A Call for Systematic Research on Solute Carriers
2015; Cell Press; Volume: 162; Issue: 3 Linguagem: Inglês
10.1016/j.cell.2015.07.022
ISSN1097-4172
AutoresAdrián César‐Razquin, Berend Snijder, Tristan Frappier‐Brinton, Ruth Isserlin, Gergely Gyimesi, Xiaoyun Bai, R.A. Reithmeier, David Hepworth, Matthias A. Hediger, A.M. Edwards, Giulio Superti‐Furga,
Tópico(s)Enzyme Catalysis and Immobilization
ResumoSolute carrier (SLC) membrane transport proteins control essential physiological functions, including nutrient uptake, ion transport, and waste removal. SLCs interact with several important drugs, and a quarter of the more than 400 SLC genes are associated with human diseases. Yet, compared to other gene families of similar stature, SLCs are relatively understudied. The time is right for a systematic attack on SLC structure, specificity, and function, taking into account kinship and expression, as well as the dependencies that arise from the common metabolic space. Solute carrier (SLC) membrane transport proteins control essential physiological functions, including nutrient uptake, ion transport, and waste removal. SLCs interact with several important drugs, and a quarter of the more than 400 SLC genes are associated with human diseases. Yet, compared to other gene families of similar stature, SLCs are relatively understudied. The time is right for a systematic attack on SLC structure, specificity, and function, taking into account kinship and expression, as well as the dependencies that arise from the common metabolic space. Individual cells, be they prokaryotic or eukaryotic, must control chemical exchange with their environments, and they use lipid membranes and proteinaceous channels and transporters to this end. The lipid environment of the membrane prevents intrusion or leakage into the sancta sanctorum of the inner milieu and buffers the cell against changing and noxious environmental conditions, as well as against attack by phages, viruses, or bacteria (Koberlin et al., 2015Koberlin M.S. Snijder B. Heinz L.X. Baumann C.L. Fauster A. Vladimer G.I. Gavin A.C. Superti-Furga G. A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses.Cell. 2015; 162: 170-183Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, Mulkidjanian et al., 2009Mulkidjanian A.Y. Galperin M.Y. Koonin E.V. Co-evolution of primordial membranes and membrane proteins.Trends Biochem. Sci. 2009; 34: 206-215Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar). In many respects, the integrity of the membranes represents as critical an element to cellular individuality as does the preservation and transmission of genetic information (Schrum et al., 2010Schrum J.P. Zhu T.F. Szostak J.W. The origins of cellular life.Cold Spring Harb. Perspect. Biol. 2010; 2: a002212Crossref Scopus (146) Google Scholar). The protein components of cell membranes import and export most of the chemical matter essential for life, including water, ions, gases, nutrients, vitamins, cofactors, and many drugs (Kell et al., 2011Kell D.B. Dobson P.D. Oliver S.G. Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only.Drug Discov. Today. 2011; 16: 704-714Crossref PubMed Scopus (142) Google Scholar, Kell and Oliver, 2014Kell D.B. Oliver S.G. How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion.Front. Pharmacol. 2014; 5: 231Crossref PubMed Google Scholar, Lin et al., 2015Lin L. Yee S.W. Kim R.B. Giacomini K.M. SLC transporters as therapeutic targets: emerging opportunities.Nat. Rev. Drug Discov. 2015; (Published online June 26, 2015)https://doi.org/10.1038/nrd4626Crossref PubMed Scopus (413) Google Scholar). Therefore, regulation of small-molecule transport across membranes is key to a cell’s internal physiology and is the gatekeeper to its interface with the environment (Nigam, 2015Nigam S.K. What do drug transporters really do?.Nat. Rev. Drug Discov. 2015; 14: 29-44Crossref PubMed Scopus (347) Google Scholar). Yet, despite their central role in mediating the discussion between chemistry and biology and despite the fact that ∼10% of the human genome encodes for transport-related functions (Hediger et al., 2013Hediger M.A. Clemencon B. Burrier R.E. Bruford E.A. The ABCs of membrane transporters in health and disease (SLC series): introduction.Mol. Aspects Med. 2013; 34: 95-107Crossref PubMed Scopus (376) Google Scholar), transporters, as a class of proteins, do not appear to garner quite the attention that they deserve. Transporters comprise solute carriers, ion channels, water channels, and ATP-driven pumps, including ABC transporters. Of these, the largest group is formed by the solute carrier proteins (SLCs), which according to the current counting comprises 456 members, distributed in 52 subfamilies that can be further phylogenetically grouped (Hediger et al., 2013Hediger M.A. Clemencon B. Burrier R.E. Bruford E.A. The ABCs of membrane transporters in health and disease (SLC series): introduction.Mol. Aspects Med. 2013; 34: 95-107Crossref PubMed Scopus (376) Google Scholar, Hediger et al., 2004Hediger M.A. Romero M.F. Peng J.B. Rolfs A. Takanaga H. Bruford E.A. The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction.Pflugers Arch. 2004; 447: 465-468Crossref PubMed Scopus (738) Google Scholar, Schlessinger et al., 2010Schlessinger A. Matsson P. Shima J.E. Pieper U. Yee S.W. Kelly L. Apeltsin L. Stroud R.M. Ferrin T.E. Giacomini K.M. et al.Comparison of human solute carriers.Protein Sci. 2010; 19: 412-428Crossref PubMed Scopus (79) Google Scholar, Schlessinger et al., 2013bSchlessinger A. Yee S.W. Sali A. Giacomini K.M. SLC classification: an update.Clin. Pharmacol. Ther. 2013; 94: 19-23Crossref PubMed Scopus (60) Google Scholar). SLCs are membrane integral proteins localized on the cell surface and in organellar membranes and comprise facilitative transporters, which are equilibrative, and secondary active transporters (symporters and antiporters), which may be concentrative (Hediger et al., 2013Hediger M.A. Clemencon B. Burrier R.E. Bruford E.A. The ABCs of membrane transporters in health and disease (SLC series): introduction.Mol. Aspects Med. 2013; 34: 95-107Crossref PubMed Scopus (376) Google Scholar). After G-protein-coupled receptors (GPCRs), SLCs are the second-largest family of membrane proteins in the human genome (Hoglund et al., 2011Hoglund P.J. Nordstrom K.J. Schioth H.B. Fredriksson R. The solute carrier families have a remarkably long evolutionary history with the majority of the human families present before divergence of Bilaterian species.Mol. Biol. Evol. 2011; 28: 1531-1541Crossref PubMed Scopus (122) Google Scholar). For detailed information about the individual SLC family members, please refer to www.bioparadigms.org. Much research on SLCs has been spurred by their relevance to pharmacology and drug discovery, either as drug targets themselves or as mediators of drug disposition. Drug targets include SLC6A4 (SERT), the target of the hugely important serotonin uptake inhibitor drug class. Mediators of drug transport include SLCO1B1, which transports statins and allows for preferential drug distribution into the liver compared to other tissues, such as muscle. This tissue distribution of statins is important in driving their therapeutic index by increasing the lipid lowering over the myopathy-causing activity (Giacomini et al., 2010Giacomini K.M. Huang S.M. Tweedie D.J. Benet L.Z. Brouwer K.L. Chu X. Dahlin A. Evers R. Fischer V. Hillgren K.M. et al.Membrane transporters in drug development.Nat. Rev. Drug Discov. 2010; 9: 215-236Crossref PubMed Scopus (2526) Google Scholar). SLC-mediated transport of statins and other drug classes can also render their pharmacokinetics susceptible to drug-drug interactions. For example, naringin from citrus fruits inhibits the enterohepatic transporter SLCO1A2 and thus can reduce the bioavailability of drugs that rely on this transporter, such as fexofenadine (Bailey, 2010Bailey D.G. Fruit juice inhibition of uptake transport: a new type of food-drug interaction.Br. J. Clin. Pharmacol. 2010; 70: 645-655Crossref PubMed Scopus (183) Google Scholar). Transport can also be affected by the natural pharmacogenomic variability in SLCs (Giacomini et al., 2013Giacomini K.M. Balimane P.V. Cho S.K. Eadon M. Edeki T. Hillgren K.M. Huang S.M. Sugiyama Y. Weitz D. Wen Y. et al.International Transporter Consortium commentary on clinically important transporter polymorphisms.Clin. Pharmacol. Ther. 2013; 94: 23-26Crossref PubMed Scopus (124) Google Scholar). Other SLCs have been studied for their roles in physiology, like SLC25A7 (UCP1), the mitochondrial uncoupling protein involved in the thermogenesis process of brown adipose tissue. Newer research has implicated SLCs in the action of chemotherapeutics; YM155, a cancer drug in clinical evaluation, was found to be completely dependent on SLC35F2 for entry into human tumor cells (Winter et al., 2014Winter G.E. Radic B. Mayor-Ruiz C. Blomen V.A. Trefzer C. Kandasamy R.K. Huber K.V. Gridling M. Chen D. Klampfl T. et al.The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity.Nat. Chem. Biol. 2014; 10: 768-773Crossref PubMed Scopus (122) Google Scholar). Increasingly, SLCs are attracting attention because they mediate drug-drug and nutrient-drug interactions. For instance, the investigational JAK2 inhibitor fedratinib, which was recently terminated from development due to incidence of Wernicke’s encephalopathy during trials, has been shown to inhibit thiamine uptake mediated by SLC19A2 (hTHTR2), possibly contributing to the offside effects (Zhang et al., 2014Zhang Q. Zhang Y. Diamond S. Boer J. Harris J.J. Li Y. Rupar M. Behshad E. Gardiner C. Collier P. et al.The Janus kinase 2 inhibitor fedratinib inhibits thiamine uptake: a putative mechanism for the onset of Wernicke’s encephalopathy.Drug Metab. Dispos. 2014; 42: 1656-1662Crossref PubMed Scopus (79) Google Scholar). It would not be surprising if further unplanned SLC-drug interactions were uncovered in the future. There is also growing interest in SLCs because of their clear genetic link to human diseases; about 190 different SLCs have been found mutated in human disease and through genome-wide association studies (Williams et al., 2012Williams A.J. Harland L. Groth P. Pettifer S. Chichester C. Willighagen E.L. Evelo C.T. Blomberg N. Ecker G. Goble C. et al.Open PHACTS: semantic interoperability for drug discovery.Drug Discov. Today. 2012; 17: 1188-1198Crossref PubMed Scopus (240) Google Scholar, Williams et al., 2014Williams A.L. Jacobs S.B. Moreno-Macias H. Huerta-Chagoya A. Churchhouse C. Marquez-Luna C. Garcia-Ortiz H. Gomez-Vazquez M.J. Burtt N.P. Aguilar-Salinas C.A. et al.Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.Nature. 2014; 506: 97-101Crossref PubMed Scopus (334) Google Scholar). Our sense was that the SLC protein family, despite its clear relevance to health and disease, was comparatively less well studied than other gene families. In an attempt to quantify “SLC knowledge” versus other gene families, we surveyed the literature and analyzed the distribution of publications as reported by NCBI for each gene family annotated by HGNC in an automated, unbiased fashion (Bruford et al., 2008Bruford E.A. Lush M.J. Wright M.W. Sneddon T.P. Povey S. Birney E. The HGNC Database in 2008: a resource for the human genome.Nucleic Acids Res. 2008; 36: D445-D448Crossref PubMed Scopus (192) Google Scholar). We then visualized the publication asymmetry, defined by the coefficient of skewness, versus the average number of publications for each family (Figure 1A). SLCs show by far the greatest publication asymmetry of all gene families, i.e., the most uneven distribution of papers over the group members. This does not seem to be simply due to a bias against membrane proteins in general, as ABC proteins, ion channels, and GPCRs appear not so unevenly distributed. Further, SLCs have an average number of publications per member of around 35, which is half of what is observed on average over all families (66 publications). At the other end of the spectrum, one finds, among others, that the small TNF superfamily of ligands are all equally and very well studied. We then analyzed the asymmetry within the SLC knowledge domain. We performed an automated search for publications per each of the 456 SLC genes (including 65 pseudogenes), which indeed displayed a highly skewed SLC knowledge distribution curve (Figure 1B). A manually annotated search revealed the same general pattern (Figure S1B). Both analyses reveal that some gene members are extremely well studied, whereas most have very few publications. In a phenomenon that appears to be general to all human protein families, the most well-studied SLCs in the last 2 years are almost identical to those that were the most well studied a decade ago (Edwards et al., 2011Edwards A.M. Isserlin R. Bader G.D. Frye S.V. Willson T.M. Yu F.H. Too many roads not taken.Nature. 2011; 470: 163-165Crossref PubMed Scopus (274) Google Scholar). Prior to 2003, 20 of the ∼400 SLC family members accrued 29% of the publications for the entire family, and those exact same family members garnered 32% of all SLC publications over the period 2012–2014 (Figure S1A). Rankings of the SLC family members do not seem to be indicative of biological relevance. Some of the most well-studied SLCs appear to have become objects of investigation simply due to their abundance and tissue-specific expression in easily isolated cell types, which greatly facilitated their study in the era before molecular biology. Examples of this type include the so-called “band 3 of erythrocytes” protein (SLC4A1) and the erythrocyte glucose transporter GLUT1 (SLC2A1). An important factor that contributes to the elevated publication rate of particular transporters has been expression cloning. In the case of the intestinal Na+-glucose transporter SGLT1 (SLC5A1), due to its hydrophobic nature and difficulty in purifying, functional expression in Xenopus laevis oocytes finally opened the door to successful cloning and molecular characterization (Hediger et al., 1987Hediger M.A. Coady M.J. Ikeda T.S. Wright E.M. Expression cloning and cDNA sequencing of the Na+/glucose co-transporter.Nature. 1987; 330: 379-381Crossref PubMed Scopus (807) Google Scholar). This progress led to a substantial increase in SLC study, ultimately leading to structural determination (Faham et al., 2008Faham S. Watanabe A. Besserer G.M. Cascio D. Specht A. Hirayama B.A. Wright E.M. Abramson J. The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport.Science. 2008; 321: 810-814Crossref PubMed Scopus (437) Google Scholar) and development of an antidiabetic drug class (Abdul-Ghani and DeFronzo, 2014Abdul-Ghani M.A. DeFronzo R.A. Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport.J. Intern. Med. 2014; 276: 352-363Crossref PubMed Scopus (41) Google Scholar) that acts on its renal homolog SGLT2 (SLC5A2). Other SLCs became highly studied because they were discovered as targets of existing drugs, with VMAT2 (SLC18A2) representing a specific example of this. Reserpine is a drug that was first marketed in the 1950s as a tranquilizer. The actual mode of action of reserpine was only uncovered 40 years later by scoring for cDNAs conferring the ability to sequester the neurotoxin 1-methyl-4-phenylpyridinium (MPP+) in CHO cells, leading to the discovery of the vesicular amine transporter family SLC18 (Liu et al., 1992Liu Y. Peter D. Roghani A. Schuldiner S. Prive G.G. Eisenberg D. Brecha N. Edwards R.H. A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter.Cell. 1992; 70: 539-551Abstract Full Text PDF PubMed Scopus (523) Google Scholar). As an example of how the availability of research tools has influenced SLC research, there were no publications at all on SLC30A8 until its first cloning and expression in 2004 (Chimienti et al., 2004Chimienti F. Devergnas S. Favier A. Seve M. Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules.Diabetes. 2004; 53: 2330-2337Crossref PubMed Scopus (400) Google Scholar). Following this publication and a series of papers genetically linking mutations in this protein with diabetes, in recent years SLC30A8 has become one of the most highly studied SLCs (Rutter and Chimienti, 2015Rutter G.A. Chimienti F. SLC30A8 mutations in type 2 diabetes.Diabetologia. 2015; 58: 31-36Crossref PubMed Scopus (75) Google Scholar). This spike of activity is clearly displayed in Figure S1A. Even more recently, some SLCs that were previously barely studied have been identified to play key roles in physiology. SLC38A9, an SLC recently found to contribute to amino-acid sensing of mTOR, was ranked 288th in the automated ranking of all time SLC publications (Rebsamen et al., 2015Rebsamen M. Pochini L. Stasyk T. de Araujo M.E. Galluccio M. Kandasamy R.K. Snijder B. Fauster A. Rudashevskaya E.L. Bruckner M. et al.SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1.Nature. 2015; 519: 477-481Crossref PubMed Scopus (450) Google Scholar, Wang et al., 2015Wang S. Tsun Z.Y. Wolfson R.L. Shen K. Wyant G.A. Plovanich M.E. Yuan E.D. Jones T.D. Chantranupong L. Comb W. et al.Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1.Science. 2015; 347: 188-194Crossref PubMed Scopus (540) Google Scholar). With the importance of this SLC now clear and tools available to allow its study, one can anticipate an increase in publication rate for this transporter. As for the bottom-ranked 15% of SLC family members, there are more publications in a PubMed search for “star wars” (72 citations) than on these 70 SLCs combined. Regarding SLCs as drug targets, a recent publication suggests 26 different SLCs being the targets of known drugs, or drugs in development (Lin et al., 2015Lin L. Yee S.W. Kim R.B. Giacomini K.M. SLC transporters as therapeutic targets: emerging opportunities.Nat. Rev. Drug Discov. 2015; (Published online June 26, 2015)https://doi.org/10.1038/nrd4626Crossref PubMed Scopus (413) Google Scholar, Rask-Andersen et al., 2013Rask-Andersen M. Masuram S. Fredriksson R. Schioth H.B. Solute carriers as drug targets: current use, clinical trials and prospective.Mol. Aspects Med. 2013; 34: 702-710Crossref PubMed Scopus (68) Google Scholar). A closer inspection using more stringent criteria (FDA-approved drugs whose primary mode of action is considered to be through action on an SLC) revealed just 12 drug classes. Only 8 of these drug classes are believed to act through selective action at a single SLC, while 4 classes are believed to act non-selectively via two or more SLCs. Only 6 further SLCs are targeted by drugs in active development in phase II clinical trials or beyond (Table 1). Several drugs interact with SLCs in addition to their purported primary target, e.g., amiloride (SLC9A1, NHE1) or sulfasalazine (SLC7A11, xCT), but in such examples, it has not been clearly established that these effects contribute to their clinical pharmacology. The GPCR family, in contrast, is a well-established drug target class that has been the subject of systematic drug discovery efforts for half a century. Even when considering the possibility that GPCRs may be intrinsically more relevant as drug targets, the difference between a few SLC targets and ∼100 GPCR targets is likely to reflect a historical bias. Clearly the SLC family is underexplored from the standpoint of drug discovery. Druggability of SLCs appears not to be the main or only barrier here, as the majority of the well-studied SLCs have reported small-molecule inhibitors.Table 1SLCs Specifically Targeted by FDA-Approved Drugs or Drugs in Active DevelopmentDrug StatusSLCCommon Protein NameExamplesApprovedSLC5A2SGLT2canagliflozin; dapagliflozinSLC6A1GAT1tiagabineSLC6A2NETatomoxetineSLC6A3DATmethylphenidateSLC6A4SERTfluoxetine; sertraline; citalopram (SSRIs)SLC12A1/2NKCC1/2furosemide (loop diuretics)SLC12A3NCChydrochlorothiazide (thiazide diuretics)SLC18A1/2VMAT1/2reserpineSLC18A2VMAT2tetrabenazineSLC22 familyOATsprobenecidSLC25A4/5/6ANT1/2/3clodronateSLC29A1ENT1dipyridamolePhase II+ Clinical TrialSLC5A1 (and SLC5A2)SGLT1 (and SGLT2)sotagliflozinSLC6A9GlyT1bitopertinSLC9A3NHE3tenapanorSLC10A2IBATelobixibatSLC22A12URAT1lesinuradSLC40A1Ferroportin-1LY2928057 Open table in a new tab Is it reasonable to expect more SLC-targeting drugs? Around 75% of SLCs are predicted to carry small organic molecules. It has been proposed that proteins that have evolved to bind such species are, on average, privileged with respect to small-molecule druggability (Fauman et al., 2011Fauman E.B. Rai B.K. Huang E.S. Structure-based druggability assessment–identifying suitable targets for small molecule therapeutics.Curr. Opin. Chem. Biol. 2011; 15: 463-468Crossref PubMed Scopus (124) Google Scholar). Experiences thus far appear to support this prediction, with molecules of high ligand efficiency (an indicator or protein druggability) (Hopkins et al., 2014Hopkins A.L. Keseru G.M. Leeson P.D. Rees D.C. Reynolds C.H. The role of ligand efficiency metrics in drug discovery.Nat. Rev. Drug Discov. 2014; 13: 105-121Crossref PubMed Scopus (710) Google Scholar) being identified in the cases where medicinal chemistry efforts have been attempted against SLCs. Even SLCs that carry only inorganic species have been shown to be druggable, including, for example, the SLC12 family targets of the loop and thiazide diuretics. Thus, SLCs appear to offer the rare potential of an underexplored gene family with high disease relevance and general small-molecule druggability. Current thinking in biomedicine and drug discovery contends that human genomics will provide the clues to those genes and proteins of particular relevance to disease and therapy. Accordingly, we looked at all SLC genes that are associated with human disease and counted the number of compounds reported for each (IC50 < 10 μM), using OpenPHACTS, a platform that provides a single access to disease, chemical, and target databases (Ratnam et al., 2014Ratnam J. Zdrazil B. Digles D. Cuadrado-Rodriguez E. Neefs J.M. Tipney H. Siebes R. Waagmeester A. Bradley G. Chau C.H. et al.The application of the open pharmacological concepts triple store (open PHACTS) to support drug discovery research.PLoS ONE. 2014; 9: e115460Crossref PubMed Scopus (29) Google Scholar, Williams et al., 2012Williams A.J. Harland L. Groth P. Pettifer S. Chichester C. Willighagen E.L. Evelo C.T. Blomberg N. Ecker G. Goble C. et al.Open PHACTS: semantic interoperability for drug discovery.Drug Discov. Today. 2012; 17: 1188-1198Crossref PubMed Scopus (240) Google Scholar). 76% of SLCs (145 out of 190) with an already identified disease link have no compound associated with them (Figure S2). It is notable how few SLC targets have more than 100 active compounds against them in the database, likely to represent another measure indicative of how few drug discovery programs have been run against the family. In contrast, the most popular targets of monoamine uptake inhibitors (SLC6A2,3,4) have more than a thousand compounds associated with each, with likely thousands more such compounds in pharmaceutical company collections as a result of extensive drug discovery campaigns against these targets. Of course, it could be argued that involvement of SLC genes in monogenic disorders is a poor reason to call for drug discovery efforts in the corresponding disease areas, as it appears counterintuitive. Yet such arguments need not be always valid, as there is a fundamental difference between life-long genetic loss of function (LOF) and the titrated, reversible pharmacological blockade of a protein. For instance, LOF mutations in the dopamine transporter SLC6A3 lead to early stage Parkinsonism disease (Kurian et al., 2009Kurian M.A. Zhen J. Cheng S.Y. Li Y. Mordekar S.R. Jardine P. Morgan N.V. Meyer E. Tee L. Pasha S. et al.Homozygous loss-of-function mutations in the gene encoding the dopamine transporter are associated with infantile parkinsonism-dystonia.J. Clin. Invest. 2009; 119: 1595-1603PubMed Google Scholar), but SLC6A3 is also a principal target of methlyphenidate and in the treatment of psychiatric disorders. Further, LOF mutations in SLC12A3 have been found associated with Gitelman’s syndrome, characterized by low blood pressure, and SLC12A3 could be mechanistically linked to the action of thiazides that treat hypertension (Brinkman et al., 2006Brinkman R.R. Dube M.P. Rouleau G.A. Orr A.C. Samuels M.E. Human monogenic disorders - a source of novel drug targets.Nat. Rev. Genet. 2006; 7: 249-260Crossref PubMed Scopus (74) Google Scholar). Even if we take a more stringent connection to disease by counting only the genetic mutations in the OMIM database (103 different SLCs) (Amberger et al., 2015Amberger J.S. Bocchini C.A. Schiettecatte F. Scott A.F. Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM(R)), an online catalog of human genes and genetic disorders.Nucleic Acids Res. 2015; 43: D789-D798Crossref PubMed Scopus (1120) Google Scholar), it is clear that the “disease” zones of the SLC network are not covered nearly enough by chemical agents. What might have contributed to this apparent anomaly in the distribution of research attention for the SLC gene family, where some members are well studied and so many members not studied at all? First, a unifying nomenclature has been adopted only recently (Hediger et al., 2013Hediger M.A. Clemencon B. Burrier R.E. Bruford E.A. The ABCs of membrane transporters in health and disease (SLC series): introduction.Mol. Aspects Med. 2013; 34: 95-107Crossref PubMed Scopus (376) Google Scholar, Hediger et al., 2004Hediger M.A. Romero M.F. Peng J.B. Rolfs A. Takanaga H. Bruford E.A. The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction.Pflugers Arch. 2004; 447: 465-468Crossref PubMed Scopus (738) Google Scholar), and as a consequence, common principles and features may have been overlooked. Second, there are a number of technical barriers that may have impeded research in this area. In particular, acquiring competent biological reagents for SLC study can be highly challenging. These are complex integral membrane proteins that are difficult to express and purify and are often poorly detected by typical protocols for mass spectrometry. Accordingly, biochemical, biophysical, and structural biology characterization of SLCs has also been challenging. Indeed, there are so far only three reported human SLC structures (Deng et al., 2014Deng D. Xu C. Sun P. Wu J. Yan C. Hu M. Yan N. Crystal structure of the human glucose transporter GLUT1.Nature. 2014; 510: 121-125Crossref PubMed Scopus (489) Google Scholar, Gruswitz et al., 2010Gruswitz F. Chaudhary S. Ho J.D. Schlessinger A. Pezeshki B. Ho C.M. Sali A. Westhoff C.M. Stroud R.M. Function of human Rh based on structure of RhCG at 2.1 A.Proc. Natl. Acad. Sci. USA. 2010; 107: 9638-9643Crossref PubMed Scopus (158) Google Scholar, Schlessinger et al., 2013aSchlessinger A. Khuri N. Giacomini K.M. Sali A. Molecular modeling and ligand docking for solute carrier (SLC) transporters.Curr. Top. Med. Chem. 2013; 13: 843-856Crossref PubMed Scopus (65) Google Scholar, Deng et al., 2015Deng D. Sun P. Yan C. Ke M. Jiang X. Xiong L. Ren W. Hirata K. Yamamoto M. Fan S. et al.Molecular basis of ligand recognition and transport by glucose transporters.Nature. 2015; (Published online July 15, 2015)https://doi.org/10.1038/nature14655Crossref Scopus (247) Google Scholar) (Table S1). Cell-based systems for studying SLC function can likewise be challenging to obtain, as overexpression can cause toxicity (presumably as a result of metabolic perturbation), and loss- or gain-of-function studies can be confounded by endogenous SLCs with overlapping specificities or by compensatory transport or metabolic effects. Even when cell systems with functionally competent SLCs can be obtained, defining their relevant endogenous substrates is not trivial, and establishing screening assays can be difficult. Third, high-quality antibodies are available for only a few SLCs, with the human protein atlas reporting just 45 SLCs for which they have raised reliable antibodies (Uhlen et al., 2015Uhlen M. Fagerberg L. Hallstrom B.M. Lindskog C. Oksvold P. Mardinoglu A. Sivertsson A. Kampf C. Sjostedt E. Asplund A. et al.Proteomics. Tissue-based map of the human proteome.Science. 2015; 347: 1260419Crossref PubMed Scopus (7243) Google Scholar). As a consequence, the current understanding of the subcellular localization of SLCs, crucial for the interpretation of their function, is indeed partial at best. Finally, the transport assays are often challenging, even for those SLCs with known substrates. Artificial lipid vesicles or microinjected frog oocytes, two other useful assay systems, do not necessarily allow for testing function in the context of the regulatory intricacies, and the latter is not always robust enough for large-scale compound screening. In short, despite the post-genomic era, ample evidence for their important physiological role and their druggability, the systematic and parallel structural and functional interrogation of human SLC proteins has not yet been carried out. Here, we argue that an energetic and detailed exploration of the human “SLCome” is warranted because the family comprises one of the largest “sparse zones” of human biology. Indeed, the concept of the rational filling of sparse zones of knowledge is starting to guide strategies in other collaborative efforts (Rolland et al., 2014Rolland T. Tasan M. Charloteaux B. Pevzner S.J. Zhong Q. Sahni N. Yi S. Lemmens I. Fontanillo C. Mosca R. et al.A proteome-scale map of the human interactome network.Cell. 2014; 159: 1212-1226Abstract Full Text Full Text PDF PubMed Scopus (890) Google Schol
Referência(s)