Enzymes最新文献

Post-translational modifications of histone proteins control the expression of genes. Metabolites from central and one-carbon metabolism act as donor moieties to modify histones and regulate gene expression. Thus, histone modification and gene regulation are connected to the metabolite status of the cell. Histone modifiers, such as the SIN3 complex, regulate genes involved in proliferation and metabolism. The SIN3 complex contains a histone deacetylase and a histone demethylase, which regulate the chromatin landscape and gene expression. In this chapter, we review the cross-talk between metabolic pathways that produce donor moieties, and epigenetic complexes regulating proliferation and metabolic genes. This cross-talk between gene regulation and metabolism is tightly controlled, and disruption of this cross-talk leads to metabolic diseases. We discuss promising therapeutics that directly regulate histone modifiers, and can affect the metabolic status of the cell, alleviating some metabolic diseases.

Nucleotide excision repair (NER) is a major DNA repair pathway conserved from bacteria to humans. Various DNA helicases, a group of enzymes capable of separating DNA duplex into two strands through ATP binding and hydrolysis, are required by NER to unwind the DNA duplex around the lesion to create a repair bubble and for damage verification and removal. In prokaryotes, UvrB helicase is required for repair bubble formation and damage verification, while UvrD helicase is responsible for the removal of the excised damage containing single-strand (ss) DNA fragment. In addition, UvrD facilitates transcription-coupled repair (TCR) by backtracking RNA polymerase stalled at the lesion. In eukaryotes, two helicases XPB and XPD from the transcription factor TFIIH complex fulfill the helicase requirements of NER. Interestingly, homologs of all these four helicases UvrB, UvrD, XPB, and XPD have been identified in archaea. This review summarizes our current understanding about the structure, function, and mechanism of these four helicases.

Metalloenzymes have been detailed in The Enzymes since its inception over half a century ago. Here, I review selected metal-containing enzyme highlights from early chapters in this series and I describe advances made since those contributions. Three topics are emphasized: nickel-containing enzymes, Fe(II)/2-oxoglutarate-dependent oxygenases, and enzymes containing non-canonical iron-sulfur clusters.

The desired outcome of cancer therapies is the eradication of disease. This can be achieved when therapy exposure leads to therapy-induced cancer cell death as the dominant outcome. Theoretically, a permanent therapy-induced growth arrest could also contribute to a complete response, which has the potential to lead to remission. However, preclinical models have shown that therapy-induced growth arrest is not always durable, as recovering cancer cell populations can contribute to the recurrence of cancer. Significant research efforts have been expended to develop strategies focusing on the prevention of recurrence. Recovery of cells from therapy exposure can occur as a result of several cell stress adaptations. These include cytoprotective autophagy, cellular quiescence, a reversable form of senescence, and the suppression of apoptosis and necroptosis. It is well documented that microRNAs regulate the response of cancer cells to anti-cancer therapies, making targeting microRNAs therapeutically a viable strategy to sensitization and the prevention of recovery. We propose that the use of microRNA-targeting therapies in prolonged sequence, that is, a significant period after initial therapy exposure, could reduce toxicity from the standard combination strategy, and could exploit new epigenetic states essential for cancer cells to recover from therapy exposure. In a step toward supporting this strategy, we survey the available scientific literature to identify microRNAs which could be targeted in sequence to eliminate residual cancer cell populations that were arrested as a result of therapy exposure. It is our hope that by successfully identifying microRNAs which could be targeted in sequence we can prevent disease recurrence.

Transcriptional regulation in eukaryotic cells involves the activity of multifarious DNA-binding transcription factors and recruited corepressor complexes. Together, these complexes interact with the core transcriptional machinery, chromatin, and nuclear environment to effect complex patterns of gene regulation. Much focus has been paid to the action of master regulatory switches that are key to developmental and environmental responses, as these genetic elements have important phenotypic effects. The regulation of widely-expressed metabolic control genes has been less well studied, particularly in cases in which physically-interacting repressors and corepressors have subtle influences on steady-state expression. This latter phenomenon, termed "soft repression" is a topic of increasing interest as genomic approaches provide ever more powerful tools to uncover the significance of this level of control. This review provides an oversight of classic and current approaches to the study of transcriptional repression in eukaryotic systems, with a specific focus on opportunities and challenges that lie ahead in the study of soft repression.

Since the discovery of DNA as the genetic material, scientists have been investigating how the information contained in this biological polymer is transmitted from generation to generation. X-ray crystallography, and more recently, cryo-electron microscopy techniques have been instrumental in providing essential information about the structure, functions and interactions of the DNA and the protein machinery (replisome) responsible for its replication. In this chapter, we highlight several works that describe the structure and structure-function relationships of the core components of the prokaryotic and eukaryotic replisomes. We also discuss the most recent studies on the structural organization of full replisomes.

We present a brief review of the mitochondrial respiratory chain with emphasis on complexes I, III and IV, which contribute to the generation of protonmotive force across the inner mitochondrial membrane, and drive the synthesis of ATP by the process called oxidative phosphorylation. The basic structural and functional details of these complexes are discussed. In addition, we briefly review the information on the so-called supercomplexes, aggregates of complexes I-IV, and summarize basic physiological aspects of cell respiration.

In late November 2019, Prof. Lina M. Obeid passed away from cancer, a disease she spent her life researching and studying its intricate molecular underpinnings. Along with her husband, Prof. Yusuf A. Hannun, Obeid laid down the foundations of sphingolipid biochemistry and oversaw its remarkable evolution over the years. Lipids are a class of macromolecules that are primarily associated with cellular architecture. In fact, lipids constitute the perimeter of the cell in such a way that without them, there cannot be cells. Hence, much of the early research on lipids identified the function of this class of biological molecules as merely structural. Nevertheless, unlike proteins, carbohydrates, and nucleic acids, lipids are elaborately diverse as they are not made up of monomers in polymeric forms. This diversity in structure is clearly mirrored by functional pleiotropy. In this chapter, we focus on a major subset of lipids, sphingolipids, and explore their historic rise from merely inert structural components of plasma membranes to lively and necessary signaling molecules that transmit various signals and control many cellular processes. We will emphasize the works of Lina Obeid since she was an integral pillar of the sphingolipid research world.

Mitochondria are multifunctional organelles that play a central role in a wide range of life-sustaining tasks in eukaryotic cells, including adenosine triphosphate (ATP) production, calcium storage and coenzyme generation pathways such as iron-sulfur cluster biosynthesis. The wide range of mitochondrial functions is carried out by a diverse array of proteins comprising approximately 1500 proteins or polypeptides. Degradation of these proteins is mainly performed by four AAA+ proteases localized in mitochondria. These AAA+ proteases play a quality control role in degrading damaged or misfolded proteins and perform various other functions. This chapter describes previously identified roles for these AAA+ proteases that are localized in the mitochondria of animal cells.