scholarly journals Discovery and synthesis of hydroxy-L-proline based blockers of the neutral amino acid transporters SLC1A4 (ASCT1) and SLC1A5 (ASCT2).

2021 ◽  
Author(s):  
Michael P Kavanaugh ◽  
Brent R. Lyda ◽  
Gregory P. Leary ◽  
Derek Silvius ◽  
Nicholas R. Natale ◽  
...  
Keyword(s):  
Amino Acid ◽  
Homology Model ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Biological Targets ◽  
Conformationally Restricted ◽  
New Class ◽  
Wide Range ◽  
Ligand Binding Sites ◽  
Proline Derivatives

The conformationally restricted heterocycle hydroxy-ʟ-proline is a versatile scaffold for the synthesis of diverse multi-functionalized pyrrolidines for probing the ligand binding sites of biological targets. With the goal to develop new inhibitors of the widely expressed amino acid transporters SLC1A4 and SLC1A5 (also known as ASCT1 and ASCT2), we synthesized and functionally screened a series of hydroxy-ʟ-proline derivatives or 'prolinols' using electrophysiological and radio-labeled uptake assays on amino acid transporters from the SLC1, SLC7, and SLC38 solute carrier families. We identified a number of synthetic prolinols that act as selective high-affinity inhibitors of the SLC1 functional subfamily comprising the neutral amino acid transporters SLC1A4 and SLC1A5. The active and inactive prolinols were computationally docked into a threaded homology model and analyzed with respect to predicted molecular orientation and observed pharmacological activity. The series of hydroxy-L-proline derivatives identified here represents a new class of potential agents to pharmacologically modulate SLC1A4 and SLC1A5, amino acid exchangers that play important roles in a wide range of physiological and pathophysiological processes.

scholarly journals Inhibitors of the Neutral Amino Acid Transporters ASCT1 and ASCT2 Are Effective in In Vivo Models of Schizophrenia and Visual Dysfunction

2018 ◽  
Vol 367 (2) ◽  
pp. 292-301 ◽  
Author(s):  
Yong-Xin Li ◽  
Jia-Ying Yang ◽  
Miguel Alcantara ◽  
Grigor Abelian ◽  
Ashutosh Kulkarni ◽  
...  
Keyword(s):  
Amino Acid ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Visual Dysfunction ◽  
In Vivo Models

scholarly journals Deletion of P2X7 Receptor Decreases Basal Glutathione Level by Changing Glutamate-Glutamine Cycle and Neutral Amino Acid Transporters

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 995 ◽  
Author(s):  
Hana Park ◽  
Ji-Eun Kim
Keyword(s):  
Amino Acid ◽  
P2x7 Receptor ◽  
Neuronal Excitability ◽  
Defense Mechanism ◽  
Glutamate Uptake ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Glutamine Synthase ◽  
Expression Activity ◽  
P2x7r Activation

Glutathione (GSH) is an endogenous tripeptide antioxidant that consists of glutamate-cysteine-glycine. GSH content is limited by the availability of glutamate and cysteine. Furthermore, glutamine is involved in the regulation of GSH synthesis via the glutamate–glutamine cycle. P2X7 receptor (P2X7R) is one of the cation-permeable ATP ligand-gated ion channels, which is involved in neuronal excitability, neuroinflammation and astroglial functions. In addition, P2X7R activation decreases glutamate uptake and glutamine synthase (GS) expression/activity. In the present study, we found that P2X7R deletion decreased the basal GSH level without altering GSH synthetic enzyme expressions in the mouse hippocampus. P2X7R deletion also increased expressions of GS and ASCT2 (a glutamine:cysteine exchanger), but diminished the efficacy of N-acetylcysteine (NAC, a GSH precursor) in the GSH level. SIN-1 (500 μM, a generator nitric oxide, superoxide and peroxynitrite), which facilitates the cystine–cysteine shuttle mediated by xCT (a glutamate/cystein:cystine/NAC antiporter), did not affect basal GSH concentration in WT and P2X7R knockout (KO) mice. However, SIN-1 effectively reduced the efficacy of NAC in GSH synthesis in WT mice, but not in P2X7R KO mice. Therefore, our findings indicate that P2X7R may be involved in the maintenance of basal GSH levels by regulating the glutamate–glutamine cycle and neutral amino acid transports under physiological conditions, which may be the defense mechanism against oxidative stress during P2X7R activation.

scholarly journals Structural basis for amino acid exchange by a human heteromeric amino acid transporter

2020 ◽  
Vol 117 (35) ◽  
pp. 21281-21287 ◽  
Author(s):  
Di Wu ◽  
Tamara N. Grund ◽  
Sonja Welsch ◽  
Deryck J. Mills ◽  
Max Michel ◽  
...  
Keyword(s):  
Amino Acid ◽  
Heavy Chain ◽  
Light Chain ◽  
Basic Amino Acid ◽  
Binding Pocket ◽  
Structural Basis ◽  
Amino Acid Transporters ◽  
Wide Range ◽  
Functional Complex ◽  
Protein Components

Heteromeric amino acid transporters (HATs) comprise a group of membrane proteins that belong to the solute carrier (SLC) superfamily. They are formed by two different protein components: a light chain subunit from an SLC7 family member and a heavy chain subunit from the SLC3 family. The light chain constitutes the transport subunit whereas the heavy chain mediates trafficking to the plasma membrane and maturation of the functional complex. Mutation, malfunction, and dysregulation of HATs are associated with a wide range of pathologies or represent the direct cause of inherited and acquired disorders. Here we report the cryogenic electron microscopy structure of the neutral and basic amino acid transport complex (b[0,+]AT1-rBAT) which reveals a heterotetrameric protein assembly composed of two heavy and light chain subunits, respectively. The previously uncharacterized interaction between two HAT units is mediated via dimerization of the heavy chain subunits and does not include participation of the light chain subunits. The b(0,+)AT1 transporter adopts a LeuT fold and is captured in an inward-facing conformation. We identify an amino-acid–binding pocket that is formed by transmembrane helices 1, 6, and 10 and conserved among SLC7 transporters.

scholarly journals Amino Acid Transporters in Cancer and Their Relevance to “Glutamine Addiction”: Novel Targets for the Design of a New Class of Anticancer Drugs

2015 ◽  
Vol 75 (9) ◽  
pp. 1782-1788 ◽  
Author(s):  
Yangzom D. Bhutia ◽  
Ellappan Babu ◽  
Sabarish Ramachandran ◽  
Vadivel Ganapathy
Keyword(s):  
Amino Acid ◽  
Anticancer Drugs ◽  
Amino Acid Transporters ◽  
New Class ◽  
Novel Targets

Glycine enhances microglial intracellular calcium signaling. A role for sodium-coupled neutral amino acid transporters

2011 ◽  
Vol 461 (4) ◽  
pp. 481-491 ◽  
Author(s):  
Jimmy Van den Eynden ◽  
Kristof Notelaers ◽  
Bert Brône ◽  
Daniel Janssen ◽  
Katherine Nelissen ◽  
...  
Keyword(s):  
Amino Acid ◽  
Calcium Signaling ◽  
Intracellular Calcium ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Intracellular Calcium Signaling

scholarly journals Boramino acid as a marker for amino acid transporters

2015 ◽  
Vol 1 (8) ◽  
pp. e1500694 ◽  
Author(s):  
Zhibo Liu ◽  
Haojun Chen ◽  
Kai Chen ◽  
Yihan Shao ◽  
Dale O. Kiesewetter ◽  
...  
Keyword(s):  
Amino Acid ◽  
Animal Studies ◽  
Cell Uptake ◽  
Great Promise ◽  
Amino Acid Transporters ◽  
New Class ◽  
Mental Diseases ◽  
Imaging Probes ◽  
Specific Accumulation

Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics—boramino acids (BAAs)—that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3−. Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.

scholarly journals Structural Features of the Glutamate Transporter Family

1999 ◽  
Vol 63 (2) ◽  
pp. 293-307 ◽  
Author(s):  
Dirk Jan Slotboom ◽  
Wil N. Konings ◽  
Juke S. Lolkema
Keyword(s):  
Amino Acid ◽  
Glutamate Transporter ◽  
Glutamate Transporters ◽  
Amino Acid Sequences ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Conserved Sequence ◽  
Transporter Family ◽  
The Family ◽  
Membrane Spanning

SUMMARY Neuronal and glial glutamate transporters remove the excitatory neurotransmitter glutamate from the synaptic cleft and thus prevent neurotoxicity. The proteins belong to a large and widespread family of secondary transporters, including bacterial glutamate, serine, and C4-dicarboxylate transporters; mammalian neutral-amino-acid transporters; and an increasing number of bacterial, archaeal, and eukaryotic proteins that have not yet been functionally characterized. Sixty members of the glutamate transporter family were found in the databases on the basis of sequence homology. The amino acid sequences of the carriers have diverged enormously. Homology between the members of the family is most apparent in a stretch of approximately 150 residues in the C-terminal part of the proteins. This region contains four reasonably well-conserved sequence motifs, all of which have been suggested to be part of the translocation pore or substrate binding site. Phylogenetic analysis of the C-terminal stretch revealed the presence of five subfamilies with characterized members: (i) the eukaryotic glutamate transporters, (ii) the bacterial glutamate transporters, (iii) the eukaryotic neutral-amino-acid transporters, (iv) the bacterial C4-dicarboxylate transporters, and (v) the bacterial serine transporters. A number of other subfamilies that do not contain characterized members have been defined. In contrast to their amino acid sequences, the hydropathy profiles of the members of the family are extremely well conserved. Analysis of the hydropathy profiles has suggested that the glutamate transporters have a global structure that is unique among secondary transporters. Experimentally, the unique structure of the transporters was recently confirmed by membrane topology studies. Although there is still controversy about part of the topology, the most likely model predicts the presence of eight membrane-spanning α-helices and a loop-pore structure which is unique among secondary transporters but may resemble loop-pores found in ion channels. A second distinctive structural feature is the presence of a highly amphipathic membrane-spanning helix that provides a hydrophilic path through the membrane. Recent data from analysis of site-directed mutants and studies on the mechanism and pharmacology of the transporters are discussed in relation to the structural model.

ACE2 and gut amino acid transport

2020 ◽  
Vol 134 (21) ◽  
pp. 2823-2833 ◽  
Author(s):  
Simone M.R. Camargo ◽  
Raphael N. Vuille-dit-Bille ◽  
Chantal F. Meier ◽  
François Verrey
Keyword(s):  
Amino Acids ◽  
Small Intestine ◽  
Amino Acid ◽  
Amino Acid Transporter ◽  
Neutral Amino Acid ◽  
Amino Acid Transporters ◽  
Type I ◽  
Small Intestinal Mucosa ◽  
Neutral Amino Acid Transporter ◽  
Acid Transporter

Abstract ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.

Sign in / Sign up

Export Citation Format

Share Document