Submit to IJMS Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Amino Acids Transport and Metabolism 3.0

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 21558

Share This Special Issue

Special Issue Editors

Prof. Dr. Cesare Indiveri

E-Mail Website
Guest Editor

Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via P. Bucci 4c, 87036 Arcavacata di Rende (CS), Italy
Interests: carnitine; cell metabolism; membrane transporters; bioenergetics
Special Issues, Collections and Topics in MDPI journals

Dr. Mariafrancesca Scalise

E-Mail Website
Guest Editor

Department DiBEST (Biologia, Ecologia, Scienze della Terra), University of Calabria, Via P. Bucci 4c, 87036 Arcavacata di Rende (CS), Italy
Interests: proteoliposome; membrane transporters; plasma membrane; protein purification; amino acids; cancer cell line; exosomes
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

This Special Issue is the continuation of our 2019 Special Issue, “Amino Acids Transport and Metabolism” (https://www.mdpi.com/journal/ijms/special_issues/amino_acids_transport_2.0).

A Special Issue on the novel topic "Amino Acids Transport and Metabolism" is being prepared for the journal IJMS. The idea works on the basis that amino acid homeostasis is essential for life. A complex network of enzymes and transporters cooperate to maintain homeostasis. The network is regulated in response to both cell need and nutritional state. In this frame, transporters are major players since they mediate the absorption of amino acids and distribution for the entire organism. Identification, functional studies and classification of many amino acid transporters have been performed over the years using different and complementary experimental tools, from ex vivo to in vitro systems, as well as in silico methodologies. The few solved structures of amino acid transporters from prokaryotes or eukaryotes recently boosted investigations of molecular mechanisms and structure/function relationships. Altered functions and expressions of amino acid transporters underlie various severe human pathologies. Taken together, these observations also drove novel drug design methodologies with the aim of improving the specific targeting of a single protein whose expression/function is altered in human pathologies.

Original manuscripts and reviews dealing with specific and/or systematic aspects of amino acid transport, metabolism, and pathophysiology are very welcome from outstanding experts of the topic.

Prof. Cesare Indiveri
Dr. Mariafrancesca Scalise
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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.

Keywords

amino acid transporters
bioinformatics
gene expression
post-translational modification
human pathology
transport mechanism
structure/function relationships
uniport
antiport
symport

Published Papers (7 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

15 pages, 5437 KiB

Open AccessArticle

Amino Acid Transporter LAT1 (SLC7A5) Mediates MeHg-Induced Oxidative Stress Defense in the Human Placental Cell Line HTR-8/SVneo

by Sebastian Granitzer, Raimund Widhalm, Martin Forsthuber, Isabella Ellinger, Gernot Desoye, Markus Hengstschläger, Harald Zeisler, Hans Salzer and Claudia Gundacker

Int. J. Mol. Sci. 2021, 22(4), 1707; https://doi.org/10.3390/ijms22041707 - 08 Feb 2021

Cited by 14 | Viewed by 2776

Abstract

The placental barrier can protect the fetus from contact with harmful substances. The potent neurotoxin methylmercury (MeHg), however, is very efficiently transported across the placenta. Our previous data suggested that L-type amino acid transporter (LAT)1 is involved in placental MeHg uptake, accepting MeHg-L-cysteine conjugates as substrate due to structural similarity to methionine. The aim of the present study was to investigate the antioxidant defense of placental cells to MeHg exposure and the role of LAT1 in this response. When trophoblast-derived HTR-8/SVneo cells were LAT1 depleted by siRNA-mediated knockdown, they accumulated less MeHg. However, they were more susceptible to MeHg-induced toxicity. This was evidenced in decreased cell viability at a usually noncytotoxic concentration of 0.03 µM MeHg (~6 µg/L). Treatment with ≥0.3 µM MeHg increased cytotoxicity, apoptosis rate, and oxidative stress of HTR-8/SVneo cells. These effects were enhanced under LAT1 knockdown. Reduced cell number was seen when MeHg-exposed cells were cultured in medium low in cysteine, a constituent of the tripeptide glutathione (GSH). Because LAT1-deficient HTR-8/SVneo cells have lower GSH levels than control cells (independent of MeHg treatment), we conclude that LAT1 is essential for de novo synthesis of GSH, required to counteract oxidative stress. Genetic predisposition to decreased LAT1 function combined with MeHg exposure could increase the risk of placental damage. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism 3.0)

► Show Figures

Figure 1

11 pages, 1373 KiB

Open AccessArticle

The Heavy Chain 4F2hc Modulates the Substrate Affinity and Specificity of the Light Chains LAT1 and LAT2

by Satish Kantipudi, Jean-Marc Jeckelmann, Zöhre Ucurum, Patrick D. Bosshart and Dimitrios Fotiadis

Int. J. Mol. Sci. 2020, 21(20), 7573; https://doi.org/10.3390/ijms21207573 - 14 Oct 2020

Cited by 18 | Viewed by 3540

Abstract

The human L-type amino acid transporters LAT1 and LAT2 mediate the transport of amino acids and amino acid derivatives across plasma membranes in a sodium-independent, obligatory antiport mode. In mammalian cells, LAT1 and LAT2 associate with the type-II membrane N-glycoprotein 4F2hc to form heteromeric amino acid transporters (HATs). The glycosylated ancillary protein 4F2hc is known to be important for successful trafficking of the unglycosylated transporters to the plasma membrane. The heavy (i.e., 4F2hc) and light (i.e., LAT1 and LAT2) chains belong to the solute carrier (SLC) families SLC3 and SLC7, and are covalently linked by a conserved disulfide bridge. Overexpression, absence, or malfunction of certain HATs is associated with human diseases and HATs are therefore considered therapeutic targets. Here, we present a comparative, functional characterization of the HATs 4F2hc-LAT1 and 4F2hc-LAT2, and their light chains LAT1 and LAT2. For this purpose, the HATs and the light chains were expressed in the methylotrophic yeast Pichia pastoris and a radiolabel transport assay was established. Importantly and in contrast to mammalian cells, P. pastoris has proven useful as eukaryotic expression system to successfully express human LAT1 and LAT2 in the plasma membrane without the requirement of co-expressed trafficking chaperone 4F2hc. Our results show a novel function of the heavy chain 4F2hc that impacts transport by modulating the substrate affinity and specificity of corresponding LATs. In addition, the presented data confirm that the light chains LAT1 and LAT2 constitute the substrate-transporting subunits of the HATs, and that light chains are also functional in the absence of the ancillary protein 4F2hc. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism 3.0)

► Show Figures

Graphical abstract

17 pages, 2997 KiB

Open AccessArticle

Nitrogen Assimilation and Transport by Ex Planta Nitrogen-Fixing Bradyrhizobium diazoefficiens Bacteroids Is Modulated by Oxygen, Bacteroid Density and l-Malate

by James K. Waters, Thomas P. Mawhinney and David W. Emerich

Int. J. Mol. Sci. 2020, 21(20), 7542; https://doi.org/10.3390/ijms21207542 - 13 Oct 2020

Cited by 7 | Viewed by 2323

Abstract

Symbiotic nitrogen fixation requires the transfer of fixed organic nitrogen compounds from the symbiotic bacteria to a host plant, yet the chemical nature of the compounds is in question. Bradyrhizobium diazoefficiens bacteroids were isolated anaerobically from soybean nodules and assayed at varying densities, varying partial pressures of oxygen, and varying levels of l-malate. Ammonium was released at low bacteroid densities and high partial pressures of oxygen, but was apparently taken up at high bacteroid densities and low partial pressures of oxygen in the presence of l-malate; these later conditions were optimal for amino acid excretion. The ratio of partial pressure of oxygen/bacteroid density of apparent ammonium uptake and of alanine excretion displayed an inverse relationship. Ammonium uptake, alanine and branch chain amino acid release were all dependent on the concentration of l-malate displaying similar K_0.5 values of 0.5 mM demonstrating concerted regulation. The hyperbolic kinetics of ammonium uptake and amino acid excretion suggests transport via a membrane carrier and also suggested that transport was rate limiting. Glutamate uptake displayed exponential kinetics implying transport via a channel. The chemical nature of the compounds released were dependent upon bacteroid density, partial pressure of oxygen and concentration of l-malate demonstrating an integrated metabolism. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism 3.0)

► Show Figures

Graphical abstract

13 pages, 4163 KiB

Open AccessArticle

Sub-Nanometer Cryo-EM Density Map of the Human Heterodimeric Amino Acid Transporter 4F2hc-LAT2

by Jean-Marc Jeckelmann and Dimitrios Fotiadis

Int. J. Mol. Sci. 2020, 21(19), 7094; https://doi.org/10.3390/ijms21197094 - 25 Sep 2020

Cited by 10 | Viewed by 3299

Abstract

Heterodimeric amino acid transporters (HATs) are protein complexes mediating the transport of amino acids and derivatives thereof across biological membranes. HATs are composed of two subunits, a heavy and a light chain subunit belonging to the solute carrier (SLC) families SLC3 and SLC7. The human HAT 4F2hc-LAT2 is composed of the type-II membrane N-glycoprotein 4F2hc (SCL3A2) and the L-type amino acid transporter LAT2 (SLC7A8), which are covalently linked to each other by a conserved disulfide bridge. Whereas LAT2 catalyzes substrate transport, 4F2hc is important for the successful trafficking of the transporter to the plasma membrane. The overexpression, malfunction, or absence of 4F2hc-LAT2 is associated with human diseases, and therefore, this heterodimeric complex represents a potential drug target. The recombinant human 4F2hc-LAT2 can be functionally overexpressed in the methylotrophic yeast Pichia pastoris, and the protein can be purified. Here, we present the cryo-EM density map of the human 4F2hc-LAT2 amino acid transporter at sub-nanometer resolution. A homology model of 4F2hc-LAT2 in the inward-open conformation was generated and fitted into the cryo-EM density and analyzed. In addition, disease-causing point mutations in human LAT2 were mapped on the homology model of 4F2hc-LAT2, and the possible functional implications on the molecular level are discussed. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism 3.0)

► Show Figures

Graphical abstract

26 pages, 3313 KiB

Open AccessArticle

Esophageal Squamous Cell Carcinoma Is Accompanied by Local and Systemic Changes in L-arginine/NO Pathway

by Iwona Bednarz-Misa, Paulina Fortuna, Mariusz G. Fleszar, Łukasz Lewandowski, Dorota Diakowska, Joanna Rosińczuk and Małgorzata Krzystek-Korpacka

Int. J. Mol. Sci. 2020, 21(17), 6282; https://doi.org/10.3390/ijms21176282 - 30 Aug 2020

Cited by 7 | Viewed by 3356

Abstract

The L-arginine/NO pathway holds promise as a source of potential therapy target and biomarker; yet, its status and utility in esophageal squamous cell carcinoma (ESCC) is unclear. We aimed at quantifying pathway metabolites in sera from patients with ESCC (n = 61) and benign conditions (n = 62) using LC-QTOF-MS and enzyme expression in esophageal tumors and matched noncancerous samples (n = 40) using real-time PCR with reference to ESCC pathology and circulating immune/inflammatory mediators, quantified using Luminex xMAP technology. ESCC was associated with elevated systemic arginine and asymmetric dimethylarginine. Citrulline decreased and arginine bioavailability increased along with increasing ESCC advancement. Compared to adjacent tissue, tumors overexpressed ODC1, NOS2, PRMT1, and PRMT5 but had downregulated ARG1, ARG2, and DDAH1. Except for markedly higher NOS2 and lower ODC1 in tumors from M1 patients, the pathology-associated changes in enzyme expression were subtle and present also in noncancerous tissue. Both the local enzyme expression level and systemic metabolite concentration were related to circulating inflammatory and immune mediators, particularly those associated with eosinophils and those promoting viability and self-renewal of cancer stem cells. Metabolic reprogramming in ESCC manifests itself by the altered L-arginine/NO pathway. Upregulation of PRMTs in addition to NOS2 and ODC1 and the pathway link with stemness-promoting cytokines warrants further investigation. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism 3.0)

► Show Figures

Figure 1

16 pages, 1760 KiB

Open AccessArticle

2-(3-Hydroxy-5-phosphonooxymethyl-2-methyl-4-pyridyl)-1,3-thiazolidine-4-carboxylic Acid, Novel Metabolite of Pyridoxal 5′-Phosphate and Cysteine Is Present in Human Plasma—Chromatographic Investigations

by Justyna Piechocka, Monika Wrońska, Iwona E. Głowacka and Rafał Głowacki

Int. J. Mol. Sci. 2020, 21(10), 3548; https://doi.org/10.3390/ijms21103548 - 18 May 2020

Cited by 5 | Viewed by 2786

Abstract

It is well-established that aminothiols, to which cysteine (Cys) belongs, are highly reactive towards aldehydes in an aqueous environment, forming substituted thiazolidine carboxylic acids. This report provides evidence that formation of the product containing a thiazolidine ring through non-enzymatic condensation of Cys and an active form of vitamin B6 pyridoxal 5′-phosphate (PLP) occurs in vivo in humans. To prove this point, a new method, based on a gas chromatography coupled with mass spectrometry (GC-MS), has been designed to identify and quantify Cys and PLP adduct, 2-(3-hydroxy-5-phosphonooxymethyl-2-methyl-4-pyridyl)-1,3-thiazolidine-4-carboxylic acid (HPPTCA) in human plasma. The GC-MS assay relies on sample deproteinization by ultrafiltration over cut-off membranes and preconcentration by drying under vacuum, followed by treatment of the residue with derivatization mixture containing anhydrous pyridine, N-trimethylsilyl-N-methyl trifluoroacetamide (MSTFA) and trimethylchlorosilane (TMCS). The method quantifies HPPTCA in a linear range from 1 to 20 µmol L⁻¹, where the lowest standard on the calibration curve refers to the limit of quantification (LOQ). The validity of the method was demonstrated. Furthermore, the method was successfully applied to plasma samples donated by apparently healthy volunteers and breast cancer patients. The GC-MS assay provides a new tool that will hopefully facilitate studies on the role of HPPTCA in living systems. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism 3.0)

► Show Figures

Graphical abstract

13 pages, 2051 KiB

Open AccessArticle

Functional Consequences of Low Activity of Transport System A for Neutral Amino Acids in Human Bone Marrow Mesenchymal Stem Cells

by Martina Chiu, Giuseppe Taurino, Massimiliano G. Bianchi, Erica Dander, Alessandra Fallati, Nicola Giuliani, Giovanna D’Amico and Ovidio Bussolati

Int. J. Mol. Sci. 2020, 21(5), 1899; https://doi.org/10.3390/ijms21051899 - 10 Mar 2020

Cited by 6 | Viewed by 2696

Abstract

In cultured human fibroblasts, SNAT transporters (System A) account for the accumulation of non-essential neutral amino acids, are adaptively up-regulated upon amino acid deprivation and play a major role in cell volume recovery upon hypertonic stress. No information is instead available on the expression and activity of SNAT transporters in human bone marrow mesenchymal stromal cells (MSC), although they are increasingly investigated for their staminal and immunomodulatory properties and used for several therapeutic applications. The uptake of glutamine and proline, two substrates of SNAT1 and SNAT2 transporters, was measured in primary human MSC and an MSC line. The amino acid analogue MeAIB, a specific substrate of these carriers, has been used to selectively inhibit SNAT-dependent transport of glutamine and, through its sodium-dependent transport, as an indicator of SNAT1/2 activity. SNAT1/2 expression and localization were assessed with RT-PCR and confocal microscopy, respectively. Cell volume was assessed from urea distribution space. In all these experiments, primary human fibroblasts were used as the positive control for SNAT expression and activity. Compared with fibroblasts, MSC have a lower SNAT1 expression and hardly detectable membrane localization of both SNAT1 and SNAT2. Moreover, they exhibit no sodium-dependent MeAIB uptake or MeAIB-inhibitable glutamine transport, and exhibit a lower ability to accumulate glutamine and proline than fibroblasts. MSC exhibited an only marginal increase in MeAIB transport upon amino acid starvation and did not recover cell volume after hypertonic stress. In conclusion, the activity of SNAT transporters is low in human MSC. MSC adaptation to amino acid shortage is expected to rely on intracellular synthesis, given the absence of an effective up-regulation of the SNAT transporters. Full article

(This article belongs to the Special Issue Amino Acids Transport and Metabolism 3.0)

► Show Figures

Journal Menu

Journal Browser

Amino Acids Transport and Metabolism 3.0

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (7 papers)

Research

Further Information

Guidelines

MDPI Initiatives

Follow MDPI