-
Nature Metabolism May 2021Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show...
Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS-STING-TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.
Topics: Animals; Cytosol; DNA, Mitochondrial; Immunity, Innate; Membrane Proteins; Metalloendopeptidases; Mice; Mitochondria; Models, Biological; Nucleotidyltransferases; Protein Serine-Threonine Kinases; Pyrimidine Nucleotides; Signal Transduction
PubMed: 33903774
DOI: 10.1038/s42255-021-00385-9 -
Molecules (Basel, Switzerland) Aug 2022Rhamnose-associated molecules are attracting attention because they are present in bacteria but not mammals, making them potentially useful as antibacterial agents.... (Review)
Review
Rhamnose-associated molecules are attracting attention because they are present in bacteria but not mammals, making them potentially useful as antibacterial agents. Additionally, they are also valuable for tumor immunotherapy. Thus, studies on the functions and biosynthetic pathways of rhamnose-containing compounds are in progress. In this paper, studies on the biosynthetic pathways of three rhamnose donors, i.e., deoxythymidinediphosphate-L-rhamnose (dTDP-Rha), uridine diphosphate-rhamnose (UDP-Rha), and guanosine diphosphate rhamnose (GDP-Rha), are firstly reviewed, together with the functions and crystal structures of those associated enzymes. Among them, dTDP-Rha is the most common rhamnose donor, and four enzymes, including glucose-1-phosphate thymidylyltransferase RmlA, dTDP-Glc-4,6-dehydratase RmlB, dTDP-4-keto-6-deoxy-Glc-3,5-epimerase RmlC, and dTDP-4-keto-Rha reductase RmlD, are involved in its biosynthesis. Secondly, several known rhamnosyltransferases from , , , , and are discussed. In these studies, however, the functions of rhamnosyltransferases were verified by employing gene knockout and radiolabeled substrates, which were almost impossible to obtain and characterize the products of enzymatic reactions. Finally, the application of rhamnose-containing compounds in disease treatments is briefly described.
Topics: Biosynthetic Pathways; Racemases and Epimerases; Rhamnose; Thymine Nucleotides; Uridine Diphosphate
PubMed: 36014553
DOI: 10.3390/molecules27165315 -
Photochemistry and Photobiology Mar 2023Light is one way to excite an electron in biology. Another is chemiexcitation, birthing a reaction product in an electronically excited state rather than exciting from... (Review)
Review
Light is one way to excite an electron in biology. Another is chemiexcitation, birthing a reaction product in an electronically excited state rather than exciting from the ground state. Chemiexcited molecules, as in bioluminescence, can release more energy than ATP. Excited states also allow bond rearrangements forbidden in ground states. Molecules with low-lying unoccupied orbitals, abundant in biology, are particularly susceptible. In mammals, chemiexcitation was discovered to transfer energy from excited melanin, neurotransmitters, or hormones to DNA, creating the lethal and carcinogenic cyclobutane pyrimidine dimer. That process was initiated by nitric oxide and superoxide, radicals triggered by ultraviolet light or inflammation. Several poorly understood chronic diseases share two properties: inflammation generates those radicals across the tissue, and cells that die are those containing melanin or neuromelanin. Chemiexcitation may therefore be a pathogenic event in noise- and drug-induced deafness, Parkinson's disease, and Alzheimer's; it may prevent macular degeneration early in life but turn pathogenic later. Beneficial evolutionary selection for excitable biomolecules may thus have conferred an Achilles heel. This review of recent findings on chemiexcitation in mammalian cells also describes the underlying physics, biochemistry, and potential pathogenesis, with the goal of making this interdisciplinary phenomenon accessible to researchers within each field.
Topics: Animals; Melanins; Photochemistry; Pyrimidine Dimers; Ultraviolet Rays; Mammals
PubMed: 36681894
DOI: 10.1111/php.13781 -
Scientific Reports Aug 2022Insulin secretion is regulated in multiple steps, and one of the main steps is in the endoplasmic reticulum (ER). Here, we show that UDP-glucose induces proinsulin...
Insulin secretion is regulated in multiple steps, and one of the main steps is in the endoplasmic reticulum (ER). Here, we show that UDP-glucose induces proinsulin ubiquitination by cereblon, and uridine binds and competes for proinsulin degradation and behaves as sustainable insulin secretagogue. Using insulin mutagenesis of neonatal diabetes variant-C43G and maturity-onset diabetes of the young 10 (MODY10) variant-R46Q, UDP-glucose:glycoprotein glucosyltransferase 1 (UGGT1) protects cereblon-dependent proinsulin ubiquitination in the ER. Cereblon is a ligand-inducible E3 ubiquitin ligase, and we found that UDP-glucose is the first identified endogenous proinsulin protein degrader. Uridine-containing compounds, such as uridine, UMP, UTP, and UDP-galactose, inhibit cereblon-dependent proinsulin degradation and stimulate insulin secretion from 3 to 24 h after administration in β-cell lines as well as mice. This late and long-term insulin secretion stimulation is designated a day sustainable insulin secretion stimulation. Uridine-containing compounds are designated as proinsulin degradation regulators.
Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Insulin; Insulin-Secreting Cells; Mice; Proinsulin; Uridine; Uridine Diphosphate Glucose
PubMed: 36028536
DOI: 10.1038/s41598-022-18902-5 -
The Journal of Histochemistry and... Jan 2021Hyaluronan (HA) is a linear glycosaminoglycan (GAG) of extracellular matrix (ECM) synthesized by three hyaluronan synthases (HASes) at the plasma membrane using uridine... (Review)
Review
Hyaluronan (HA) is a linear glycosaminoglycan (GAG) of extracellular matrix (ECM) synthesized by three hyaluronan synthases (HASes) at the plasma membrane using uridine diphosphate (UDP)-glucuronic acid (UDP-GlcUA) and UDP-acetylglucosamine (UDP-GlcNAc) as substrates. The production of HA is mainly regulated by hyaluronan synthase 2 (HAS2), that can be controlled at different levels, from epigenetics to transcriptional and post-translational modifications. HA biosynthesis is an energy-consuming process and, along with HA catabolism, is strongly connected to the maintenance of metabolic homeostasis. The cytoplasmic pool of UDP-sugars is critical for HA synthesis. UDP-GlcNAc is an important nutrient sensor and serves as donor substrate for the -GlcNAcylation of many cytosolic proteins, including HAS2. This post-translational modification stabilizes HAS2 in the membrane and increases HA production. Conversely, HAS2 can be phosphorylated by AMP activated protein kinase (AMPK), a master metabolic regulator activated by low ATP/AMP ratios, which inhibits HA secretion. Similarly, HAS2 expression and the deposition of HA within the pericellular coat are inhibited by sirtuin 1 (SIRT1), another important energetic sensor, confirming the tight connection between nutrients availability and HA metabolism.
Topics: Animals; Biosynthetic Pathways; Energy Metabolism; Humans; Hyaluronan Synthases; Hyaluronic Acid; Uridine Diphosphate Glucuronic Acid; Uridine Diphosphate N-Acetylglucosamine
PubMed: 32623953
DOI: 10.1369/0022155420929772 -
Naunyn-Schmiedeberg's Archives of... Dec 2022Coronavirus disease 2019 (COVID-19) is a current pandemic disease caused by a novel severe acute respiratory syndrome coronavirus virus respiratory type 2 (SARS-CoV-2).... (Review)
Review
Coronavirus disease 2019 (COVID-19) is a current pandemic disease caused by a novel severe acute respiratory syndrome coronavirus virus respiratory type 2 (SARS-CoV-2). SARS-CoV-2 infection is linked with various neurological manifestations due to cytokine-induced disruption of the blood brain barrier (BBB), neuroinflammation, and peripheral neuronal injury, or due to direct SARS-CoV-2 neurotropism. Of note, many repurposed agents were included in different therapeutic protocols in the management of COVID-19. These agents did not produce an effective therapeutic eradication of SARS-CoV-2, and continuing searching for novel anti-SARS-CoV-2 agents is a type of challenge nowadays. Therefore, this study aimed to review the potential anti-inflammatory and antioxidant effects of citicoline in the management of COVID-19.
Topics: Humans; SARS-CoV-2; Cytidine Diphosphate Choline; Pandemics; Blood-Brain Barrier; COVID-19 Drug Treatment
PubMed: 36063198
DOI: 10.1007/s00210-022-02284-6 -
Molecules (Basel, Switzerland) Nov 2019Dinucleoside 5',5'-polyphosphates (DNPs) are endogenous substances that play important intra- and extracellular roles in various biological processes, such as cell... (Review)
Review
Dinucleoside 5',5'-polyphosphates (DNPs) are endogenous substances that play important intra- and extracellular roles in various biological processes, such as cell proliferation, regulation of enzymes, neurotransmission, platelet disaggregation and modulation of vascular tone. Various methodologies have been developed over the past fifty years to access these compounds, involving enzymatic processes or chemical procedures based either on P(III) or P(V) chemistry. Both solution-phase and solid-support strategies have been developed and are reported here. Recently, green chemistry approaches have emerged, offering attracting alternatives. This review outlines the main synthetic pathways for the preparation of dinucleoside 5',5'-polyphosphates, focusing on pharmacologically relevant compounds, and highlighting recent advances.
Topics: Deoxycytosine Nucleotides; Dinucleoside Phosphates; Dry Eye Syndromes; Green Chemistry Technology; Humans; Ophthalmic Solutions; Phosphorylation; Polyphosphates; Purinergic P2Y Receptor Agonists; Receptors, Purinergic; Uracil Nucleotides; Uridine
PubMed: 31783537
DOI: 10.3390/molecules24234334 -
Frontiers in Endocrinology 2022Purinergic receptors are ubiquitously expressed throughout the body and they participate in the autocrine and paracrine regulation of cell function during normal... (Review)
Review
Purinergic receptors are ubiquitously expressed throughout the body and they participate in the autocrine and paracrine regulation of cell function during normal physiological and pathophysiological conditions. Extracellular nucleotides activate several types of plasma membrane purinergic receptors that form three distinct families: P1 receptors are activated by adenosine, P2X receptors are activated by ATP, and P2Y receptors are activated by nucleotides including ATP, ADP, UTP, UDP, and UDP-glucose. These specific pharmacological fingerprints and the distinct intracellular signaling pathways they trigger govern a large variety of cellular responses in an organ-specific manner. As such, purinergic signaling regulates several physiological cell functions, including cell proliferation, differentiation and death, smooth muscle contraction, vasodilatation, and transepithelial transport of water, solute, and protons, as well as pathological pathways such as inflammation. While purinergic signaling was first discovered more than 90 years ago, we are just starting to understand how deleterious signals mediated through purinergic receptors may be involved in male infertility. A large fraction of male infertility remains unexplained illustrating our poor understanding of male reproductive health. Purinergic signaling plays a variety of physiological and pathophysiological roles in the male reproductive system, but our knowledge in this context remains limited. This review focuses on the distribution of purinergic receptors in the testis, epididymis, and vas deferens, and their role in the establishment and maintenance of male fertility.
Topics: Humans; Male; Testis; Infertility, Male; Nucleotides; Adenosine Triphosphate; Uridine Diphosphate
PubMed: 36419764
DOI: 10.3389/fendo.2022.1049511 -
Glycobiology Nov 2019l-arabinofuranose is a ubiquitous component of the cell wall and various natural products in plants, where it is synthesized from cytosolic UDP-arabinopyranose... (Review)
Review
l-arabinofuranose is a ubiquitous component of the cell wall and various natural products in plants, where it is synthesized from cytosolic UDP-arabinopyranose (UDP-Arap). The biosynthetic machinery long remained enigmatic in terms of responsible enzymes and subcellular localization. With the discovery of UDP-Arap mutase in plant cytosol, the demonstration of its role in cell-wall arabinose incorporation and the identification of UDP-arabinofuranose transporters in the Golgi membrane, it is clear that the cytosolic UDP-Arap mutases are the key enzymes converting UDP-Arap to UDP-arabinofuranose for cell wall and natural product biosynthesis. This has recently been confirmed by several genotype/phenotype studies. In contrast to the solid evidence pertaining to UDP-Arap mutase function in vivo, the molecular features, including enzymatic mechanism and oligomeric state, remain unknown. However, these enzymes belong to the small family of proteins originally identified as reversibly glycosylated polypeptides (RGPs), which has been studied for >20 years. Here, we review the UDP-Arap mutase and RGP literature together, to summarize and systemize reported molecular characteristics and relations to other proteins.
Topics: Biological Products; Cell Wall; Intramolecular Transferases; Oryza; Uridine Diphosphate Sugars
PubMed: 31679023
DOI: 10.1093/glycob/cwz067 -
Cell Communication and Signaling : CCS May 2023Ferroptosis is an iron-dependent regulated cell death that suppresses tumor growth. It is activated by extensive peroxidation of membrane phospholipids caused by... (Review)
Review
Ferroptosis is an iron-dependent regulated cell death that suppresses tumor growth. It is activated by extensive peroxidation of membrane phospholipids caused by oxidative stress. GPX4, an antioxidant enzyme, reduces these peroxidized membrane phospholipids thereby inhibiting ferroptosis. This enzyme has two distinct subcellular localization; the cytosol and mitochondria. Dihydroorotate dehydrogenase (DHODH) complements mitochondrial GPX4 in reducing peroxidized membrane phospholipids. It is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis. Its role in ferroptosis inhibition suggests that DHODH inhibitors could have two complementary mechanisms of action against tumors; inhibiting de novo pyrimidine nucleotide biosynthesis and enhancing ferroptosis. However, the link between mitochondrial function and ferroptosis, and the involvement of DHODH in the ETC suggests that its role in ferroptosis could be modulated by the Warburg effect. Therefore, we reviewed relevant literature to get an insight into the possible effect of this metabolic reprogramming on the role of DHODH in ferroptosis. Furthermore, an emerging link between DHODH and cellular GSH pool has also been highlighted. These insights could contribute to the rational design of ferroptosis-based anticancer drugs. Video Abstract.
Topics: Dihydroorotate Dehydrogenase; Oxidoreductases Acting on CH-CH Group Donors; Ferroptosis; Phospholipids; Pyrimidine Nucleotides
PubMed: 37147673
DOI: 10.1186/s12964-022-01025-9