Classification Systems of Secondary Active Transporters

doi:10.1016/j.tips.2016.11.008

Trends in Pharmacological Sciences

Volume 38, Issue 3, March 2017, Pages 305-315

https://doi.org/10.1016/j.tips.2016.11.008 Get rights and content

Trends

SLCs are crucial for maintaining homeostasis within the body as they control molecular trafficking across cellular lipid membranes. SLCs are also implicated in several diseases and they constitute possible drug targets.

There are fewer publications on SLCs than on other protein families, showing that the SLC family is understudied. Systematic research has been requested within the field.

There are several SLC classification systems in use, to facilitate efficient communication between researchers.

However, the many classification systems result in ambiguities and misunderstandings.

Understanding the different classification systems in use today aids a systematic approach on SLC research and should be considered when studying disease processes or novel potential drug targets.

Membrane-bound solute carrier (SLC) transporter proteins are vital to the human body, as they sustain homeostasis by moving soluble molecule as nutrients, drugs, and waste across lipid membranes. Of the 430 identified secondary active transporters in humans, 30% are still orphans, and systematic research has been requested to elaborate on their possible involvement in diseases and their potential as drug targets. To enable this, the various classification systems in use must be understood and used correctly. In this review, we describe how various classification systems for human SLCs are constructed, and how they overlap and differ. To facilitate communication between researchers and to avoid ambiguities, everyone must clearly state which classification system they are referring to when writing scientific articles.

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

References (31)

A. Cesar-Razquin
A call for systematic research on solute carriers
Cell
(2015)
M.A. Hediger
The ABCs of membrane transporters in health and disease (SLC series): introduction
Mol. Aspects Med.
(2013)
M. Rask-Andersen
Solute carriers as drug targets: current use, clinical trials and prospective
Mol. Aspects Med.
(2013)
A.A. Khan et al.
Heme and FLVCR-related transporter families SLC48 and SLC49
Mol. Aspects Med.
(2013)
R. Fredriksson
The solute carrier (SLC) complement of the human genome: phylogenetic classification reveals four major families
FEBS Lett.
(2008)
M.G. Hagglund
Identification of SLC38A7 (SNAT7) protein as a glutamine transporter expressed in neurons
J. Biol. Chem.
(2011)
M.G. Hagglund
Transport of L-glutamine, L-alanine, L-arginine and L-histidine by the neuron-specific Slc38a8 (SNAT8) in CNS
J. Mol. Biol.
(2015)
S. Sreedharan
Long evolutionary conservation and considerable tissue specificity of several atypical solute carrier transporters
Gene
(2011)
H. Ushijima
Expression and function of TETRAN, a new type of membrane transporter
Biochem. Biophys. Res. Commun.
(2008)
N. Horiba
Na(+)-dependent fructose transport via rNaGLT1 in rat kidney
FEBS Lett.
(2003)

M.D. Marger et al.

A major superfamily of transmembrane facilitators that catalyse uniport, symport and antiport

Trends Biochem. Sci.

(1993)

M.A. Hediger

The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction

Pflugers Arch.

(2004)

L. Lin

SLC transporters as therapeutic targets: emerging opportunities

Nat. Rev. Drug Discov.

(2015)

K.A. Gray

A review of the new HGNC gene family resource

Hum. Genomics

(2016)

P.J. Hoglund

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)

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Trends in Pharmacological Sciences

ReviewClassification Systems of Secondary Active Transporters

Trends

Section snippets

A Unified View of SLC Classification Systems

The HUGO Nomenclature Committee Gives Human SLCs Names Using a Family Root System

TC System Gives Proteins Specific Identity Numbers to Highlight Their Relationship

Identification of Novel Plausible SLC Proteins

Divergences between the Systems, and How They Interact

Concluding Remarks

Acknowledgments

Cell

Mol. Aspects Med.

Mol. Aspects Med.

Mol. Aspects Med.

FEBS Lett.

J. Biol. Chem.

J. Mol. Biol.

Gene

Biochem. Biophys. Res. Commun.

FEBS Lett.

Trends Biochem. Sci.

The ABCs of solute carriers: physiological, pathological and therapeutic implications of human membrane transport proteinsIntroduction

Pflugers Arch.

SLC transporters as therapeutic targets: emerging opportunities

Nat. Rev. Drug Discov.

A review of the new HGNC gene family resource

Hum. Genomics

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.

Review
Classification Systems of Secondary Active Transporters