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International Journal of Molecular... Aug 2022The proper regulation of nucleotide pools is essential for all types of cellular functions and depends on de novo nucleotide biosynthesis, salvage, and degradation... (Review)
Review
The proper regulation of nucleotide pools is essential for all types of cellular functions and depends on de novo nucleotide biosynthesis, salvage, and degradation pathways. Despite the apparent essentiality of these processes, a significant number of rare diseases associated with mutations in genes encoding various enzymes of these pathways have been already identified, and others are likely yet to come. However, knowledge on genetic alterations impacting on nucleoside and nucleobase transporters is still limited. At this moment three gene-encoding nucleoside and nucleobase transporter proteins have been reported to be mutated in humans, , , and , impacting on the expression and function of ENT1, ENT3, and CNT1, respectively. ENT1 alterations determine Augustine-null blood type and cause ectopic calcification during aging. ENT3 deficiency translates into various clinical manifestations and syndromes, altogether listed in the OMIM catalog as histiocytosis-lymphoadenopathy plus syndrome (OMIM#602782). CNT1 deficiency causes uridine-cytidineuria (URCTU) (OMIM#618477), a unique type of pyrimidineuria with an as yet not well-known clinical impact. Increasing knowledge on the physiological, molecular and structural features of these transporter proteins is helping us to better understand the biological basis behind the biochemical and clinical manifestations caused by these deficiencies. Moreover, they also support the view that some metabolic compensation might occur in these disturbances, because they do not seem to significantly impact nucleotide homeostasis, but rather other biological events associated with particular subtypes of transporter proteins.
Topics: Blood Group Antigens; Humans; Membrane Transport Proteins; Nucleoside Transport Proteins; Nucleosides; Nucleotides
PubMed: 35955904
DOI: 10.3390/ijms23158770 -
Molecular Microbiology Apr 2023The pentavalent organoarsenical arsinothricin (AST) is a natural product synthesized by the rhizosphere bacterium Burkholderia gladioli GSRB05. AST is a broad-spectrum...
The pentavalent organoarsenical arsinothricin (AST) is a natural product synthesized by the rhizosphere bacterium Burkholderia gladioli GSRB05. AST is a broad-spectrum antibiotic effective against human pathogens such as carbapenem-resistant Enterobacter cloacae. It is a non-proteogenic amino acid and glutamate mimetic that inhibits bacterial glutamine synthetase. The AST biosynthetic pathway is composed of a three-gene cluster, arsQML. ArsL catalyzes synthesis of reduced trivalent hydroxyarsinothricin (R-AST-OH), which is methylated by ArsM to the reduced trivalent form of AST (R-AST). In the culture medium of B. gladioli, both trivalent species appear as the corresponding pentavalent arsenicals, likely due to oxidation in air. ArsQ is an efflux permease that is proposed to transport AST or related species out of the cells, but the chemical nature of the actual transport substrate is unclear. In this study, B. gladioli arsQ was expressed in Escherichia coli and shown to confer resistance to AST and its derivatives. Cells of E. coli accumulate R-AST, and exponentially growing cells expressing arsQ take up less R-AST. The cells exhibit little transport of their pentavalent forms. Transport was independent of cellular energy and appears to be equilibrative. A homology model of ArsQ suggests that Ser320 is in the substrate binding site. A S320A mutant exhibits reduced R-AST-OH transport, suggesting that it plays a role in ArsQ function. The ArsQ permease is proposed to be an energy-independent uniporter responsible for downhill transport of the trivalent form of AST out of cells, which is oxidized extracellularly to the active form of the antibiotic.
Topics: Humans; Membrane Transport Proteins; Anti-Bacterial Agents; Escherichia coli; Arsenicals; Escherichia coli Proteins; Symporters; Biological Transport, Active
PubMed: 36785875
DOI: 10.1111/mmi.15045 -
The Journal of General Physiology Mar 2019A special issue of celebrates the 2018 Symposium of the Society of General Physiologists, where diversity and world-class science went hand in hand.
A special issue of celebrates the 2018 Symposium of the Society of General Physiologists, where diversity and world-class science went hand in hand.
Topics: Animals; Cell Membrane; Congresses as Topic; Humans; Membrane Transport Proteins; Research Personnel
PubMed: 30796094
DOI: 10.1085/jgp.201912340 -
Trends in Biochemical Sciences Mar 2020Membrane transporters are key gatekeeper proteins at cellular membranes that closely control the traffic of materials. Their function relies on structural rearrangements... (Review)
Review
Membrane transporters are key gatekeeper proteins at cellular membranes that closely control the traffic of materials. Their function relies on structural rearrangements of varying degrees that facilitate substrate translocation across the membrane. Characterizing these functionally important molecular events at a microscopic level is key to our understanding of membrane transport, yet challenging to achieve experimentally. Recent advances in simulation technology and computing power have rendered molecular dynamics (MD) simulation a powerful biophysical tool to investigate a wide range of dynamical events spanning multiple spatial and temporal scales. Here, we review recent studies of diverse membrane transporters using computational methods, with an emphasis on highlighting the technical challenges, key lessons learned, and new opportunities to illuminate transporter structure and function.
Topics: Biological Transport; Cryoelectron Microscopy; Crystallography, X-Ray; Membrane Transport Proteins; Molecular Dynamics Simulation; Protein Conformation
PubMed: 31813734
DOI: 10.1016/j.tibs.2019.09.001 -
International Journal of Molecular... May 2020Ammonium transporter (AMT)-mediated acquisition of ammonium nitrogen from soils is essential for the nitrogen demand of plants, especially for those plants growing in... (Review)
Review
Ammonium transporter (AMT)-mediated acquisition of ammonium nitrogen from soils is essential for the nitrogen demand of plants, especially for those plants growing in flooded or acidic soils where ammonium is dominant. Recent advances show that AMTs additionally participate in many other physiological processes such as transporting ammonium from symbiotic fungi to plants, transporting ammonium from roots to shoots, transferring ammonium in leaves and reproductive organs, or facilitating resistance to plant diseases via ammonium transport. Besides being a transporter, several AMTs are required for the root development upon ammonium exposure. To avoid the adverse effects of inadequate or excessive intake of ammonium nitrogen on plant growth and development, activities of AMTs are fine-tuned not only at the transcriptional level by the participation of at least four transcription factors, but also at protein level by phosphorylation, pH, endocytosis, and heterotrimerization. Despite these progresses, it is worth noting that stronger growth inhibition, not facilitation, unfortunately occurs when AMT overexpression lines are exposed to optimal or slightly excessive ammonium. This implies that a long road remains towards overcoming potential limiting factors and achieving AMT-facilitated yield increase to accomplish the goal of persistent yield increase under the present high nitrogen input mode in agriculture.
Topics: Ammonium Compounds; Arabidopsis; Cation Transport Proteins; Gene Expression Regulation, Plant; Ion Transport; Membrane Transport Proteins; Plant Leaves; Plant Physiological Phenomena; Plant Roots; Plants
PubMed: 32443561
DOI: 10.3390/ijms21103557 -
Protein Science : a Publication of the... Nov 2015It is widely accepted that the increased use of antibiotics has resulted in bacteria with developed resistance to such treatments. These organisms are capable of forming... (Review)
Review
It is widely accepted that the increased use of antibiotics has resulted in bacteria with developed resistance to such treatments. These organisms are capable of forming multi-protein structures that bridge both the inner and outer membrane to expel diverse toxic compounds directly from the cell. Proteins of the resistance nodulation cell division (RND) superfamily typically assemble as tripartite efflux pumps, composed of an inner membrane transporter, a periplasmic membrane fusion protein, and an outer membrane factor channel protein. These machines are the most powerful antimicrobial efflux machinery available to bacteria. In Escherichia coli, the CusCFBA complex is the only known RND transporter with a specificity for heavy metals, detoxifying both Cu(+) and Ag(+) ions. In this review, we discuss the known structural information for the CusCFBA proteins, with an emphasis on their assembly, interaction, and the relationship between structure and function.
Topics: Drug Resistance, Multiple, Bacterial; Escherichia coli; Escherichia coli Proteins; Membrane Transport Proteins; Metals, Heavy; Models, Molecular
PubMed: 26258953
DOI: 10.1002/pro.2764 -
Cells Apr 2022Sugars are the major source of energy in living organisms and play important roles in osmotic regulation, cell signaling and energy storage. SWEETs (Sugars Will... (Review)
Review
Sugars are the major source of energy in living organisms and play important roles in osmotic regulation, cell signaling and energy storage. SWEETs (Sugars Will Eventually be Exported Transporters) are the most recent family of sugar transporters that function as uniporters, facilitating the diffusion of sugar molecules across cell membranes. In plants, SWEETs play roles in multiple physiological processes including phloem loading, senescence, pollen nutrition, grain filling, nectar secretion, abiotic (drought, heat, cold, and salinity) and biotic stress regulation. In this review, we summarized the role of SWEET transporters in plant development and abiotic stress. The gene expression dynamics of various SWEET transporters under various abiotic stresses in different plant species are also discussed. Finally, we discuss the utilization of genome editing tools (TALENs and CRISPR/Cas9) to engineer SWEET genes that can facilitate trait improvement. Overall, recent advancements on SWEETs are highlighted, which could be used for crop trait improvement and abiotic stress tolerance.
Topics: Gene Expression Regulation, Plant; Membrane Transport Proteins; Plant Development; Plant Proteins; Plants; Stress, Physiological; Sugars
PubMed: 35455982
DOI: 10.3390/cells11081303 -
Cells Sep 2022Peptide transporter 2 (PepT2) in mammals plays essential roles in the reabsorption and conservation of peptide-bound amino acids in the kidney and in maintaining... (Review)
Review
Peptide transporter 2 (PepT2) in mammals plays essential roles in the reabsorption and conservation of peptide-bound amino acids in the kidney and in maintaining neuropeptide homeostasis in the brain. It is also of significant medical and pharmacological significance in the absorption and disposing of peptide-like drugs, including angiotensin-converting enzyme inhibitors, β-lactam antibiotics and antiviral prodrugs. Understanding the structure, function and regulation of PepT2 is of emerging interest in nutrition, medical and pharmacological research. In this review, we provide a comprehensive overview of the structure, substrate preferences and localization of PepT2 in mammals. As PepT2 is expressed in various organs, its function in the liver, kidney, brain, heart, lung and mammary gland has also been addressed. Finally, the regulatory factors that affect the expression and function of PepT2, such as transcriptional activation and posttranslational modification, are also discussed.
Topics: Amino Acids; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Bacterial Agents; Antiviral Agents; Biology; Mammals; Membrane Transport Proteins; Peptides; Prodrugs; Symporters; beta-Lactams
PubMed: 36139448
DOI: 10.3390/cells11182874 -
Current Opinion in Structural Biology Aug 2017The POT family of membrane transporters use the inwardly directed proton electrochemical gradient to drive the uptake of essential nutrients into the cell. Originally... (Review)
Review
The POT family of membrane transporters use the inwardly directed proton electrochemical gradient to drive the uptake of essential nutrients into the cell. Originally discovered in bacteria, members of the family have been found in all kingdoms of life except the archaea. A remarkable feature of the family is their diverse substrate promiscuity. Whereas in mammals and bacteria they are predominantly di- and tri-peptide transporters, in plants the family has diverged to recognize nitrate, plant defence compounds and hormones. This promiscuity has led to the development of peptide-based pro-drugs that use PepT1 and PepT2, the mammalian homologues, to improve oral drug delivery. Recent crystal structures from bacterial and plant members of the family have revealed conserved features of the ligand-binding site and provided insights into post-translational regulation. Here I review the current understanding of transport, ligand promiscuity and regulation within the POT family.
Topics: Animals; Disulfides; Humans; Membrane Transport Proteins; Peptides; Protein Transport; Protons
PubMed: 27865112
DOI: 10.1016/j.sbi.2016.10.018 -
Comprehensive Physiology Mar 2018Mammalian members of the proton-coupled oligopeptide transporter family are integral membrane proteins that mediate the cellular uptake of di/tripeptides and... (Review)
Review
Mammalian members of the proton-coupled oligopeptide transporter family are integral membrane proteins that mediate the cellular uptake of di/tripeptides and peptide-like drugs and couple substrate translocation to the movement of H , with the transmembrane electrochemical proton gradient providing the driving force. Peptide transporters are responsible for the (re)absorption of dietary and/or bacterial di- and tripeptides in the intestine and kidney and maintaining homeostasis of neuropeptides in the brain. These proteins additionally contribute to absorption of a number of pharmacologically important compounds. In this overview article, we have provided updated information on the structure, function, expression, localization, and activities of PepT1 (SLC15A1), PepT2 (SLC15A2), PhT1 (SLC15A4), and PhT2 (SLC15A3). Peptide transporters, in particular, PepT1 are discussed as drug-delivery systems in addition to their implications in health and disease. Particular emphasis has been placed on the involvement of PepT1 in the physiopathology of the gastrointestinal tract, specifically, its role in inflammatory bowel diseases. © 2018 American Physiological Society. Compr Physiol 8:731-760, 2018.
Topics: Amino Acid Sequence; Animals; Biological Transport; Humans; Inflammatory Bowel Diseases; Membrane Transport Proteins; Peptide Transporter 1; Sequence Alignment; Symporters
PubMed: 29687900
DOI: 10.1002/cphy.c170032