Trends in Pharmacological Sciences
ReviewClassification Systems of Secondary Active Transporters
Section snippets
A Unified View of SLC Classification Systems
The time is right for a coordinated research effort on SLC structures, specificities and functions [1], as research has shown they play crucial roles in health and disease. SLCs are secondary active or facilitated transporters that translocate soluble molecules across cellular membranes [2]. They can use ion gradients to drive uphill transports, work as exchangers, or facilitate passive diffusion of specific molecules [2]. SLCs are vital for maintaining homeostasis in the body and in individual
The HUGO Nomenclature Committee Gives Human SLCs Names Using a Family Root System
The HUGO Gene Nomenclature Committee (HGNC) provides human genes with unique symbols and manually curates the genes into larger families based on function, homology, or phenotype [6]. The database can be found at http://www.genenames.org/ and a search for solute carrier returns 391 SLCs and four pseudogenes (19 July 2016). In the HGNC database, genes are usually grouped under a common root symbol to indicate a family; solute carriers have been given the root SLC. HGNC ensures that a certain
TC System Gives Proteins Specific Identity Numbers to Highlight Their Relationship
The Transporter Classification database (TCDB) (http://www.tcdb.org/) uses both functional and phylogenetic information when creating superfamilies [20]. It is a representative database [21], meaning that if two orthologs or homologs share the same properties, only one item is entered into the database. Therefore, when creating the Online Supplemental Information in Table S1, the TC numbers were obtained primarily from Homo sapiens, but in some cases from Mus musculus and Rattus norvegicus.
TCDB
Identification of Novel Plausible SLC Proteins
Approximately half of the known SLCs belong to the MFS or APC Pfam clan [9], and they have MFS or APC domains. This provides a possibility to search the human genome for proteins containing these domains, as a way to identify novel transporters. Therefore, we used Pfam hidden Markov models (Seed models) to search for MFS and APC proteins among all sequences in the Ensembl database [11] (Ensembl release 84). Subsequently, we removed all sequences originating from the same position on the genome
Divergences between the Systems, and How They Interact
The major difference between the larger systems is that HGNC and SLC tables only include human sequences, whereas both TCDB and Pfam include sequences from multiple species. HGNC also focus on genes, whereas the SLC tables, TCDB and Pfam include proteins. There are also some variations in the number of human SLC entries included in each system: HGNC has 421; the SLC tables have 397; TCDB has 394 and Pfam has 414 of the proteins listed in Online Supplemental Information Table S1. All systems
Concluding Remarks
There was recently a request for systematic research about SLCs [1] to understand more about them, but for this to be effective, we must agree on how to name proteins and on how to classify them into various systems (see Outstanding Questions). In this review, we have described the scope of the most commonly used systems and how they inter-relate. By understanding these systems, potential novel secondary active transporters can be properly classified and assimilated by researchers. The HGNC
Acknowledgments
This work was supported by the Swedish Research Council, Swedish Brain Foundation, Novo Nordisk Foundation, Gunvor and Josef Anérs Foundation, Magnus Bergvalls Foundation, Tore Nilssons Foundation and Åhléns Foundation. We also wish to express special thanks to Dr. Sofie V. Hellsten for help with the amino acid transport systems, to Dr. Karin Nordenankar for critically reading the manuscript, to Emilia Lekholm for the scientific discussions, and to Anders Bergman for final proofreading of the
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