Small molecule inhibitors provide insights into the relevance of LAT1 and LAT2 in materno‐foetal amino acid transport

Zaugg, Jonas; Huang, Xiao; Ziegler, Fabian; Rubin, Matthias; Graff, Julien; Müller, Jennifer; Moser-Hässig, Ruedi; Powell, Theresa L.; Gertsch, Jürg; Altmann, Karl‐Heinz; Albrecht, Christiane

doi:10.1111/jcmm.15840

Cited by 11 publications

(5 citation statements)

References 60 publications

(138 reference statements)

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“…2d,e). This may be explained by enhanced aromatic interaction between the introduced tryptophan and the terminal phenyl moiety of JPH203, consistent with the observation that adding a methoxy group to the terminal ring of JPH203 improves its affinity (20), presumably by enhancing the aromaticity.…”

Section: Jph203 Binds To the Outward-open Pocket Of Lat1supporting

confidence: 81%

Structural basis of anticancer drug recognition and amino acid transport by LAT1

Lee,

Jin,

Ohgaki

et al. 2023

Preprint

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LAT1 (SLC7A5) transports large neutral amino acids and their derivatives across the plasma membrane and plays pivotal roles in cancer cell proliferation, immune response and drug delivery across the blood-brain barrier. Despite recent advances in structural understanding of LAT1, how it discriminates substrates and inhibitors including the clinically relevant anticancer drugs remains elusive. Here we report six structures of LAT1, captured in three different conformations and bound with diverse bioactive ligands, elucidating its substrate transport and inhibitory mechanisms. JPH203, also known as nanvuranlat or KYT-0353 and currently in clinical trials as an anticancer drug, binds to the wide-open substrate-binding pocket of LAT1. It adopts a U-shaped conformer, with its amino-phenylbenzoxazol moiety pushing against transmembrane helix 3 (TM3), bending TM10 and arresting the transporter in the outward-facing conformation. In contrast, the physiological substrate L-Phe does not exhibit such inhibitory interactions, whereas melphalan, a slow substrate, poses steric hindrance in the pocket, explaining its inhibitory activity. Unexpectedly, the “classical” system L inhibitor BCH induces an occluded state, a key structural intermediate required for substrate transport.Transstimulation assays show that BCH facilitates transporter turnover and is therefore a transportable substrate. These findings provide a structural framework for the intricate mechanisms of substrate recognition and inhibition of LAT1, paving the way for developing more specific and effective drugs against it.

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Section: Jph203 Binds To the Outward-open Pocket Of Lat1supporting

confidence: 81%

Structural basis of anticancer drug recognition and amino acid transport by LAT1

Lee,

Jin,

Ohgaki

et al. 2023

Preprint

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“…To further understand the complex relationship between trophoblast differentiation and SLC7A5/3A2, we investigated their protein and functional expression in CTB and STB cells. In line with our previous reports (Zaugg et al, 2020a), we show that the expression of these proteins and uptake of leucine (SLC7A5 substrate) is significantly enhanced in STB compared to the CTB cells. These findings suggest that trophoblast differentiation is associated with a parallel upregulated transport capacity.…”

Section: Discussionsupporting

confidence: 93%

“…Emerging evidence highlights that placental transporters may participate in intracellular signaling and cell differentiation ( Apáti et al, 2016 ; Bloise et al, 2016 ). Nonetheless, while there is a general concept that the STB represents the main transport surface in the fetoplacental unit, only a limited number of studies have investigated the transport capacities of trophoblast cells in relation to their differentiation state ( Evseenko et al, 2006 ; Kallol et al, 2018a ; Kallol et al, 2018b ; Zaugg et al, 2020a ).…”

Section: Introductionmentioning

confidence: 99%

Trophoblast Differentiation Affects Crucial Nutritive Functions of Placental Membrane Transporters

Karahoda

Zaugg²,

Fuenzalida³

et al. 2022

Front. Cell Dev. Biol.

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Cytotrophoblasts are progenitor cells that proliferate and fuse to form the multinucleated syncytiotrophoblast layer, implicated in placental endocrine and transport functions. While membrane transporters play a critical role in the distribution of nutrients, hormones, and xenobiotics at the maternal-fetal interface, their selectivity to the syncytiotrophoblast layer is poorly characterized. We aimed to evaluate the regulation of placental transporters in response to trophoblast differentiation in vitro. Experiments were carried out in isolated primary human trophoblast cells before and after syncytialization. Gene expression of six molecular markers and thirty membrane transporters was investigated by qPCR analysis. Subsequently, functional expression was evaluated for proteins involved in the transplacental transfer of essential nutrients i.e., cholesterol (ABCA1, ABCG1), glucose (SLC2A1), leucine (SLC3A2, SLC7A5), and iron (transferrin receptor, TfR1). We identified that human chorionic gonadotropin, placental lactogen, endoglin, and cadherin-11 serve as optimal gene markers for the syncytialization process. We showed that trophoblast differentiation was associated with differential gene expression (mostly up-regulation) of several nutrient and drug transporters. Further, we revealed enhanced protein expression and activity of ABCG1, SLC3A2, SLC7A5, and TfR1 in syncytialized cells, with ABCA1 and GLUT1 displaying no change. Taken together, these results indicate that the syncytiotrophoblast has a dominant role in transporting essential nutrients cholesterol, leucine, and iron. Nonetheless, we present evidence that the cytotrophoblast cells may also be linked to transport functions that could be critical for the cell fusion processes. Our findings collectively yield new insights into the cellular functions associated with or altered by the trophoblast fusion. Importantly, defective syncytialization could lead to nutrient transfer imbalance, ultimately compromising fetal development and programming.

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“…In pancreatic cancer, LAT2 ( SLC7A8 ) was shown to decrease gemcitabine sensitivity by regulating glutamine-dependent mTOR activation to promote proliferation and inhibit apoptosis (Feng et al, 2018 ). Recently, several specific small molecule inhibitors of LAT1 ( SLC7A5 ) and LAT2 ( SLC7A8 ) have been discovered, which facilitate the clinical application of system L transporters ( Table 1 ; Zaugg et al, 2020 ).…”

Section: Amino Acid Metabolism In Cancermentioning

confidence: 99%

Metabolism of Amino Acids in Cancer

Wei

Liu

Cheng

et al. 2021

Front. Cell Dev. Biol.

205

193

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Metabolic reprogramming has been widely recognized as a hallmark of malignancy. The uptake and metabolism of amino acids are aberrantly upregulated in many cancers that display addiction to particular amino acids. Amino acids facilitate the survival and proliferation of cancer cells under genotoxic, oxidative, and nutritional stress. Thus, targeting amino acid metabolism is becoming a potential therapeutic strategy for cancer patients. In this review, we will systematically summarize the recent progress of amino acid metabolism in malignancy and discuss their interconnection with mammalian target of rapamycin complex 1 (mTORC1) signaling, epigenetic modification, tumor growth and immunity, and ferroptosis. Finally, we will highlight the potential therapeutic applications.

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Small molecule inhibitors provide insights into the relevance of LAT1 and LAT2 in materno‐foetal amino acid transport

Cited by 11 publications

References 60 publications

Structural basis of anticancer drug recognition and amino acid transport by LAT1

Structural basis of anticancer drug recognition and amino acid transport by LAT1

Trophoblast Differentiation Affects Crucial Nutritive Functions of Placental Membrane Transporters

Metabolism of Amino Acids in Cancer

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