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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 -
Current Topics in Membranes 2019
Topics: Genome, Human; Humans; Ion Transport; Membrane Transport Proteins
PubMed: 31196612
DOI: 10.1016/S1063-5823(19)30024-9 -
Sub-cellular Biochemistry 2019Transport of solutes across biological membranes is essential for cellular life. This process is mediated by membrane transport proteins which move nutrients, waste... (Review)
Review
Transport of solutes across biological membranes is essential for cellular life. This process is mediated by membrane transport proteins which move nutrients, waste products, certain drugs and ions into and out of cells. Secondary active transporters couple the transport of substrates against their concentration gradients with the transport of other solutes down their concentration gradients. The alternating access model of membrane transporters and the coupling mechanism of secondary active transporters are introduced in this book chapter. Structural studies have identified typical protein folds for transporters that we exemplify by the major facilitator superfamily (MFS) and LeuT folds. Finally, substrate binding and substrate translocation of the transporters LacY of the MFS and AdiC of the amino acid-polyamine-organocation (APC) superfamily are described.
Topics: Amino Acid Transport Systems; Biological Transport; Membrane Transport Proteins
PubMed: 31214990
DOI: 10.1007/978-3-030-18768-2_9 -
FEMS Microbiology Letters Jun 2018The most simple membrane protein insertion catalyst known so far is the universal YidC/Oxa/Alb insertase that is composed of a single multi-spanning protein present in... (Review)
Review
The most simple membrane protein insertion catalyst known so far is the universal YidC/Oxa/Alb insertase that is composed of a single multi-spanning protein present in archaea, bacteria and in eukaryotic organelles. In bacteria, YidC is known to integrate small membrane proteins on its own and more complex proteins in conjunction with the SecYEG translocase. In mitochondria, the YidC homologue Oxa is responsible for the insertion of all membrane proteins synthesized in the matrix since no Sec homologues are present in the mitochondrial inner membrane. This is tantamount to the observation that YidC is able to operate also independently of SecYEG in bacteria. Reconstituted into liposomes, YidC rapidly and efficiently binds to substrate proteins and leads to their integration into the bilayer. Additionally, single molecule force spectroscopy experiments show that YidC binds to unfolded membrane proteins and promotes their folding into the membrane bilayer. To achieve membrane insertion and the correct folding, the periplasmic regions of the substrate have to cross the membrane with the help of YidC by a mechanism that is presently explored.
Topics: Cell Membrane; Escherichia coli Proteins; Membrane Transport Proteins; Protein Folding; Protein Transport
PubMed: 29800285
DOI: 10.1093/femsle/fny106 -
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 -
Biological & Pharmaceutical Bulletin 2018
Topics: Amino Acid Transport Systems; Animals; Carrier Proteins; GABA Plasma Membrane Transport Proteins; Humans; Membrane Transport Proteins
PubMed: 30270316
DOI: 10.1248/bpb.b18-ctf4110 -
Advances in Protein Chemistry and... 2021PTR2/POT/NPF are a family of primarily proton coupled transporters that belong to the major facilitator super family and are found across most kingdoms of life. They are... (Review)
Review
PTR2/POT/NPF are a family of primarily proton coupled transporters that belong to the major facilitator super family and are found across most kingdoms of life. They are involved in uptake of nutrients, hormones, ions and several orally administered drug molecules. A wealth of structural and functional data is available for this family; the similarity between the protein structural features have been discussed and investigated in detail on several occasions, however there are no reports on the unification of substrate information. In order to fill this gap, we have collected information about substrates across the entire PTR2/POT/NPF family in order to provide key insights into what makes a molecule a substrate and whether there are common features among confirmed substrates. This review will be of particular interest for researchers in the field trying to probe the mechanisms responsible for the different selectivity of these transporters at a molecular resolution, and to design novel substrates.
Topics: Animals; Biological Transport; Humans; Membrane Transport Proteins; Substrate Specificity
PubMed: 33485485
DOI: 10.1016/bs.apcsb.2020.10.002 -
Environment International May 2019Arsenic is a non-essential, environmentally ubiquitous toxic metalloid. In response to this pervasive environmental challenge, organisms evolved mechanisms to confer... (Review)
Review
Arsenic is a non-essential, environmentally ubiquitous toxic metalloid. In response to this pervasive environmental challenge, organisms evolved mechanisms to confer resistance to arsenicals. Inorganic pentavalent arsenate is taken into most cells adventitiously by phosphate uptake systems. Similarly, inorganic trivalent arsenite is taken into most cells adventitiously, primarily via aquaglyceroporins or sugar permeases. The most common strategy for tolerance to both inorganic and organic arsenicals is by efflux that extrude them from the cytosol. These efflux transporters span across kingdoms and belong to various families such as aquaglyceroporins, major facilitator superfamily (MFS) transporters, ATP-binding cassette (ABC) transporters and potentially novel, yet to be discovered families. This review will outline the properties and substrates of known arsenic transport systems, the current knowledge gaps in the field, and aims to provide insight into the importance of arsenic transport in the context of the global arsenic biogeocycle and human health.
Topics: Animals; Arsenic; Arsenicals; Biological Transport; Humans; Membrane Transport Proteins
PubMed: 30852446
DOI: 10.1016/j.envint.2019.02.058 -
Biochemical Society Transactions Aug 2020The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope... (Review)
Review
The unique architecture of the mycobacterial cell envelope plays an important role in Mycobacterium tuberculosis (Mtb) pathogenesis. A critical protein in cell envelope biogenesis in mycobacteria, required for transport of precursors, trehalose monomycolates (TMMs), is the Mycobacterial membrane protein large 3 (MmpL3). Due to its central role in TMM transport, MmpL3 has been an attractive therapeutic target and a key target for several preclinical agents. In 2019, the first crystal structures of the MmpL3 transporter and its complexes with lipids and inhibitors were reported. These structures revealed several unique structural features of MmpL3 and provided invaluable information on the mechanism of TMM transport. This review aims to highlight the recent advances made in the function of MmpL3 and summarises structural findings. The overall goal is to provide a mechanistic perspective of MmpL3-mediated lipid transport and inhibition, and to highlight the prospects for potential antituberculosis therapies.
Topics: Antitubercular Agents; Bacterial Proteins; Biological Transport; Drug Development; Lipids; Membrane Transport Proteins; Mycolic Acids; Protein Conformation
PubMed: 32662825
DOI: 10.1042/BST20190950 -
Proteins Oct 2022Membrane transport proteins, which include transporters and channels, are delicate protein machineries that mediate the exchange of a variety of substances across... (Review)
Review
Membrane transport proteins, which include transporters and channels, are delicate protein machineries that mediate the exchange of a variety of substances across biomembranes. Accumulated structural and functional knowledge allows for the de novo design of transport proteins with new structures that do not exist in nature. Analysis based on these novel proteins provides new insights into the principles that govern protein assembly, conformational change, and substrate recognition. Here, we review the advances in the de novo design of transporters and channels over recent years and highlight the challenges and opportunities in this field.
Topics: Biological Transport; Carrier Proteins; Membrane Transport Proteins
PubMed: 35305033
DOI: 10.1002/prot.26336