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.

Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1α

Pharmacology ◽  
2017 ◽  
Vol 101 (1-2) ◽  
pp. 64-71 ◽  
Author(s):  
Tetsuhiro Horie ◽  
Kazuya Fukasawa ◽  
Takashi Iezaki ◽  
Gyujin Park ◽  
Yuki Onishi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Hypoxia Inducible Factor ◽  
Amino Acid Transporters ◽  
Hypoxic Stress ◽  
Gene Encoding ◽  
Brown Adipocytes ◽  
Hypoxia Inducible Factor 1Α ◽  
Brown Adipose

The availability of amino acid in the brown adipose tissue (BAT) has been shown to be altered under various conditions; however, little is known about the possible expression and pivotal role of amino acid transporters in BAT under physiological and pathological conditions. The present study comprehensively investigated whether amino acid transporters are regulated by obesogenic conditions in BAT in vivo. Moreover, we investigated the mechanism underlying the regulation of the expression of amino acid transporters by various stressors in brown adipocytes in vitro. The expression of solute carrier family 38 member 1 (Slc38a1; gene encoding sodium-coupled neutral amino acid transporter 1) was preferentially upregulated in the BAT of both genetic and acquired obesity mice in vivo. Moreover, the expression of Slc38a1 was induced by hypoxic stress through hypoxia-inducible factor-1α, which is a master transcription factor of the adaptive response to hypoxic stress, in brown adipocytes in vitro. These results indicate that Slc38a1 is an obesity-associated gene in BAT and a hypoxia-responsive gene in brown adipocytes.

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 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

scholarly journals Functional characterization of the alanine-serine-cysteine exchanger of Carnobacterium sp AT7

2019 ◽  
Vol 151 (4) ◽  
pp. 505-517 ◽  
Author(s):  
Paola Bartoccioni ◽  
Joana Fort ◽  
Antonio Zorzano ◽  
Ekaitz Errasti-Murugarren ◽  
Manuel Palacín
Keyword(s):  
Amino Acid ◽  
Molecular Mechanisms ◽  
Structural Information ◽  
Functional Characterization ◽  
Physiological Role ◽  
Cell Uptake ◽  
Amino Acid Transporters ◽  
Inhibitor Selectivity ◽  
Substrate Binding Sites

Many key cell processes require prior cell uptake of amino acids from the environment, which is facilitated by cell membrane amino acid transporters such as those of the L-type amino acid transporter (LAT) subfamily. Alterations in LAT subfamily amino acid transport are associated with several human diseases, including cancer, aminoacidurias, and neurodegenerative conditions. Therefore, from the perspective of human health, there is considerable interest in obtaining structural information about these transporter proteins. We recently solved the crystal structure of the first LAT transporter, the bacterial alanine-serine-cysteine exchanger of Carnobacterium sp AT7 (BasC). Here, we provide a complete functional characterization of detergent-purified, liposome-reconstituted BasC transporter to allow the extension of the structural insights into mechanistic understanding. BasC is a sodium- and proton-independent small neutral amino acid exchanger whose substrate and inhibitor selectivity are almost identical to those previously described for the human LAT subfamily member Asc-1. Additionally, we show that, like its human counterparts, this transporter has apparent affinity asymmetry for the intra- and extracellular substrate binding sites—a key feature in the physiological role played by these proteins. BasC is an excellent paradigm of human LAT transporters and will contribute to our understanding of the molecular mechanisms underlying substrate recognition and translocation at both sides of the plasma membrane.

scholarly journals CD98hc (SLC3A2) regulation of skin homeostasis wanes with age

2013 ◽  
Vol 210 (1) ◽  
pp. 173-190 ◽  
Author(s):  
Etienne Boulter ◽  
Soline Estrach ◽  
Aurélia Errante ◽  
Catherine Pons ◽  
Laurence Cailleteau ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Amino Acid ◽  
Molecular Mechanisms ◽  
Skin Aging ◽  
Amino Acid Transporters ◽  
Appreciable Effect ◽  
Nucleotide Exchange ◽  
Aged Skin

Skin aging is linked to reduced epidermal proliferation and general extracellular matrix atrophy. This involves factors such as the cell adhesion receptors integrins and amino acid transporters. CD98hc (SLC3A2), a heterodimeric amino acid transporter, modulates integrin signaling in vitro. We unravel CD98hc functions in vivo in skin. We report that CD98hc invalidation has no appreciable effect on cell adhesion, clearly showing that CD98hc disruption phenocopies neither CD98hc knockdown in cultured keratinocytes nor epidermal β1 integrin loss in vivo. Instead, we show that CD98hc deletion in murine epidermis results in improper skin homeostasis and epidermal wound healing. These defects resemble aged skin alterations and correlate with reduction of CD98hc expression observed in elderly mice. We also demonstrate that CD98hc absence in vivo induces defects as early as integrin-dependent Src activation. We decipher the molecular mechanisms involved in vivo by revealing a crucial role of the CD98hc/integrins/Rho guanine nucleotide exchange factor (GEF) leukemia-associated RhoGEF (LARG)/RhoA pathway in skin homeostasis. Finally, we demonstrate that the deregulation of RhoA activation in the absence of CD98hc is also a result of impaired CD98hc-dependent amino acid transports.

scholarly journals Amino acid transporters and nutrient-sensing mechanisms: new targets for treating insulin-linked disorders?

2007 ◽  
Vol 35 (5) ◽  
pp. 1215-1217 ◽  
Author(s):  
B. Reynolds ◽  
R. Laynes ◽  
M.H. Ögmundsdóttir ◽  
C.A.R. Boyd ◽  
D.C.I. Goberdhan
Keyword(s):  
Amino Acid ◽  
Normal Development ◽  
Nutrient Sensing ◽  
Amino Acid Transporters ◽  
Cancer Type ◽  
Growth Factor Signalling ◽  
In Vivo Analysis ◽  
Signalling Cascade

The IIS (insulin/IGF (insulin-like growth factor) signalling) cascade has an important role in regulating normal development and physiology, as evidenced by its effects in a host of major human diseases including cancer, Type 2 diabetes and neurodegeneration. Recently, it has become clear that multiple types of local nutrient-sensing mechanisms have an impact on cellular insulin-sensitivity through the downstream kinase TOR (target of rapamycin). In vivo analysis in flies has surprisingly highlighted PATs (proton-assisted amino acid transporters) as having a uniquely potent role in regulating IIS/TOR activity and growth, potentially via a novel signalling mechanism. Other molecules such as the heterodimeric amino acid transporter, CD98, which provides the principal route for cellular uptake of leucine, an amino acid implicated in regulating TOR, also appear to have important effects. As our understanding of how nutrient sensing has an impact on IIS/TOR increases, novel targets to modulate aberrant IIS in disease are likely to emerge, which could complement current strategies designed to block kinases in this pathway.

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 Substrate-mediated regulation of the arginine transporter ofToxoplasma gondii

2019 ◽  
Author(s):  
Esther Rajendran ◽  
Morgan Clark ◽  
Cibelly Goulart ◽  
Birte Steinhöfel ◽  
Erick T. Tjhin ◽  
...  
Keyword(s):  
Amino Acid ◽  
External Environment ◽  
Apicomplexan Parasite ◽  
Upstream Open Reading Frame ◽  
Amino Acid Transporters ◽  
Reading Frame ◽  
Intracellular Parasites ◽  
Biosensor Strain ◽  
Sense And Respond

ABSTRACTIntracellular parasites, such as the apicomplexanToxoplasma gondii, are adept at scavenging nutrients from their host. However, there is little understanding of how parasites sense and respond to the changing nutrient environments they encounter during an infection.TgApiAT1, a member of the apicomplexan ApiAT family of amino acid transporters, is the major uptake route for the essential amino acid L-arginine (Arg) inT. gondii. Here, we show that the abundance ofTgApiAT1, and hence the rate of uptake of Arg, is regulated by the availability of Arg in the parasite’s external environment, increasing in response to decreased [Arg]. Using a luciferase-based ‘biosensor’ strain ofT. gondii, we demonstrate that parasites vary the expression ofTgApiAT1 in different organs within their host, indicating that parasites are able to modulateTgApiAT1-dependent uptake of Arg as they encounter different nutrient environmentsin vivo. Finally, we show that Arg-dependent regulation ofTgApiAT1 expression is post-transcriptional, mediated by an upstream open reading frame (uORF) in theTgApiAT1 transcript, and we provide evidence that the peptide encoded by this uORF is critical for mediating regulation. Together, our data reveal the mechanism by which an apicomplexan parasite responds to changes in the availability of a key nutrient.

scholarly journals Exploiting the Concept of Multivalency with 68Ga- and 89Zr-Labelled Fusarinine C-Minigastrin Bioconjugates for Targeting CCK2R Expression

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Dominik Summer ◽  
Christine Rangger ◽  
Maximilian Klingler ◽  
Peter Laverman ◽  
Gerben M. Franssen ◽  
...  
Keyword(s):  
Metabolic Stability ◽  
Cell Uptake ◽  
Late Time ◽  
Biodistribution Studies ◽  
Imaging Probes ◽  
Gallium 68 ◽  
Late Time Point ◽  
Time Point

Cholecystokinin-2 receptors (CCK2R) are overexpressed in a variety of malignant diseases and therefore have gained certain attention for peptide receptor radionuclide imaging. Among extensive approaches to improve pharmacokinetics and metabolic stability of minigastrin (MG) based radioligands, the concept of multivalency for enhanced tumour targeting has not been investigated extensively. We therefore utilized fusarinine C (FSC) as chelating scaffold for novel mono-, di-, and trimeric bioconjugates for targeting CCK2R expression. FSC-based imaging probes were radiolabelled with positron emitting radionuclides (gallium-68 and zirconium-89) and characterized in vitro (log⁡D, IC50, and cell uptake) and in vivo (metabolic stability in BALB/c mice, biodistribution profile, and microPET/CT imaging in A431-CCK2R/A431-mock tumour xenografted BALB/c nude mice). Improved targeting did not fully correlate with the grade of multimerization. The divalent probe showed higher receptor affinity and increased CCK2R mediated cell uptake while the trimer remained comparable to the monomer. In vivo biodistribution studies 1 h after administration of the 68Ga-labelled radioligands confirmed this trend, but imaging at late time point (24 h) with 89Zr-labelled counterparts showed a clearly enhanced imaging contrast of the trimeric probe compared to the mono- and dimer. Furthermore, in vivo stability studies showed a higher metabolic stability for multimeric probes compared to the monomeric bioconjugate. In summary, we could show that FSC can be utilized as suitable scaffold for novel mono- and multivalent imaging probes for CCK2R-related malignancies with partly improved targeting properties for multivalent conjugates. The increased tumour accumulation of the trimer 24 h postinjection (p.i.) can be explained by slower clearance and increased metabolic stability of multimeric conjugates.

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