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Disease Models & Mechanisms Nov 2023By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic... (Review)
Review
By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.
Topics: Humans; Membrane Transport Proteins; Solute Carrier Proteins; Biological Transport; Neoplasms; Cell Physiological Phenomena; Tumor Microenvironment
PubMed: 38037877
DOI: 10.1242/dmm.050404 -
Applied Microbiology and Biotechnology Oct 2023Carboxylic acids containing acidic groups with additional keto/hydroxyl-groups or unsaturated bond have displayed great applicability in the food, agricultural,... (Review)
Review
Carboxylic acids containing acidic groups with additional keto/hydroxyl-groups or unsaturated bond have displayed great applicability in the food, agricultural, cosmetic, textile, and pharmaceutical industries. The traditional approach for carboxylate production through chemical synthesis is based on petroleum derivatives, resulting in concerns for the environmental complication and energy crisis, and increasing attention has been attracted to the eco-friendly and renewable bio-based synthesis for carboxylate production. The efficient and specific export of target carboxylic acids through the microbial membrane is essential for high productivity, yield, and titer of bio-based carboxylates. Therefore, understanding the characteristics, regulations, and efflux mechanisms of carboxylate transporters will efficiently increase industrial biotechnological production of carboxylic acids. Several transporters from fungi have been reported and used for improved synthesis of target products. The transport activity and substrate specificity are two key issues that need further improvement in the application of carboxylate transporters. This review presents developments in the structural and functional diversity of carboxylate transporters, focusing on the modification and regulation of carboxylate transporters to alter the transport activity and substrate specificity, providing new strategy for transporter engineering in constructing microbial cell factory for carboxylate production. KEY POINTS: • Structures of multiple carboxylate transporters have been predicted. • Carboxylate transporters can efficiently improve production. • Modification engineering of carboxylate transporters will be more popular in the future.
Topics: Carboxylic Acids; Membrane Transport Proteins; Biological Transport; Biotechnology; Metabolic Engineering
PubMed: 37561180
DOI: 10.1007/s00253-023-12720-z -
Nature Structural & Molecular Biology Jul 2019Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain... (Review)
Review
Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from extra-neuronal regions and thus maintain neurotransmitter homeostasis. As targets of a wide range of compounds, including antidepressants, substances of abuse and drugs for neuropsychiatric and neurodegenerative disorders, their mechanism of action and their modulation by small molecules have long been of broad interest. Recent advances in the structural characterization of dopamine and serotonin transporters have opened the way for structure-based modeling and simulations, which, together with experimental data, now provide mechanistic understanding of their transport function and interactions. Here we review recent progress in the elucidation of the structural dynamics of MATs and their conformational landscape and transitions, as well as allosteric regulation mechanisms.
Topics: Allosteric Regulation; Animals; Binding Sites; Dopamine Plasma Membrane Transport Proteins; Drug Discovery; Humans; Models, Molecular; Norepinephrine Plasma Membrane Transport Proteins; Protein Conformation; Serotonin Plasma Membrane Transport Proteins
PubMed: 31270469
DOI: 10.1038/s41594-019-0253-7 -
Nature Feb 2024Transporting small molecules across cell membranes is an essential process in cell physiology. Many structurally diverse, secondary active transporters harness... (Review)
Review
Transporting small molecules across cell membranes is an essential process in cell physiology. Many structurally diverse, secondary active transporters harness transmembrane electrochemical gradients of ions to power the uptake or efflux of nutrients, signalling molecules, drugs and other ions across cell membranes. Transporters reside in lipid bilayers on the interface between two aqueous compartments, where they are energized and regulated by symported, antiported and allosteric ions on both sides of the membrane and the membrane bilayer itself. Here we outline the mechanisms by which transporters couple ion and solute fluxes and discuss how structural and mechanistic variations enable them to meet specific physiological needs and adapt to environmental conditions. We then consider how general bilayer properties and specific lipid binding modulate transporter activity. Together, ion gradients and lipid properties ensure the effective transport, regulation and distribution of small molecules across cell membranes.
Topics: Biological Transport, Active; Ion Transport; Ions; Lipid Bilayers; Lipids; Membrane Transport Proteins; Solute Carrier Proteins
PubMed: 38418916
DOI: 10.1038/s41586-024-07062-3 -
Trends in Plant Science Mar 2022Auxin is a key regulator of many developmental processes in land plants and plays a strikingly similar role in the phylogenetically distant brown seaweeds. Emerging... (Review)
Review
Auxin is a key regulator of many developmental processes in land plants and plays a strikingly similar role in the phylogenetically distant brown seaweeds. Emerging evidence shows that the PIN and PIN-like (PILS) auxin transporter families have preceded the evolution of the canonical auxin response pathway. A wide conservation of PILS-mediated auxin transport, together with reports of auxin function in unicellular algae, would suggest that auxin function preceded the advent of multicellularity. We find that PIN and PILS transporters form two eukaryotic subfamilies within a larger bacterial family. We argue that future functional characterisation of algal PIN and PILS transporters can shed light on a common origin of an auxin function followed by independent co-option in a multicellular context.
Topics: Biological Transport; Indoleacetic Acids; Membrane Transport Proteins; Plants
PubMed: 34716098
DOI: 10.1016/j.tplants.2021.09.008 -
Journal of Molecular Biology Aug 2021The synthesis, folding, and function of membrane transport proteins are critical factors for defining cellular physiology. Since the stability of these proteins evolved... (Review)
Review
The synthesis, folding, and function of membrane transport proteins are critical factors for defining cellular physiology. Since the stability of these proteins evolved amidst the lipid bilayer, it is no surprise that we are finding that many of these membrane proteins demonstrate coupling of their structure or activity in some way to the membrane. More and more transporter structures are being determined with some information about the surrounding membrane, and computational modeling is providing further molecular details about these solvation structures. Thus, the field is moving towards identifying which molecular mechanisms - lipid interactions, membrane perturbations, differential solvation, and bulk membrane effects - are involved in linking membrane energetics to transporter stability and function. In this review, we present an overview of these mechanisms and the growing evidence that the lipid bilayer is a major determinant of the fold, form, and function of membrane transport proteins in membranes.
Topics: Cell Membrane; Lipid Bilayers; Membrane Transport Proteins; Models, Molecular; Protein Folding; Structure-Activity Relationship
PubMed: 34139219
DOI: 10.1016/j.jmb.2021.167103 -
Molecular Microbiology Apr 2021Both isomeric forms of alanine play a crucial role in bacterial growth and viability; the L-isomer of this amino acid is one of the building blocks for protein...
Both isomeric forms of alanine play a crucial role in bacterial growth and viability; the L-isomer of this amino acid is one of the building blocks for protein synthesis, and the D-isomer is incorporated into the bacterial cell wall. Despite a long history of genetic manipulation of Bacillus subtilis using auxotrophic markers, the genes involved in alanine metabolism have not been characterized fully. In this work, we genetically characterized the major enzymes involved in B. subtilis alanine biosynthesis and identified an alanine permease, AlaP (YtnA), which we show has a major role in the assimilation of D-alanine from the environment. Our results provide explanations for the puzzling fact that growth of B. subtilis does not result in the significant accumulation of extracellular D-alanine. Interestingly, we find that in B. subtilis, unlike E. coli where multiple enzymes have a biochemical activity that can generate alanine, the primary synthetic enzyme for alanine is encoded by alaT, although a second gene, dat, can support slow growth of an L-alanine auxotroph. However, our results also show that Dat mediates the synthesis of D-alanine and its activity is influenced by the abundance of L-alanine. This work provides valuable insights into alanine metabolism that suggests that the relative abundance of D- and L-alanine might be linked with cytosolic pool of D and L-glutamate, thereby coupling protein and cell envelope synthesis with the metabolic status of the cell. The results also suggest that, although some of the purified enzymes involved in alanine biosynthesis have been shown to catalyze reversible reactions in vitro, most of them function unidirectionally in vivo.
Topics: Alanine; Amino Acid Transport Systems; Bacillus subtilis; Bacterial Proteins; Biosynthetic Pathways; Membrane Transport Proteins; Transaminases
PubMed: 33155333
DOI: 10.1111/mmi.14640 -
World Journal of Microbiology &... Jul 2020The phosphoenolpyruvate-dependent glucose phosphotransferase system (PTS) is the major uptake system responsible for transporting glucose, and is involved in glucose... (Review)
Review
The phosphoenolpyruvate-dependent glucose phosphotransferase system (PTS) is the major uptake system responsible for transporting glucose, and is involved in glucose translocation and phosphorylation in Corynebacterium glutamicum. For the longest time, the PTS was considered as the only uptake system for glucose. However, some PTS-independent glucose uptake systems (non-PTS) were discovered in recent years, such as the coupling system of inositol permeases and glucokinases (IPGS) and the coupling system of β-glucoside-PTS permease and glucokinases (GPGS). The products (e.g. lysine, phenylalanine and leucine) will be increased because of the increasing intracellular level of phosphoenolpyruvate (PEP), while some by-products (e.g. lactic acid, alanine and acetic acid) will be reduced when this system become the main uptake pathway for glucose. In this review, we survey the uptake systems for glucose in C. glutamicum and their composition. Furthermore, we summarize the latest research of the regulatory mechanisms among these glucose uptake systems. Detailed strategies to manipulate glucose uptake system are addressed based on this knowledge.
Topics: Bacterial Proteins; Biological Transport; Carbohydrate Metabolism; Corynebacterium glutamicum; Glucose; Glucosides; Membrane Proteins; Membrane Transport Proteins; Mutagenesis, Site-Directed; Phosphoenolpyruvate Sugar Phosphotransferase System; Protein Kinases
PubMed: 32712859
DOI: 10.1007/s11274-020-02898-z -
Sub-cellular Biochemistry 2022ATP-binding cassette (ABC) transporters are one of the largest families of membrane proteins in prokaryotic organisms. Much is now understood about the structure of...
ATP-binding cassette (ABC) transporters are one of the largest families of membrane proteins in prokaryotic organisms. Much is now understood about the structure of these transporters and many reviews have been written on that subject. In contrast, less has been written on the assembly of ABC transporter complexes and this will be a major focus of this book chapter. The complexes are formed from two cytoplasmic subunits that are highly conserved (in terms of their primary and three-dimensional structures) across the whole family. These ATP-binding subunits give rise to the name of the family. They must assemble with two transmembrane subunits that will typically form the permease component of the transporter. The transmembrane subunits have been found to be surprisingly diverse in structure when the whole family is examined, with seven distinct folds identified so far. Hence nucleotide-binding subunits appear to have been bolted on to a variety of transmembrane platforms during evolution, leading to a greater variety in function. Furthermore, many importers within the family utilise a further external substrate-binding component to trap scarce substrates and deliver them to the correct permease components. In this chapter, we will discuss whether assembly of the various ABC transporter subunits occurs with high fidelity within the crowded cellular environment and whether promiscuity in assembly of transmembrane and cytoplasmic components can occur. We also discuss the new AlphaFold protein structure prediction tool which predicts a new type of transmembrane domain fold within the ABC transporters that is associated with cation exporters of bacteria and plants.
Topics: ATP-Binding Cassette Transporters; Adenosine Triphosphate; Membrane Transport Proteins; Nucleotides; Prokaryotic Cells
PubMed: 36151373
DOI: 10.1007/978-3-031-00793-4_2 -
MBio Feb 2023Flucytosine (5-FC) is an antifungal agent commonly used for treatment of cryptococcosis and several other systemic mycoses. In fungi, cytosine permease and cytosine...
Flucytosine (5-FC) is an antifungal agent commonly used for treatment of cryptococcosis and several other systemic mycoses. In fungi, cytosine permease and cytosine deaminase are known major players in flucytosine resistance by regulating uptake and deamination of 5-FC, respectively. Cryptococcus species have three paralogs each of cytosine permease ( and ) and cytosine deaminase ( and ). As in other fungi, we found and to be the primary cytosine deaminase and permease gene, respectively, in C. neoformans H99 (VNI), C. gattii R265 (VGIIa) and WM276 (VGI). However, when various amino acids were used as the sole nitrogen source, C. neoformans and C. gattii diverged in the function of and Though there was some lineage-dependent variability, the two genes functioned as the secondary permease and deaminase, respectively, only in C. gattii when the nitrogen source was arginine, asparagine, or proline. Additionally, the expression of genes, excluding , was under nitrogen catabolic repression in the presence of NH. Functional analysis of and gene deletion constructs demonstrated that these two genes regulate the expression of each permease and deaminase genes individually. Furthermore, the expression levels of and under different amino acids corroborated the 5-FC susceptibility in or background. Thus, the mechanism of 5-FC resistance in C. gattii under diverse nitrogen conditions is orchestrated by two transcription factors of GATA family, cytosine permease and deaminase genes. 5-FC is a commonly used antifungal drug for treatment of cryptococcosis caused by Cryptococcus neoformans and C. gattii species complexes. When various amino acids were used as the sole nitrogen source for growth, we found lineage dependent differences in 5-FC susceptibility. Deletion of the classical cytosine permease () and deaminase () genes caused increased 5-FC resistance in all tested nitrogen sources in C. neoformans but not in C. gattii. Furthermore, we demonstrate that the two GATA family transcription factor genes and are involved in the nitrogen-source dependent 5-FC resistance by regulating the expression of the paralogs of cytosine permease and deaminase genes. Our study not only identifies the new function of paralogs of the cytosine permease and deaminase and the role of their regulatory transcription factors but also denotes the differences in the mechanism of 5-FC resistance among the two etiologic agents of cryptococcosis under different nitrogen sources.
Topics: Flucytosine; Nitrogen; Cytosine Deaminase; Antifungal Agents; Cryptococcus neoformans; Cryptococcus gattii; Cryptococcosis; Amino Acids; Membrane Transport Proteins; Transcription Factors; Microbial Sensitivity Tests
PubMed: 36656038
DOI: 10.1128/mbio.03451-22