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Current Opinion in Plant Biology Dec 2018Membrane-embedded transport proteins are fundamental to life; their co-ordinated action controls the movement and distribution of solutes into, around and out of cells... (Review)
Review
Membrane-embedded transport proteins are fundamental to life; their co-ordinated action controls the movement and distribution of solutes into, around and out of cells for signalling, metabolism, nutrition, stress tolerance and development. Here we outline two case studies of transport systems that plants use to tolerate soil elemental toxicity, demonstrating how iterative studies of protein structure and function result in unparalleled insights into transport mechanics. Further, we propose that integrative platforms of biological, biochemical and biophysical tools can provide quantitative data on substrate specificity and transport rates, which are important in understanding transporter evolution and their roles in cell biology and whole plant physiology. Such knowledge equips biotechnologists and breeders with the power to deliver improvements in crop yields in sub-optimal soils.
Topics: Aquaporins; Biological Transport; Boron; Membrane Transport Proteins; Plant Proteins; Plants; Protein Conformation; Salinity; Structural Homology, Protein
PubMed: 30138844
DOI: 10.1016/j.pbi.2018.07.006 -
Trends in Cell Biology Sep 2017The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate... (Review)
Review
The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate cellular chemistry by metabolism. The mammalian MCS comprises the transporters of the 53-member canonical SLC25A family and a lesser number of identified noncanonical transporters. The recent discovery and investigations of the mitochondrial pyruvate carrier (MPC) illustrate the diverse effects a single mitochondrial carrier may exert on cellular function. However, the transport selectivities of many carriers remain unknown, and most have not been functionally investigated in mammalian cells. The mechanisms coordinating their function as a unified system remain undefined. Increased accessibility to molecular genetic and metabolomic technologies now greatly enables investigation of the MCS. Continued investigation of the MCS may reveal how mitochondria encode complex regulatory information within chemical thermodynamic gradients. This understanding may enable precision modulation of cellular chemistry to counteract the dysmetabolism inherent in disease.
Topics: Animals; Biological Transport; Humans; Membrane Transport Proteins; Mitochondria; Mitochondrial Membrane Transport Proteins; Mitochondrial Proteins; Monocarboxylic Acid Transporters
PubMed: 28522206
DOI: 10.1016/j.tcb.2017.04.004 -
Journal of Experimental Botany Sep 2023The ureides allantoin and allantoate serve as nitrogen (N) transport compounds in plants, and more recently, allantoin has been shown to play a role in signaling. In...
The ureides allantoin and allantoate serve as nitrogen (N) transport compounds in plants, and more recently, allantoin has been shown to play a role in signaling. In planta, tissue ureide levels are controlled by the activity of enzymes of the purine degradation pathway and by ureide transporters called ureide permeases (UPS). Little is known about the physiological function of UPS proteins in crop plants, and especially in monocotyledon species. Here, we identified 13 TaUPS genes in the wheat (Triticum aestivum L.) genome. Phylogenetic and genome location analyses revealed a close relationship of wheat UPSs to orthologues in other grasses and a division into TaUPS1, TaUPS2.1, and TaUPS2.2 groups, each consisting of three homeologs, with a total of four tandem duplications. Expression, localization, and biochemical analyses resolved spatio-temporal expression patterns of TaUPS genes, transporter localization at the plasma membrane, and a role for TaUPS2.1 proteins in cellular import of ureides and phloem and seed loading. In addition, positive correlations between TaUPS1 and TaUPS2.1 transcripts and ureide levels were found. Together the data support that TaUPSs function in regulating ureide pools at source and sink, along with source-to-sink transport. Moreover, comparative studies between wheat cultivars grown at low and high N strengthened a role for TaUPS1 and TaUPS2.1 transporters in efficient N use and in controlling primary metabolism. Co-expression, protein-protein interaction, and haplotype analyses further support TaUPS involvement in N partitioning, N use efficiency, and domestication. Overall, this work provides a new understanding on UPS transporters in grasses as well as insights for breeding resilient wheat varieties with improved N use efficiency.
Topics: Allantoin; Membrane Transport Proteins; Triticum; Nitrogen; Phylogeny; Plant Breeding
PubMed: 37478311
DOI: 10.1093/jxb/erad286 -
The Journal of General Physiology Jul 2019The lactose permease (LacY) of is the prototype of the major facilitator superfamily, one of the largest families of membrane transport proteins. Structurally, two... (Review)
Review
The lactose permease (LacY) of is the prototype of the major facilitator superfamily, one of the largest families of membrane transport proteins. Structurally, two pseudo-symmetrical six-helix bundles surround a large internal aqueous cavity. Single binding sites for galactoside and H are positioned at the approximate center of LacY halfway through the membrane at the apex of the internal cavity. These features enable LacY to function by an alternating-access mechanism that can catalyze galactoside/H symport in either direction across the cytoplasmic membrane. The H-binding site is fully protonated under physiological conditions, and subsequent sugar binding causes transition of the ternary complex to an occluded intermediate that can open to either side of the membrane. We review the structural and functional evidence that has provided new insight into the mechanism by which LacY achieves active transport against a concentration gradient.
Topics: Binding Sites; Catabolite Repression; Escherichia coli; Escherichia coli Proteins; Lactose; Monosaccharide Transport Proteins; Protons; Symporters
PubMed: 31147449
DOI: 10.1085/jgp.201912377 -
Trends in Biochemical Sciences Apr 2015The evolutionary relation between sugar and vitamin transporters from the SWEET and Pnu families is unclear. They have similar 3D structures, but differ in the topology... (Review)
Review
The evolutionary relation between sugar and vitamin transporters from the SWEET and Pnu families is unclear. They have similar 3D structures, but differ in the topology of their secondary structure elements, and lack significant sequence similarity. Here we analyze the structures and sequences of different members of the SWEET and Pnu transporter families and propose an evolutionary pathway by which they may have diverged from a common ancestor. A 3D domain swapping event can explain the topological differences between the families, as well as the puzzling observation that a highly conserved and essential sequence motif of the SWEET family (the PQ loop) is absent from the Pnu transporters.
Topics: Bacterial Proteins; Biological Evolution; Biological Transport; Membrane Transport Proteins; Multigene Family; Protein Structure, Secondary
PubMed: 25757400
DOI: 10.1016/j.tibs.2015.02.002 -
Research in Microbiology 2018Transporters of the RND superfamily are well-known as the major drug efflux pumps of Gram-negative bacteria. However, they are widespread in organisms ranging from... (Review)
Review
Transporters of the RND superfamily are well-known as the major drug efflux pumps of Gram-negative bacteria. However, they are widespread in organisms ranging from Archaea to Eukaryotes, and perform diverse functions. This review gives a brief overview of these diverse members of the superfamily with emphasis on their structure and functions.
Topics: Animals; Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Eukaryota; Evolution, Molecular; Humans; Membrane Transport Proteins; Models, Molecular; Multigene Family
PubMed: 29577985
DOI: 10.1016/j.resmic.2018.03.001 -
Current Drug Targets 2020Urea Transporters are a family of membrane channel proteins that facilitate the passive transport of urea across the plasma membrane. UTs are divided into two subgroups,... (Review)
Review
BACKGROUND
Urea Transporters are a family of membrane channel proteins that facilitate the passive transport of urea across the plasma membrane. UTs are divided into two subgroups, UT-A and UT-B. UT-As are primarily located in renal tubule epithelia and UT-Bs are highly expressed in renal descending vasa recta and extrarenal multiple tissues. Various urea transporter knockout mice exhibit low urine concentrating ability, which suggests that UTs are novel diuretic targets. With highthroughput screening of small molecule drug-like compound libraries, various potent UT inhibitors with IC50 at nanomolar level were identified. Furthermore, selective UT inhibitors exhibit diuretic activity without disturbing electrolyte and metabolism balance, which confirms the potential of UTs as diuretic targets and UT inhibitors as novel diuretics that do not cause electrolyte imbalance.
OBJECTIVE
This review article summarizes the identification and validation of urea transporter as a potential diuretic target and the discovery of small molecule UT inhibitors as a novel type of diuretics.
CONCLUSION
UTs are a potential diuretic target. UT inhibitors play significant diuresis and can be developed to diuretics without disturbing electrolyte balance.
Topics: Animals; Cell Line; Diuresis; Diuretics; Humans; Membrane Transport Proteins; Mice; Mice, Knockout; Small Molecule Libraries; Structure-Activity Relationship; Urea; Water-Electrolyte Balance; Urea Transporters
PubMed: 31782365
DOI: 10.2174/1389450120666191129101915 -
Basic & Clinical Pharmacology &... Feb 2024
Topics: Membrane Transport Proteins; Membrane Proteins; Carrier Proteins; Biological Transport
PubMed: 37945540
DOI: 10.1111/bcpt.13960 -
Proceedings of the National Academy of... Oct 2023Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the...
Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the existing layer of PG is remodeled and PG fragments are released. Enterics such as go to great lengths to internalize and reutilize PG fragments. is estimated to break down one-third of its cell wall, yet only loses ~0 to 5% of meso-diaminopimelic acid, a PG-specific amino acid, per generation. Two transporters were identified early on to possibly be the primary permease that facilitates PG fragment recycling, i) AmpG and ii) the Opp ATP binding cassette transporter in conjunction with a PG-specific periplasmic binding protein, MppA. The contribution of each transporter to PG recycling has been debated. Here, we have found that AmpG and MppA/Opp are differentially regulated by carbon source and growth phase. In addition, MppA/Opp is uniquely capable of high-affinity scavenging of muropeptides from growth media, demonstrating that AmpG and MppA/Opp allow for different strategies of recycling PG fragments. Altogether, this work clarifies environmental contexts under which utilizes distinct permeases for PG recycling and explores how scavenging by MppA/Opp could be beneficial in mixed communities.
Topics: Membrane Transport Proteins; Escherichia coli; Peptidoglycan; Bacterial Proteins; Bacteria; Cell Wall
PubMed: 37871219
DOI: 10.1073/pnas.2308940120 -
Clinical Pharmacology and Therapeutics Nov 2018Membrane transporters play diverse roles in the pharmacokinetics and pharmacodynamics of small-molecule drugs. Understanding the mechanisms of drug-transporter... (Review)
Review
Membrane transporters play diverse roles in the pharmacokinetics and pharmacodynamics of small-molecule drugs. Understanding the mechanisms of drug-transporter interactions at the molecular level is, therefore, essential for the design of drugs with optimal therapeutic effects. This white paper examines recent progress, applications, and challenges of molecular modeling of membrane transporters, including modeling techniques that are centered on the structures of transporter ligands, and those focusing on the structures of the transporters. The goals of this article are to illustrate current best practices and future opportunities in using molecular modeling techniques to understand and predict transporter-mediated effects on drug disposition and efficacy.Membrane transporters from the solute carrier (SLC) and ATP-binding cassette (ABC) superfamilies regulate the cellular uptake, efflux, and homeostasis of many essential nutrients and significantly impact the pharmacokinetics of drugs; further, they may provide targets for novel therapeutics as well as facilitate prodrug approaches. Because of their often broad substrate selectivity they are also implicated in many undesirable and sometimes life-threatening drug-drug interactions (DDIs)..
Topics: Animals; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Ligands; Membrane Transport Modulators; Membrane Transport Proteins; Molecular Docking Simulation; Molecular Dynamics Simulation; Pharmaceutical Preparations; Pharmacogenomic Variants; Pharmacokinetics; Phenotype; Protein Conformation; Quantitative Structure-Activity Relationship; Risk Assessment
PubMed: 29981151
DOI: 10.1002/cpt.1174