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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 -
Molecular Cell Nov 2020Metabolism reprogramming is critical for both cancer progression and effective immune responses in the tumor microenvironment. Amino acid metabolism in different cells... (Review)
Review
Metabolism reprogramming is critical for both cancer progression and effective immune responses in the tumor microenvironment. Amino acid metabolism in different cells and their cross-talk shape tumor immunity and therapy efficacy in patients with cancer. In this review, we focus on multiple amino acids and their transporters, solute carrier (SLC) members. We discuss their involvement in regulation of immune responses in the tumor microenvironment and assess their associations with cancer immunotherapy, chemotherapy, and radiation therapy, and we review their potential as targets for cancer therapy. We stress the necessity to understand individual amino acids and their transporters in different cell subsets, the molecular intersection between amino acid metabolism, and effective T cell immunity and its relevance in cancer therapies.
Topics: Amino Acid Transport Systems; Amino Acids; Animals; Humans; Immunity; Immunotherapy; Membrane Transport Proteins; Neoplasms; Solute Carrier Proteins; T-Lymphocytes; Tumor Microenvironment
PubMed: 32997964
DOI: 10.1016/j.molcel.2020.09.006 -
American Journal of Physiology.... Jul 2022Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily conserved process and aberrant pyruvate metabolism is associated with and contributes to... (Review)
Review
Pyruvate metabolism, a central nexus of carbon homeostasis, is an evolutionarily conserved process and aberrant pyruvate metabolism is associated with and contributes to numerous human metabolic disorders including diabetes, cancer, and heart disease. As a product of glycolysis, pyruvate is primarily generated in the cytosol before being transported into the mitochondrion for further metabolism. Pyruvate entry into the mitochondrial matrix is a critical step for efficient generation of reducing equivalents and ATP and for the biosynthesis of glucose, fatty acids, and amino acids from pyruvate. However, for many years, the identity of the carrier protein(s) that transported pyruvate into the mitochondrial matrix remained a mystery. In 2012, the molecular-genetic identification of the mitochondrial pyruvate carrier (MPC), a heterodimeric complex composed of protein subunits MPC1 and MPC2, enabled studies that shed light on the many metabolic and physiological processes regulated by pyruvate metabolism. A better understanding of the mechanisms regulating pyruvate transport and the processes affected by pyruvate metabolism may enable novel therapeutics to modulate mitochondrial pyruvate flux to treat a variety of disorders. Herein, we review our current knowledge of the MPC, discuss recent advances in the understanding of mitochondrial pyruvate metabolism in various tissue and cell types, and address some of the outstanding questions relevant to this field.
Topics: Anion Transport Proteins; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Monocarboxylic Acid Transporters; Pyruvic Acid
PubMed: 35635330
DOI: 10.1152/ajpendo.00074.2022 -
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 -
Immunity Oct 2022The DNA sensor cyclic GMP-AMP synthase (cGAS) is important for antiviral and anti-tumor immunity. cGAS generates cyclic GMP-AMP (cGAMP), a diffusible cyclic dinucleotide...
The DNA sensor cyclic GMP-AMP synthase (cGAS) is important for antiviral and anti-tumor immunity. cGAS generates cyclic GMP-AMP (cGAMP), a diffusible cyclic dinucleotide that activates the antiviral response through the adaptor protein stimulator of interferon genes (STING). cGAMP cannot passively cross cell membranes, but recent advances have established a role for extracellular cGAMP as an "immunotransmitter" that can be imported into cells. However, the mechanism by which cGAMP exits cells remains unknown. Here, we identifed ABCC1 as a direct, ATP-dependent cGAMP exporter in mouse and human cells. We show that ABCC1 overexpression enhanced cGAMP export and limited STING signaling and that loss of ABCC1 reduced cGAMP export and potentiated STING signaling. We demonstrate that ABCC1 deficiency exacerbated cGAS-dependent autoimmunity in the Trex1 mouse model of Aicardi-Goutières syndrome. Thus, ABCC1-mediated cGAMP export is a key regulatory mechanism that limits cell-intrinsic activation of STING and ameliorates STING-dependent autoimmune disease.
Topics: Adenosine Triphosphate; Animals; DNA; Humans; Interferons; Membrane Transport Proteins; Mice; Multidrug Resistance-Associated Proteins; Nucleotides, Cyclic; Nucleotidyltransferases
PubMed: 36070769
DOI: 10.1016/j.immuni.2022.08.006 -
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 -
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 -
Biochimica Et Biophysica Acta.... Dec 2020
Topics: Amino Acid Transport Systems; Animals; Humans; Lysosomes; Membrane Transport Proteins; Organelles; Secretory Vesicles
PubMed: 32861642
DOI: 10.1016/j.bbamem.2020.183458 -
FEBS Letters Dec 2020Bacterial membrane proteins of the SbmA/BacA family are multi-solute transporters that mediate the uptake of structurally diverse hydrophilic molecules, including...
Bacterial membrane proteins of the SbmA/BacA family are multi-solute transporters that mediate the uptake of structurally diverse hydrophilic molecules, including aminoglycoside antibiotics and antimicrobial peptides. Some family members are full-length ATP-binding cassette (ABC) transporters, whereas other members are truncated homologues that lack the nucleotide-binding domains and thus mediate ATP-independent transport. A recent cryo-EM structure of the ABC transporter Rv1819c from Mycobacterium tuberculosis has shed light on the structural basis for multi-solute transport and has provided insight into the mechanism of transport. Here, we discuss how the protein architecture makes SbmA/BacA family transporters prone to inadvertent import of antibiotics and speculate on the question which physiological processes may benefit from multi-solute transport.
Topics: ATP-Binding Cassette Transporters; Anti-Bacterial Agents; Antigens, Bacterial; Bacterial Proteins; Biological Transport; Escherichia coli Proteins; Membrane Transport Proteins; Mycobacterium tuberculosis; Phosphoric Monoester Hydrolases; Substrate Specificity
PubMed: 32810294
DOI: 10.1002/1873-3468.13912 -
Current Opinion in Chemical Biology Apr 2020Manganese (Mn) plays a complex role in the survival of pathogenic and symbiotic bacteria in eukaryotic hosts and is also important for free-living bacteria to thrive in... (Review)
Review
Manganese (Mn) plays a complex role in the survival of pathogenic and symbiotic bacteria in eukaryotic hosts and is also important for free-living bacteria to thrive in stressful environments. This review summarizes new aspects of regulatory strategies to control intracellular Mn levels and gives an overview of several newly identified families of bacterial Mn transporters. Recent illustrative examples of advances in quantification of intracellular Mn pools and characterization of the effects of Mn perturbations are highlighted. These discoveries help define mechanisms of Mn selectivity and toxicity and could enable new strategies to combat pathogenic bacteria and promote growth of desirable bacteria.
Topics: Amino Acid Sequence; Bacteria; Bacterial Proteins; Cell Membrane Permeability; Gene Expression Regulation, Bacterial; Homeostasis; Manganese; Membrane Transport Proteins; Mutation; Reactive Oxygen Species; Riboswitch; Substrate Specificity; Superoxide Dismutase; Transcription Factors
PubMed: 32086169
DOI: 10.1016/j.cbpa.2020.01.003