July 6, 2021
Office of The Director, National Institutes of Health (OD)
This request for information (RFI) seeks comments regarding currrent bioinformatic tools and future needs for analyzing Solute Carrier and ATP-Binding Cassette (ABC) transmembranetransport proteins (transporters).
Improving the bioinformatics of nutrition related genes is Objective 1-1 of the Strategic Plan for NIH Nutrition Research. As well as improved bioinformatic tools and methods this endeavor will likely benefit from coordinating novel functional experimental data related to transmembrane transporters.
The proteins of interest for this RFI are largely the product the products of two large gene families, the Solute Carrier (SLC) and ATP-Binding Cassette (ABC) family of genes. The SLC group has over 400 members in 66 subfamilies [i]. SLC proteins transport the widest variety of molecules across the plasma membrane and intracellular membranes by facilitated diffusion (e.g., SLC2A1) or secondary active transport (e.g., SLC5A2). For the human ABC proteins, 49 genes have been reported and organized into 7 sequence and domain homology subfamilies [i],[ii],[iii].
While the function of transmembrane transporters is essential for life and for nutrient and therapeutic drug disposition, few have been systematically characterized, and for many transporters the endogenous or range of substrate is not known or poorly understood. This is a significant knowledge gap because many of these genes have significant clinical correlations or allelic variants related to specific pathologies in humans and may act as therapeutic targets or have other translational relevance. The need to improve the characterization of transporters and evaluate their potential impact on precision nutrition and medicine by using novel experimental and bioinformatics approaches has been widely recognized [iv],[v],[vi],[vii],[viii],[ix],[x],[xi].
Transporters. Transporters are required for the transmembrane movement of substrates that are both endogenous (metabolites and other nutrients) and exogenous (nutrients, metabolites, other dietary components, xenobiotics, drugs and other ingested compounds and metals, etc.).Transporters are not only responsible for movement through epithelial barriers and the plasma membrane of cells but can also transport molecules between intracellular membranes of cellular organelles.
The proteins of interest for this RFI are largely the product the products of two large gene families, the Solute Carrier (SLC) and ATP-Binding Cassette (ABC) family of genes. The SLC group has over 400 members in 66 subfamilies i. SLC proteins transport the widest variety of molecules across the plasma membrane and intracellular membranes by facilitated diffusion (e.g., SLC2A1) or secondary active transport (e.g., SLC5A2). For the human ABC proteins, 49 genes have been reported and organized into 7 sequence and domain homology subfamilies ii,iii.
While the function of transmembrane transporters is essential for life and for nutrient and therapeutic drug disposition, few have been systematically characterized, and for many transporters the endogenous or range of substrate is not known or poorly understood. This is asignificant knowledge gap because many of these genes have significant clinical correlations orallelic variants related to specific pathologies in humans and may act as therapeutic targets or have other translational relevance. The need to improve the characterization of transporters and evaluate their potential impact on precision nutrition and medicine by using novelexperimental and bioinformatics approaches has been widely recognized iv,v,vi,vii,viii,ix,x,xi.
For this RFI, transporter analytics may describe a variety of approaches and methods used to define their range of substrates or other characteristics such as relative affinity and/or maximal flux per unit membrane area at high substrate concentrations. Additionally, novel functional data and bioinformatic methods that allow prediction of metabolite, nutrient, drug, and chemical flux to and within specific tissues is of interest. Modeling efforts will need to incorporate factors such as specificity of individual transporters for those substrates, their transport capacity, and polarity of transport across inter- and subcellular membranes.
Bioinformatics. Bioinformation related to transporter genes, messenger RNAs and their protein products are annotations often found in gene/protein databases such as genecards.org and NCBI. This “bioinformation” includes but is not limited to:
The NIH seeks input from researchers, academic institutions, professional societies, patient advocacy groups, pharmaceutical companies and other stakeholders on opportunities and gaps related to bioinformatic and experimental research needs for human Solute Carrier (SLC) and ATP-binding cassette (ABC) transporters. We invite comments on any or all the following areas:
Approaches that could be used to identify the endogenous solutes of transporters, where that is not known.
The relative importance of systematically characterizing the range of solutes including endogenous or exogenous for each transporter.
The relative need for systematic structural characterization (e.g., by cryo-EM or other approaches).
Experimental and bioinformatic techniques that can functionally characterize transporters in human tissue and high priority cell types.
The research needs around allelic or copy number variants, genetic and post-translational regulation, inhibitors, and activators of transporters.
Tools or resources that the community feels would be helpful to develop.
Any other issues that respondents feel are relevant.
[i] Perland E, Fredriksson R (March 2017). "Classification Systems of Secondary Active Transporters".Trends in Pharmacological Sciences.38(3): 305–315.doi:10.1016/j.tips.2016.11.008.PMID27939446.
[ii] Wilkens S. Structure and mechanism of ABC transporters.F1000Prime Rep. 2015;7:14. Published 2015 Feb 3. doi:10.12703/P7-14
[iii] Juan-Carlos PM, Perla-Lidia PP, Stephanie-Talia MM, Mónica-Griselda AM, Luz-María TE. ABC transporter superfamily. An updated overview, relevance in cancer multidrug resistance and perspectives with personalized medicine. Mol Biol Rep. 2021 Feb;48(2):1883-1901. doi: 10.1007/s11033-021-06155-w. Epub 2021 Feb 22. PMID: 33616835.
[iv] César-Razquin A, Snijder B, Frappier-Brinton T, Isserlin R, Gyimesi G, Bai X, Reithmeier RA, Hepworth D, Hediger MA, Edwards AM, Superti-Furga G. A Call for Systematic Research on Solute Carriers. Cell. 2015 Jul 30;162(3):478-87. doi: 10.1016/j.cell.2015.07.022. PMID: 26232220.
[v] Tina Schumann,Jörg König,Christine Henke,Diana M. Willmes,Stefan R. Bornstein,Jens Jordan,Martin F. FrommandAndreas L. Birkenfeld. SLC Transporters as Targets to Treat Metabolic Disease, Pharmacological ReviewsJanuary 1, 2020,72(1)343-379;DOI: https://doi.org/10.1124/pr.118.015735
[vi] Hughes MMK, Aryal E, Safari E, Mojsoska B, Jenssen H, Prabhala BK. Current State of SLC and ABC Transporters in the Skin and Their Relation to Sweat Metabolites and Skin Diseases. Proteomes. 2021 May 16;9(2):23. doi: 10.3390/proteomes9020023. PMCID: PMC8163169.
[vii] Kell DB. Implications of endogenous roles of transporters for drug discovery: hitchhiking and metabolite-likeness. Nat Rev Drug Discov. 2016 Feb;15(2):143. doi: 10.1038/nrd.2015.44. PMID: 26837595.
[viii] Lin L, Yee SW, Kim RB, Giacomini KM. SLC transporters as therapeutic targets: emerging opportunities. Nat Rev Drug Discov. 2015 Aug;14(8):543-60. doi: 10.1038/nrd4626. Epub 2015 Jun 26. PMID: 26111766.
[ix] Stieger B, Hagenbuch B. Recent advances in understanding hepatic drug transport. F1000Res. 2016 Oct 6;5:2465. doi: 10.12688/f1000research.9466.1. PMID: 27781095.
[x] Brouwer KL, Aleksunes LM, Brandys B, Giacoia GP, Knipp G, Lukacova V, Meibohm B, Nigam SK, Rieder M, de Wildt SN; Pediatric Transporter Working Group. Human Ontogeny of Drug Transporters: Review and Recommendations of the Pediatric Transporter Working Group. Clin Pharmacol Ther. 2015 Sep;98(3):266-87. doi: 10.1002/cpt.176. PMID: 26088472.
[xi] Walker N, Filis P, Soffientini U, Bellingham M, O'Shaughnessy PJ, Fowler PA. Placental transporter localization and expression in the Human: the importance of species, sex, and gestational age differences†. Biol Reprod. 2017 Apr 1;96(4):733-742. doi: 10.1093/biolre/iox012. PMID: 28339967.
Responses will be accepted through August 30, 2021.
Responses must be submitted via email to firstname.lastname@example.org, either within the body of the email or as an attachment (PDF or MS Word). No forms are required, or page limits have been instituted. Respondent comments do not have to address all of the above items, but in that case, it would be appreciated if the specific request was reiterated with the response.
This RFI is for planning purposes only and should not be construed as a solicitation for applications or as an obligation on the part of the Government to provide support for any ideas identified in response to it. Please note that the United States Government will not pay for the preparation of any information submitted or for its use of that information. The NIH will use the information submitted in response to this RFI at its discretion and will not provide comments to any responder's submission. Responses to the RFI may be reflected in future funding opportunity announcements and will be used in the long-term planning for the Office of Nutrition Research. Responses will be compiled and shared internally with Nutrition Research Implementation Working Groups convened by the NIH, as appropriate. In all cases where responses are shared, unless the respondent indicates otherwise, the names of the respondents will be withheld. We look forward to your input and hope that you will share this document with your colleagues.
Name: Christopher Lynch, Ph.D
IC Name: OD/Office of Nutrition Research (ONR)