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Methods in Molecular Biology (Clifton,... 2023Posttranslational modifications have emerged in recent years as the major biological regulators responsible for the orders of magnitude increase in complexity during...
Posttranslational modifications have emerged in recent years as the major biological regulators responsible for the orders of magnitude increase in complexity during gene expression and regulation. These "molecular switches" affect nearly every protein in vivo by modulating their structure, activity, molecular interactions, and homeostasis ultimately regulating their functions. While over 350 posttranslational modifications have been described, only a handful of them have been characterized. Until recently, protein arginylation has belonged to the list of obscure, poorly understood posttranslational modifications, before the recent explosion of studies has put arginylation on the map of intracellular metabolic pathways and biological functions. This chapter contains an overview of all the major milestones in the protein arginylation field, from its original discovery in 1963 to this day.
Topics: Aminoacyltransferases; Proteolysis; Proteins; Protein Processing, Post-Translational; Arginine
PubMed: 37010742
DOI: 10.1007/978-1-0716-2942-0_1 -
Nature Reviews. Urology Apr 2020Anabolic metabolism mediated by aberrant growth factor signalling fuels tumour growth and progression. The first biochemical descriptions of the altered metabolic nature... (Review)
Review
Anabolic metabolism mediated by aberrant growth factor signalling fuels tumour growth and progression. The first biochemical descriptions of the altered metabolic nature of solid tumours were reported by Otto Warburg almost a century ago. Now, the study of tumour metabolism is being redefined by the development of new molecular tools, tumour modelling systems and precise instrumentation together with important advances in genetics, cell biology and spectroscopy. In contrast to Warburg's original hypothesis, accumulating evidence demonstrates a critical role for mitochondrial metabolism and substantial variation in the way in which different tumours metabolize nutrients to generate biomass. Furthermore, computational and experimental approaches suggest a dominant influence of the tissue-of-origin in shaping the metabolic reprogramming that enables tumour growth. For example, the unique metabolic properties of prostate adenocarcinoma are likely to stem from the distinct metabolism of the prostatic epithelium from which it emerges. Normal prostatic epithelium employs comparatively glycolytic metabolism to sustain physiological citrate secretion, whereas prostate adenocarcinoma consumes citrate to power oxidative phosphorylation and fuel lipogenesis, enabling tumour progression through metabolic reprogramming. Current data suggest that the distinct metabolic aberrations in prostate adenocarcinoma are driven by the androgen receptor, providing opportunities for functional metabolic imaging and novel therapeutic interventions that will be complementary to existing diagnostic and treatment options.
Topics: Adenocarcinoma; Cell Proliferation; Citric Acid; Citric Acid Cycle; Glycolysis; Humans; Lipogenesis; Male; Metabolic Networks and Pathways; Oxidative Phosphorylation; Prostate; Prostatic Neoplasms; Receptors, Androgen; Tumor Microenvironment
PubMed: 32112053
DOI: 10.1038/s41585-020-0288-x -
Biochimica Et Biophysica Acta.... Jan 2020The endoplasmic reticulum (ER) is a highly organized organelle that performs vital functions including de novo membrane lipid synthesis and transport. Accordingly,... (Review)
Review
The endoplasmic reticulum (ER) is a highly organized organelle that performs vital functions including de novo membrane lipid synthesis and transport. Accordingly, numerous lipid biosynthesis enzymes are localized in the ER membrane. However, it is now evident that lipid metabolism is sub-compartmentalized within the ER and that lipid biosynthetic enzymes engage with lipid transfer proteins (LTPs) to rapidly shuttle newly synthesized lipids from the ER to other organelles. As such, intimate relationships between lipid metabolism and lipid transfer pathways exist within the ER network. Notably, certain LTPs enhance the activities of lipid metabolizing enzymes; likewise, lipid metabolism can ensure the specificity of LTP transfer/exchange reactions. Yet, our understanding of these mutual relationships is still emerging. Here, we highlight past and recent key findings on specialized ER membrane domains involved in efficient lipid metabolism and transport and consider unresolved issues in the field.
Topics: Animals; Biological Transport; Biosynthetic Pathways; Carrier Proteins; Endoplasmic Reticulum; Humans; Lipid Metabolism; Phospholipids
PubMed: 31349025
DOI: 10.1016/j.bbalip.2019.07.001 -
Cell Research Jan 2021Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells....
Whether glucose is predominantly metabolized via oxidative phosphorylation or glycolysis differs between quiescent versus proliferating cells, including tumor cells. However, how glucose metabolism is coordinated with cell cycle in mammalian cells remains elusive. Here, we report that mammalian cells predominantly utilize the tricarboxylic acid (TCA) cycle in G1 phase, but prefer glycolysis in S phase. Mechanistically, coupling cell cycle with metabolism is largely achieved by timely destruction of IDH1/2, key TCA cycle enzymes, in a Skp2-dependent manner. As such, depleting SKP2 abolishes cell cycle-dependent fluctuation of IDH1 protein abundance, leading to reduced glycolysis in S phase. Furthermore, elevated Skp2 abundance in prostate cancer cells destabilizes IDH1 to favor glycolysis and subsequent tumorigenesis. Therefore, our study reveals a mechanistic link between two cancer hallmarks, aberrant cell cycle and addiction to glycolysis, and provides the underlying mechanism for the coupling of metabolic fluctuation with periodic cell cycle in mammalian cells.
Topics: Animals; Cell Line; Citric Acid Cycle; G1 Phase; Glucose; Glycolysis; Humans; Isocitrate Dehydrogenase; Mice; Mutagenesis, Site-Directed; Nocodazole; Protein Isoforms; RNA Interference; RNA, Small Interfering; S Phase; S-Phase Kinase-Associated Proteins; Ubiquitination
PubMed: 32669607
DOI: 10.1038/s41422-020-0372-z -
The New Phytologist Feb 2022Oomycete phytopathogens have adapted to colonise plants using effectors as their molecular weapons. Intracellular effectors, mostly proteins but also small ribonucleic... (Review)
Review
Oomycete phytopathogens have adapted to colonise plants using effectors as their molecular weapons. Intracellular effectors, mostly proteins but also small ribonucleic acids, are delivered by the pathogens into the host cell cytoplasm where they interfere with normal plant physiology. The diverse host processes emerging as 'victims' of these 'specialised bullets' include gene transcription and RNA-mediated silencing, cell death, protein stability, protein secretion and autophagy. Some effector targets are directly involved in defence execution, while others participate in fundamental metabolisms whose alteration collaterally affects defences. Other effector targets are susceptibility factors (SFs), that is host components that make plants vulnerable to pathogens. SFs are mostly negative regulators of immunity, but some seem necessary to sustain or promote pathogen colonisation.
Topics: Host-Pathogen Interactions; Oomycetes; Plant Diseases; Plant Immunity; Plants; Protein Transport; Proteins
PubMed: 34705271
DOI: 10.1111/nph.17828 -
Cold Spring Harbor Perspectives in... Aug 2019Hsp104 is a hexameric AAA ATPase and protein disaggregase found in yeast, which couples ATP hydrolysis to the dissolution of diverse polypeptides trapped in toxic... (Review)
Review
Hsp104 is a hexameric AAA ATPase and protein disaggregase found in yeast, which couples ATP hydrolysis to the dissolution of diverse polypeptides trapped in toxic preamyloid oligomers, phase-transitioned gels, disordered aggregates, amyloids, and prions. Hsp104 shows plasticity in disaggregating diverse substrates, but how its hexameric architecture operates as a molecular machine has remained unclear. Here, we highlight structural advances made via cryoelectron microscopy (cryo-EM) that enhance our mechanistic understanding of Hsp104 and other related AAA translocases. Hsp104 hexamers are dynamic and adopt open "lock-washer" spiral states and closed ring structures that envelope polypeptide substrate inside the axial channel. ATP hydrolysis-driven conformational changes at the spiral seam ratchet substrate deeper into the channel. Remarkably, this mode of polypeptide translocation is reminiscent of models for how hexameric helicases unwind DNA and RNA duplexes. Thus, Hsp104 likely adapts elements of a deeply rooted, ring-translocase mechanism to the specialized task of protein disaggregation.
Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Cryoelectron Microscopy; Glycoside Hydrolases; Heat-Shock Proteins; Hydrolysis; Molecular Chaperones; Prions; Protein Binding; Protein Conformation; Protein Transport; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 30745294
DOI: 10.1101/cshperspect.a034033 -
Current Drug Metabolism 2021In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of... (Review)
Review
In vivo biotransformation of exposed chemicals is one of the major factors that determine the concentration and the duration of a substance at the systemic site of effect. Given that toxicity is expressed as a function of two factors, namely dose and time, the type and intensity of the toxicity are directly dependent on the chemical transformation of the exposed parent substance. This dependency involves two different situations. The amount of the chemical reaching the target will be decreased with the extent of metabolism if the parent chemical is toxic, and the opposite is true if the metabolite(s) is toxic instead. To date, the liver microsomal fraction in mammals has been justifiably considered as the center of biotransformation reactions because the liver and microsomes (i.e., endoplasmic reticulum component of the cell) possess the most abundant types and quantities of xenobiotic-metabolizing enzymes, especially the cytochrome P450 supergene enzyme family. These enzymes are common in all kingdoms of life, which strongly suggests that the origin of life is common. It is already known that various drugs enter mitochondria by different mechanisms, and this translocation is believed to be responsible for mitochondrial effects that are part of the therapeutic actions of various drugs such as lipid-lowering statins or antidiabetogenic thiazolidindiones. However, the discovery of mitochondrial forms of the xenobiotic-metabolizing enzymes provoked discussions about whether mitochondria metabolize drugs and other chemicals to some extent. This possibility may particularly be important as mitochondria have various critical cellular structures and functions. In the case of in situ generated metabolite(s), when there are adverse interactions with either these structures or functions, various toxic outcomes may appear. In this review, we compiled studies in the literature regarding biotransformation of drugs and other chemicals catalyzed by mitochondria where it is both an initiator and target of toxicity.
Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Humans; Mitochondria; Pharmaceutical Preparations; Xenobiotics
PubMed: 34182906
DOI: 10.2174/1389200222666210628125020 -
Biochemical Society Transactions Feb 2021Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the... (Review)
Review
Mitochondria are pivotal for normal cellular physiology, as they perform a crucial role in diverse cellular functions and processes, including respiration and the regulation of bioenergetic and biosynthetic pathways, as well as regulating cellular signalling and transcriptional networks. In this way, mitochondria are central to the cell's homeostatic machinery, and as such mitochondrial dysfunction underlies the pathology of a diverse range of diseases including mitochondrial disease and cancer. Mitochondrial import pathways and targeting mechanisms provide the means to transport into mitochondria the hundreds of nuclear-encoded mitochondrial proteins that are critical for the organelle's many functions. One such import pathway is the highly evolutionarily conserved disulfide relay system (DRS) within the mitochondrial intermembrane space (IMS), whereby proteins undergo a form of oxidation-dependent protein import. A central component of the DRS is the oxidoreductase coiled-coil-helix-coiled-coil-helix (CHCH) domain-containing protein 4 (CHCHD4, also known as MIA40), the human homologue of yeast Mia40. Here, we summarise the recent advances made to our understanding of the role of CHCHD4 and the DRS in physiology and disease, with a specific focus on the emerging importance of CHCHD4 in regulating the cellular response to low oxygen (hypoxia) and metabolism in cancer.
Topics: Animals; Disulfides; Humans; Metabolic Networks and Pathways; Mitochondria; Mitochondrial Precursor Protein Import Complex Proteins; Protein Transport; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 33599699
DOI: 10.1042/BST20190232 -
The Journal of Biological Chemistry Mar 2024The emerging roles of O-GlcNAcylation, a distinctive post-translational modification, are increasingly recognized for their involvement in the intricate processes of... (Review)
Review
The emerging roles of O-GlcNAcylation, a distinctive post-translational modification, are increasingly recognized for their involvement in the intricate processes of protein trafficking and secretion. This modification exerts its influence on both conventional and unconventional secretory pathways. Under healthy and stress conditions, such as during diseases, it orchestrates the transport of proteins within cells, ensuring timely delivery to their intended destinations. O-GlcNAcylation occurs on key factors, like coat protein complexes (COPI and COPII), clathrin, SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors), and GRASP55 (Golgi reassembly stacking protein of 55 kDa) that control vesicle budding and fusion in anterograde and retrograde trafficking and unconventional secretion. The understanding of O-GlcNAcylation offers valuable insights into its critical functions in cellular physiology and the progression of diseases, including neurodegeneration, cancer, and metabolic disorders. In this review, we summarize and discuss the latest findings elucidating the involvement of O-GlcNAc in protein trafficking and its significance in various human disorders.
Topics: Humans; Acetylglucosamine; Clathrin; Protein Processing, Post-Translational; Protein Transport; SNARE Proteins; Animals; Acetylation; Glucose
PubMed: 38272225
DOI: 10.1016/j.jbc.2024.105677 -
Methods in Molecular Biology (Clifton,... 2021The complex enzyme kinetics displayed by drug-metabolizing cytochrome P450 enzymes (CYPs) (see Chapter 9 ) can, in part, be explained by an examination of their...
The complex enzyme kinetics displayed by drug-metabolizing cytochrome P450 enzymes (CYPs) (see Chapter 9 ) can, in part, be explained by an examination of their crystallographic protein structures. Fortunately, despite low sequence similarity between different families of drug-metabolizing CYPs, there exists a high degree of structural homology within the superfamily. This similarity in the protein fold allows for a direct comparison of the structural features of CYPs that contribute toward differences in substrate binding, heterotropic and homotropic cooperativity, and genetic variability in drug metabolism. In this chapter, we first provide an overview of the nomenclature and the role of structural features that are common in all CYPs. We then apply these definitions to understand the different substrate specificities and functions in the CYP3A, CYP2C, and CYP2D families of enzymes.
Topics: Crystallography, X-Ray; Cytochrome P-450 Enzyme System; Genetic Variation; Humans; Inactivation, Metabolic; Kinetics; Models, Molecular; Protein Folding; Protein Structure, Secondary; Substrate Specificity
PubMed: 34272695
DOI: 10.1007/978-1-0716-1554-6_7