Insights into solute carriers: physiological functions and implications in disease and pharmacokinetics

Estudante, Margarida; Soveral, Graça; Morais, José; Benet, Leslie Z.

doi:10.1039/c6md00188b

Cited by 13 publications

(10 citation statements)

References 155 publications

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“…SLCs are divided into subfamilies based on sequence similarity and have been shown to transport a variety of molecules, ranging from nucleotides, sugars and lipids to amino acids and peptides 3 , 5 , often with overlapping specificities. Consistent with their critical role in drug absorption and excretion, considerable knowledge has accumulated on a few large subfamilies of SLCs prevalently expressed in kidney, liver and intestine, such as the SLC22 and SLCO families 7 , 8 . There is ample consensus in ascribing an important role for these transporters in affecting pharmacokinetics of several drugs, which has been corroborated by a number of pharmacogenomic polymorphisms 9 .…”

Section: Introductionmentioning

confidence: 99%

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

et al. 2020

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Solute Carriers (SLCs) represent the largest family of transmembrane transporters in humans and constitute major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in a haploid human cell line against 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using an SLC-focused CRISPR/Cas9 library, we identified transporters whose absence induced resistance to the drugs tested. This included dependencies involving the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the compounds screened suggests a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provides an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.

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Section: Introductionmentioning

confidence: 99%

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

et al. 2020

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“…SLCs are divided into subfamilies based on sequence similarity and have been shown to transport a variety of molecules, ranging from nucleotides, sugars and lipids to amino acids and peptides 3,5 , often with overlapping specificities. Consistent with their critical role in drug absorption and excretion, considerable knowledge has accumulated on a few large subfamilies of SLCs prevalently expressed in kidney, liver and intestine, such as the SLC22 and SLCO families 7,8 . There is ample consensus in ascribing an important role for these transporters in governing pharmacokinetics of several drugs, which has been corroborated by several pharmacogenomic polymorphisms 9 .…”

Section: Introductionmentioning

confidence: 99%

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

Gottardi

César-Razquin

Παπακώστας

et al. 2019

Preprint

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The activity and potency of a drug is inherently affected by the metabolic state of its target cell.Solute Carriers (SLCs) represent the largest family of transmembrane transporters in humans and constitute major determinants of cellular metabolism. Several SLCs have been shown to be required for the uptake of individual chemical compounds into cellular systems, but systematic surveys of transporter-drug relationships in human cells are currently lacking. We performed a series of genetic screens in the haploid human cell line HAP1 using a set of 60 cytotoxic compounds representative of the chemical space populated by approved drugs. By using a SLC-focused CRISPR/Cas9 lentiviral library, we identified transporters whose absence induced resistance to the drugs tested. Among the hundreds of drug-SLC relationships identified, we confirmed the role of the folate transporter SLC19A1 on the activity of antifolates and of SLC29A1 on several nucleoside analogs. Among the newly discovered dependencies, we identified the transporters SLC11A2/SLC16A1 for artemisinin derivatives and SLC35A2/SLC38A5 for cisplatin. The functional dependence on SLCs observed for a significant proportion of the compounds screened suggested a widespread role for SLCs in the uptake and cellular activity of cytotoxic drugs and provided an experimentally validated set of SLC-drug associations for a number of clinically relevant compounds.

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“…The lack of information on this family makes it difficult to form a precise hypothesis on what (if any) adaptive role the SLC33 family expansion may play in aphids. The SLC22 family has been more thoroughly studied and has been linked to drug transport in humans ( Estudante et al. 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…2018 ). In mammals, a role for SLCs in drug transport is well established and widespread ( Estudante et al. 2016 ; Girardi et al.…”

Section: Discussionmentioning

confidence: 99%

The Identification and Evolutionary Trends of the Solute Carrier Superfamily in Arthropods

Denecke

Driva

Lương

et al. 2020

Genome Biology and Evolution

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The Solute Carrier (SLC) transporter superfamily comprises an ancient and ubiquitous group of proteins capable of translocating a range of nutrients, endogenous molecules, and xenobiotics. Although the group has been the subject of intense investigation and identification in both bacteria and mammals, its systematic investigation in arthropods has not yet been undertaken. Here, we present a genome-wide identification of all 66 SLC families in 174 arthropod species. A pipeline (SLC_id) was constructed to identify and group SLCs using a combination of hidden Markov model and BLAST searches followed by filtering based on polypeptide length and the number of transmembrane domains. Comparative analysis of the number of transporters in each family across diverse arthropod lineages was accomplished using one-way analysis of variance (ANOVA) and the Computational Analysis of Family Expansion (CAFE). These results suggested that many SLC families have undergone expansions or contractions in particular evolutionary lineages. Notably, the sugar transporting SLC2 family was significantly larger in insects compared to arachnids. This difference may have been complemented by a rapid expansion of the SLC60 family in arachnids which also acts on dietary sugars. Furthermore, the SLC33 family underwent a recent and drastic expansion in aphids, although the biological relevance of this expansion was not possible to infer. Information on specific SLC transporter families across arthropod species can be accessed through an R shiny web application at http://chrysalida.imbb.forth.gr:3838/Arthropod_SLC_Database/. The present study greatly facilitates further study of the understudied and diverse group of SLC transporters in arthropods.

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Insights into solute carriers: physiological functions and implications in disease and pharmacokinetics

Cited by 13 publications

References 155 publications

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

A widespread role for SLC transmembrane transporters in resistance to cytotoxic drugs

The Identification and Evolutionary Trends of the Solute Carrier Superfamily in Arthropods

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