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Molecules (Basel, Switzerland) Jan 2023Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier... (Review)
Review
Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It was recognized early on that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical compositions has recently been used as a means to enhance their targeting and absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.
Topics: Membrane Transport Proteins; Biological Transport; Solute Carrier Proteins; Drug Delivery Systems; Prodrugs
PubMed: 36770817
DOI: 10.3390/molecules28031151 -
Trends in Biochemical Sciences Sep 2023Solute carrier (SLCs) transporters mediate the transport of a broad range of solutes across biological membranes. Dysregulation of SLCs has been associated with various... (Review)
Review
Solute carrier (SLCs) transporters mediate the transport of a broad range of solutes across biological membranes. Dysregulation of SLCs has been associated with various pathologies, including metabolic and neurological disorders, as well as cancer and rare diseases. SLCs are therefore emerging as key targets for therapeutic intervention with several recently approved drugs targeting these proteins. Unlocking this large and complex group of proteins is essential to identifying unknown SLC targets and developing next-generation SLC therapeutics. Recent progress in experimental and computational techniques has significantly advanced SLC research, including drug discovery. Here, we review emerging topics in therapeutic discovery of SLCs, focusing on state-of-the-art approaches in structural, chemical, and computational biology, and discuss current challenges in transporter drug discovery.
Topics: Humans; Solute Carrier Proteins; Membrane Transport Proteins; Biological Transport; Drug Discovery; Neoplasms
PubMed: 37355450
DOI: 10.1016/j.tibs.2023.05.011 -
The FEBS Journal May 2021This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily... (Review)
Review
This review aims to serve as an introduction to the solute carrier proteins (SLC) superfamily of transporter proteins and their roles in human cells. The SLC superfamily currently includes 458 transport proteins in 65 families that carry a wide variety of substances across cellular membranes. While members of this superfamily are found throughout cellular organelles, this review focuses on transporters expressed at the plasma membrane. At the cell surface, SLC proteins may be viewed as gatekeepers of the cellular milieu, dynamically responding to different metabolic states. With altered metabolism being one of the hallmarks of cancer, we also briefly review the roles that surface SLC proteins play in the development and progression of cancer through their influence on regulating metabolism and environmental conditions.
Topics: Biological Transport; Cell Membrane; Humans; Membrane Transport Proteins; Neoplasms; Solute Carrier Proteins
PubMed: 32810346
DOI: 10.1111/febs.15531 -
Cell Metabolism Jun 2023Genome-wide association studies (GWASs) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative...
Genome-wide association studies (GWASs) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative genetic analysis that associates serum metabolites to membrane transporters with a coessentiality map of metabolic genes. This analysis revealed a connection between feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) and phosphocholine, a downstream metabolite of choline metabolism. Loss of FLVCR1 in human cells strongly impairs choline metabolism due to the inhibition of choline import. Consistently, CRISPR-based genetic screens identified phospholipid synthesis and salvage machinery as synthetic lethal with FLVCR1 loss. Cells and mice lacking FLVCR1 exhibit structural defects in mitochondria and upregulate integrated stress response (ISR) through heme-regulated inhibitor (HRI) kinase. Finally, Flvcr1 knockout mice are embryonic lethal, which is partially rescued by choline supplementation. Altogether, our findings propose FLVCR1 as a major choline transporter in mammals and provide a platform to discover substrates for unknown metabolite transporters.
Topics: Humans; Animals; Mice; Genome-Wide Association Study; Receptors, Virus; Mutation; Membrane Transport Proteins; Mammals; Choline
PubMed: 37100056
DOI: 10.1016/j.cmet.2023.04.003 -
Nature Aug 2023To replicate inside macrophages and cause tuberculosis, Mycobacterium tuberculosis must scavenge a variety of nutrients from the host. The mammalian cell entry (MCE)...
To replicate inside macrophages and cause tuberculosis, Mycobacterium tuberculosis must scavenge a variety of nutrients from the host. The mammalian cell entry (MCE) proteins are important virulence factors in M. tuberculosis, where they are encoded by large gene clusters and have been implicated in the transport of fatty acids and cholesterol across the impermeable mycobacterial cell envelope. Very little is known about how cargos are transported across this barrier, and it remains unclear how the approximately ten proteins encoded by a mycobacterial mce gene cluster assemble to transport cargo across the cell envelope. Here we report the cryo-electron microscopy (cryo-EM) structure of the endogenous Mce1 lipid-import machine of Mycobacterium smegmatis-a non-pathogenic relative of M. tuberculosis. The structure reveals how the proteins of the Mce1 system assemble to form an elongated ABC transporter complex that is long enough to span the cell envelope. The Mce1 complex is dominated by a curved, needle-like domain that appears to be unrelated to previously described protein structures, and creates a protected hydrophobic pathway for lipid transport across the periplasm. Our structural data revealed the presence of a subunit of the Mce1 complex, which we identified using a combination of cryo-EM and AlphaFold2, and name LucB. Our data lead to a structural model for Mce1-mediated lipid import across the mycobacterial cell envelope.
Topics: Animals; Bacterial Proteins; Cryoelectron Microscopy; Lipids; Membrane Transport Proteins; Mycobacterium tuberculosis; Tuberculosis; Virus Internalization; Virulence Factors; ATP-Binding Cassette Transporters; Periplasm; Protein Domains; Hydrophobic and Hydrophilic Interactions; Multiprotein Complexes
PubMed: 37495693
DOI: 10.1038/s41586-023-06366-0 -
Endocrine Reviews Apr 2020Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion... (Review)
Review
Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease. (Endocrine Reviews 41: 1 - 55, 2020).
Topics: Animals; Biological Transport; Humans; Membrane Transport Proteins; Mental Retardation, X-Linked; Monocarboxylic Acid Transporters; Muscle Hypotonia; Muscular Atrophy; Organic Anion Transporters; Symporters; Thyroid Hormones
PubMed: 31754699
DOI: 10.1210/endrev/bnz008 -
Journal of Experimental Botany Mar 2022Molybdenum (Mo) is an essential element for almost all living organisms. After being taken up into the cells as molybdate, it is incorporated into the molybdenum... (Review)
Review
Molybdenum (Mo) is an essential element for almost all living organisms. After being taken up into the cells as molybdate, it is incorporated into the molybdenum cofactor, which functions as the active site of several molybdenum-requiring enzymes and thus plays crucial roles in multiple biological processes. The uptake and transport of molybdate is mainly mediated by two types of molybdate transporters. The homeostasis of Mo in plant cells is tightly controlled, and such homeostasis likely plays vital roles in plant adaptation to local environments. Recent evidence suggests that Mo is more than an essential element required for plant growth and development; it is also involved in local adaptation to coastal salinity. In this review, we summarize recent research progress on molybdate uptake and transport, molybdenum homeostasis network in plants, and discuss the potential roles of the molybdate transporter in plant adaptation to their local environment.
Topics: Biological Transport; Membrane Transport Proteins; Molybdenum
PubMed: 34864981
DOI: 10.1093/jxb/erab534 -
Scientific Reports Aug 2022Membrane transporters are an important group of proteins in physiology and disease. Their functions make them common drug targets, but their location in the lipid...
Membrane transporters are an important group of proteins in physiology and disease. Their functions make them common drug targets, but their location in the lipid bilayers poses a tremendous challenge to researchers. The current stage of development of structural biology, in addition to new research tools, has largely facilitated the acquisition of knowledge about transporters and mechanisms. This Collection presents recent studies, covering bioenergetics, structure and functional characterization of various transporters, lipids-protein interactions, and novel research tool development.
Topics: ATP-Binding Cassette Transporters; Biological Transport; Cell Membrane; Membrane Transport Proteins; Protein Conformation
PubMed: 35918457
DOI: 10.1038/s41598-022-17524-1 -
Open Biology Jun 2019Cell nutrition, detoxification, signalling, homeostasis and response to drugs, processes related to cell growth, differentiation and survival are all mediated by plasma... (Review)
Review
Cell nutrition, detoxification, signalling, homeostasis and response to drugs, processes related to cell growth, differentiation and survival are all mediated by plasma membrane (PM) proteins called transporters. Despite their distinct fine structures, mechanism of function, energetic requirements, kinetics and substrate specificities, all transporters are characterized by a main hydrophobic body embedded in the PM as a series of tightly packed, often intertwined, α-helices that traverse the lipid bilayer in a zigzag mode, connected with intracellular or extracellular loops and hydrophilic N- and C-termini. Whereas longstanding genetic, biochemical and biophysical evidence suggests that specific transmembrane segments, and also their connecting loops, are responsible for substrate recognition and transport dynamics, emerging evidence also reveals the functional importance of transporter N- and C-termini, in respect to transport catalysis, substrate specificity, subcellular expression, stability and signalling. This review highlights selected prototypic examples of transporters in which their termini play important roles in their functioning.
Topics: Allosteric Site; Animals; Cell Membrane; Humans; Membrane Transport Proteins; Models, Molecular; Protein Domains; Protein Structure, Secondary; Substrate Specificity
PubMed: 31213137
DOI: 10.1098/rsob.190083 -
Current Opinion in Plant Biology Feb 2022The directional transport of the phytohormone auxin is required for proper plant development and tropic growth. Auxin cell-to-cell transport gains directionality through... (Review)
Review
The directional transport of the phytohormone auxin is required for proper plant development and tropic growth. Auxin cell-to-cell transport gains directionality through the polar distribution of 'canonical' long PIN-FORMED (PIN) auxin efflux carriers. In recent years, AGC kinases, MAP kinases, Ca/CALMODULIN-DEPENDENT PROTEIN KINASE-RELATED KINASEs and receptor kinases have been implicated in the control of PIN activity, polarity and trafficking. In this review, we summarize the current knowledge in understanding the posttranslational regulation of PINs by these different protein kinase families. The proposed regulation of PINs by AGC kinases after salt stress and by the stress-activated MAP kinases suggest that abiotic and biotic stress factors may modulate auxin transport and thereby plant growth.
Topics: Arabidopsis; Arabidopsis Proteins; Biological Transport; Indoleacetic Acids; Membrane Transport Proteins; Phosphorylation; Plant Roots; Protein Kinases
PubMed: 34974229
DOI: 10.1016/j.pbi.2021.102146