from oxidative stress. This bifunctional enzyme is equipped with a unique, protein-derived cofactor, methionine-tyrosine-tryptophan (MYW), which enables catalase activity to efficiently disproportionate hydrogen peroxide in phagocytes. Recent studies reveal that the MYW cofactor naturally exists in a hydroperoxylated form (MYW-OOH) when cell cultures are grown under ambient conditions. New findings highlight a dynamic regulation of KatG activity, wherein the modification of the protein cofactor is removable-from MYW-OOH to MYW-at body temperature or in the presence of micromolar concentrations of hydrogen peroxide. This reversible modification modulates KatG's dual activities: MYW-OOH inhibits catalase activity while enhancing peroxidase activity, demonstrating the chemical accessibility of the cofactor. Such duality positions KatG as a unique target for tuberculosis drug development. Therapeutic strategies that exploit cofactor modification could hold promise, particularly against drug-resistant strains with impaired peroxidase activity. By selectively inhibiting catalase activity, these approaches would render Mtb more vulnerable to oxidative stress while enhancing isoniazid activation-a double-edged strategy for combating tuberculosis.

Mononuclear non-heme iron enzymes catalyze a wide array of important oxidative transformations. They are correspondingly diverse in both structure and mechanism. Despite significant evolutionary distance, it is becoming increasingly apparent that these enzymes nonetheless illustrate a compelling case of mechanistic convergence via the formation of peroxo species bridging metal and substrate. Aromatic amino acid hydroxylases and 2-oxoglutarate (2OG)-dependent enzymes, for example, form bridged acyl- or alkylperoxo intermediates en route to highly oxidizing ferryl species, while catechol dioxygenases utilize such 'bridged' peroxos directly. Analogous acylperoxoiron intermediates have also been demonstrated to precede a perferryl oxidant in biomimetic systems. Herein, we synthesize the results of structural, spectroscopic and computational studies on these systems to gain insight into the shared chemical logic that drives iron-peracid formation and reactivity. In all cases, reactions are tuned via the electron-donating properties of coordinating ligands. Second-sphere residues have also been demonstrated to modulate the orientation of the bridge, thereby influencing reaction outcomes. The effect of carboxylic acid addition to relevant biomimetic catalyst reactions further underscores these fundamental chemical principles. Altogether, we provide a comprehensive analysis of the cross-cutting mechanisms that guide peroxo formation and subsequent oxidative chemistry performed by non-heme mononuclear iron catalysts.

The nickel-pincer nucleotide (NPN) is an organometallic cofactor that was first discovered in lactate racemase from Lactiplantibacillus plantarum. In this review, we provide an overview on the structure-function relationships of enzymes that utilize or are involved in the biosynthesis of the NPN cofactor. Recent structural advances have greatly extended our understanding of the biological role of the NPN cofactor in a diverse family of 2-hydroxyacid racemases and epimerases. Moreover, structural studies of the accessory proteins LarB (a combined carboxylase/hydrolase), two distinct forms of LarE (an ATP-dependent sulfur transferase), and LarC (a CTP-dependent nickel insertase) have elucidated key features in the biosynthetic pathway for the NPN cofactor. Finally, we discuss the potential of future structural investigations to uncover additional enzymes that synthesize and use the NPN cofactor to catalyze new reactions.

This review documents investigations leading to the unprecedented discovery of filamentation as a mode of enzyme regulation in the type II restriction endonuclease SgrAI. Filamentation is defined here as linear or helical polymerization of a single enzyme as occurs for SgrAI, and has now been shown to occur in many other enzyme systems, including conserved metabolic enzymes. In the case of SgrAI, filamentation activates the DNA cleavage rate by up to 1000-fold and also alters the enzyme's DNA sequence specificity. The investigations began with the observation that SgrAI cleaves two types of recognition sequences, primary and secondary, but cleaves the secondary sequences only when present on the same DNA as at least one primary. DNA cleavage rate measurements showed how the primary sequence is both a substrate and an allosteric effector of SgrAI. Biophysical measurements indicated that the activated form of SgrAI, stimulated by binding to the primary sequence, consisted of varied numbers of the SgrAI bound to DNA. Structural studies revealed the activated state of SgrAI as a left-handed helical filament which stabilizes an altered enzyme conformation, which binds a second divalent cation in the active site. Efforts to determine the mechanism of DNA sequence specificity alteration are ongoing and current models are discussed. Finally, global kinetic modeling of the filament mediated DNA cleavage reaction and simulations of in vivo activity suggest that the filament mechanism evolved to rapidly cleave invading DNA while protecting the Streptomyces host genome.

To adapt to low-iron environments, many bacteria produce siderophores, low molecular weight iron chelators that are secreted into the environment where they bind ferric iron. The production of siderophore uptake systems then allows retrieval of the iron-complexed siderophore into the cell, where the metal ion can be used for structural and catalytic roles in many proteins. While many siderophores are produced by the activity of a family of large modular nonribosomal peptide synthetase (NRPS) enzymes, a second class of siderophores are produced by an alternate pathway. These so-called NRPS-independent siderophores (NIS) are biosynthesized through a shared catalytic step that is performed by an NIS synthetase. These enzymes catalyze the formation of an amide linkage between a carboxylate and an amine or, more rarely, form an ester with a hydroxyl substrate. Here we describe the discovery and biochemical studies of diverse NIS synthetases from different siderophore pathways to provide insight into their substrate specificity and catalytic mechanism. The structures of a small number of family members are additionally described that correlates the functional work with the enzyme structure. While the field has come a long way since it was described as a "long-overlooked" family in 2009, there remains much to discover in this large and important enzyme family.

Space exploration and research are uncovering the potential for terrestrial life to survive in outer space, as well as the environmental factors that affect life during interplanetary transfer. The presence of methane in the Martian atmosphere suggests the possibility of methanogens, either extant or extinct, on Mars. Understanding how methanogens survive and adapt under space-exposed conditions is crucial for understanding the implications of extraterrestrial life. In this article, we discuss methanogens as model organisms for obtaining energy transducers and producing methane in a simulated Martian environment. We also explore the chemical evolution of cellular composition and growth maintenance to support survival in extraterrestrial environments. Neutral selective pressure is imposed on the chemical composition of cellular components to increase cell survival and reduce growth under physiological conditions. Energy limitation is an evolutionary driver of macromolecular polymerization, growth maintenance, and survival fitness of methanogens. Methanogens grown in a Martian environment may exhibit global alterations in their metabolic function and gene expression at the system scale. A space systems biology approach would further elucidate molecular survival mechanisms and adaptation to a drastic outer space environment. Therefore, identifying a genetically stable methanogenic community is essential for biomethane production from waste recycling to achieve sustainable space-life support functions.