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Biomolecules
Special Issues
Recent Advances in Amino Acid Transporters
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Recent Advances in Amino Acid Transporters

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (20 November 2021) | Viewed by 13452

Special Issue Editor

Prof. Dr. Stefan Broer

E-Mail Website
Guest Editor
College of Medicine, Biology & Environment, Building 134, The Australian National University, Canberra, ACT 2601, Australia
Interests: amino acid transport; metabolic diseases; amino acid homeostasis; cancer metabolism; transport inhibitors

Special Issue Information

Dear Colleagues,

Amino acid transport is a field which has witnessed enormous advances in numerous aspects. High-resolution structures of bacterial and mammalian transporters are appearing at an increasing rate, and the first heteromeric complexes are becoming resolved. Our understanding of the role of amino acid transporters in inherited and acquired diseases is expanding rapidly thanks to studies using a variety of experimental approaches and model systems. Amino acid transporters have been identified in many organelles, highlighting their role in signalling and metabolism. Amino acid transporters have also emerged as a group of drug targets in cancer metabolism and metabolic disorders. We hope that this Special Issue will reflect the diversity of this field and its recent developments.

Prof. Stefan Bröer
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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19 pages, 2650 KiB  
Article
Do Amino Acid Antiporters Have Asymmetric Substrate Specificity?
by Gregory Gauthier-Coles, Stephen J. Fairweather, Angelika Bröer and Stefan Bröer
Biomolecules 2023, 13(2), 301; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13020301 - 06 Feb 2023
Cited by 4 | Viewed by 1391
Abstract
Amino acid antiporters mediate the 1:1 exchange of groups of amino acids. Whether substrate specificity can be different for the inward and outward facing conformation has not been investigated systematically, although examples of asymmetric transport have been reported. Here we used LC–MS to [...] Read more.
Amino acid antiporters mediate the 1:1 exchange of groups of amino acids. Whether substrate specificity can be different for the inward and outward facing conformation has not been investigated systematically, although examples of asymmetric transport have been reported. Here we used LC–MS to detect the movement of 12C- and 13C-labelled amino acid mixtures across the plasma membrane of Xenopus laevis oocytes expressing a variety of amino acid antiporters. Differences of substrate specificity between transporter paralogs were readily observed using this method. Our results suggest that antiporters are largely symmetric, equalizing the pools of their substrate amino acids. Exceptions are the antiporters y+LAT1 and y+LAT2 where neutral amino acids are co-transported with Na+ ions, favouring their import. For the antiporters ASCT1 and ASCT2 glycine acted as a selective influx substrate, while proline was a selective influx substrate of ASCT1. These data show that antiporters can display non-canonical modes of transport. Full article
(This article belongs to the Special Issue Recent Advances in Amino Acid Transporters)
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19 pages, 2874 KiB  
Article
Reshaping the Binding Pocket of the Neurotransmitter:Solute Symporter (NSS) Family Transporter SLC6A14 (ATB0,+) Selectively Reduces Access for Cationic Amino Acids and Derivatives
by Catriona M. H. Anderson, Noel Edwards, Andrew K. Watson, Mike Althaus and David T. Thwaites
Biomolecules 2022, 12(10), 1404; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12101404 - 01 Oct 2022
Cited by 3 | Viewed by 1833
Abstract
SLC6A14 (ATB0,+) is unique among SLC proteins in its ability to transport 18 of the 20 proteinogenic (dipolar and cationic) amino acids and naturally occurring and synthetic analogues (including anti-viral prodrugs and nitric oxide synthase (NOS) inhibitors). SLC6A14 mediates amino acid [...] Read more.
SLC6A14 (ATB0,+) is unique among SLC proteins in its ability to transport 18 of the 20 proteinogenic (dipolar and cationic) amino acids and naturally occurring and synthetic analogues (including anti-viral prodrugs and nitric oxide synthase (NOS) inhibitors). SLC6A14 mediates amino acid uptake in multiple cell types where increased expression is associated with pathophysiological conditions including some cancers. Here, we investigated how a key position within the core LeuT-fold structure of SLC6A14 influences substrate specificity. Homology modelling and sequence analysis identified the transmembrane domain 3 residue V128 as equivalent to a position known to influence substrate specificity in distantly related SLC36 and SLC38 amino acid transporters. SLC6A14, with and without V128 mutations, was heterologously expressed and function determined by radiotracer solute uptake and electrophysiological measurement of transporter-associated current. Substituting the amino acid residue occupying the SLC6A14 128 position modified the binding pocket environment and selectively disrupted transport of cationic (but not dipolar) amino acids and related NOS inhibitors. By understanding the molecular basis of amino acid transporter substrate specificity we can improve knowledge of how this multi-functional transporter can be targeted and how the LeuT-fold facilitates such diversity in function among the SLC6 family and other SLC amino acid transporters. Full article
(This article belongs to the Special Issue Recent Advances in Amino Acid Transporters)
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12 pages, 1881 KiB  
Article
Functional and Kinetic Comparison of Alanine Cysteine Serine Transporters ASCT1 and ASCT2
by Jiali Wang, Yang Dong and Christof Grewer
Biomolecules 2022, 12(1), 113; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12010113 - 11 Jan 2022
Cited by 4 | Viewed by 1673
Abstract
Neutral amino acid transporters ASCT1 and ASCT2 are two SLC1 (solute carrier 1) family subtypes, which are specific for neutral amino acids. The other members of the SLC1 family are acidic amino acid transporters (EAATs 1–5). While the functional similarities and differences between [...] Read more.
Neutral amino acid transporters ASCT1 and ASCT2 are two SLC1 (solute carrier 1) family subtypes, which are specific for neutral amino acids. The other members of the SLC1 family are acidic amino acid transporters (EAATs 1–5). While the functional similarities and differences between the EAATs have been well studied, less is known about how the subtypes ASCT1 and 2 differ in kinetics and function. Here, by performing comprehensive electrophysiological analysis, we identified similarities and differences between these subtypes, as well as novel functional properties, such as apparent substrate affinities of the inward-facing conformation (in the range of 70 μM for L-serine as the substrate). Key findings were: ASCT1 has a higher apparent affinity for Na+, as well as a larger [Na+] dependence of substrate affinity compared to ASCT2. However, the general sequential Na+/substrate binding mechanism with at least one Na+ binding first, followed by amino acid substrate, followed by at least one more Na+ ion, appears to be conserved between the two subtypes. In addition, the first Na+ binding step, presumably to the Na3 site, occurs with high apparent affinity (<1 mM) in both transporters. In addition, ASCT1 and 2 show different substrate selectivities, where ASCT1 does not respond to extracellular glutamine. Finally, in both transporters, we measured rapid, capacitive charge movements upon application and removal of amino acid, due to rearrangement of the translocation equilibrium. This charge movement decays rapidly, with a time constant of 4–5 ms and recovers with a time constant in the 15 ms range after substrate removal. This places a lower limit on the turnover rate of amino acid exchange by these two transporters of 60–80 s−1. Full article
(This article belongs to the Special Issue Recent Advances in Amino Acid Transporters)
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17 pages, 2820 KiB  
Article
Insights into the Interaction of Lysosomal Amino Acid Transporters SLC38A9 and SLC36A1 Involved in mTORC1 Signaling in C2C12 Cells
by Dan Wang, Xuebin Wan, Xiaoli Du, Zhuxia Zhong, Jian Peng, Qi Xiong, Jin Chai and Siwen Jiang
Biomolecules 2021, 11(9), 1314; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11091314 - 06 Sep 2021
Cited by 5 | Viewed by 3647
Abstract
Amino acids are critical for mammalian target of rapamycin complex 1 (mTORC1) activation on the lysosomal surface. Amino acid transporters SLC38A9 and SLC36A1 are the members of the lysosomal amino acid sensing machinery that activates mTORC1. The current study aims to clarify the [...] Read more.
Amino acids are critical for mammalian target of rapamycin complex 1 (mTORC1) activation on the lysosomal surface. Amino acid transporters SLC38A9 and SLC36A1 are the members of the lysosomal amino acid sensing machinery that activates mTORC1. The current study aims to clarify the interaction of SLC38A9 and SLC36A1. Here, we discovered that leucine increased expressions of SLC38A9 and SLC36A1, leading to mTORC1 activation. SLC38A9 interacted with SLC36A1 and they enhanced each other’s expression levels and locations on the lysosomal surface. Additionally, the interacting proteins of SLC38A9 in C2C12 cells were identified to participate in amino acid sensing mechanism, mTORC1 signaling pathway, and protein synthesis, which provided a resource for future investigations of skeletal muscle mass. Full article
(This article belongs to the Special Issue Recent Advances in Amino Acid Transporters)
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Review

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15 pages, 936 KiB  
Review
Unconventional Functions of Amino Acid Transporters: Role in Macropinocytosis (SLC38A5/SLC38A3) and Diet-Induced Obesity/Metabolic Syndrome (SLC6A19/SLC6A14/SLC6A6)
by Yangzom D. Bhutia, Marilyn Mathew, Sathish Sivaprakasam, Sabarish Ramachandran and Vadivel Ganapathy
Biomolecules 2022, 12(2), 235; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12020235 - 31 Jan 2022
Cited by 7 | Viewed by 4165
Abstract
Amino acid transporters are expressed in mammalian cells not only in the plasma membrane but also in intracellular membranes. The conventional function of these transporters is to transfer their amino acid substrates across the lipid bilayer; the direction of the transfer is dictated [...] Read more.
Amino acid transporters are expressed in mammalian cells not only in the plasma membrane but also in intracellular membranes. The conventional function of these transporters is to transfer their amino acid substrates across the lipid bilayer; the direction of the transfer is dictated by the combined gradients for the amino acid substrates and the co-transported ions (Na+, H+, K+ or Cl−) across the membrane. In cases of electrogenic transporters, the membrane potential also contributes to the direction of the amino acid transfer. In addition to this expected traditional function, several unconventional functions are known for some of these amino acid transporters. This includes their role in intracellular signaling, regulation of acid–base balance, and entry of viruses into cells. Such functions expand the biological roles of these transporters beyond the logical amino acid homeostasis. In recent years, two additional unconventional biochemical/metabolic processes regulated by certain amino acid transporters have come to be recognized: macropinocytosis and obesity. This adds to the repertoire of biological processes that are controlled and regulated by amino acid transporters in health and disease. In the present review, we highlight the unusual involvement of selective amino acid transporters in macropinocytosis (SLC38A5/SLC38A3) and diet-induced obesity/metabolic syndrome (SLC6A19/SLC6A14/SLC6A6). Full article
(This article belongs to the Special Issue Recent Advances in Amino Acid Transporters)
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