The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond

  title={The SLC16 gene family—from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond},
  author={Andrew P. Halestrap and David Meredith},
  journal={Pfl{\"u}gers Archiv},
The monocarboxylate cotransporter (MCT) family now comprises 14 members, of which only the first four (MCT1–MCT4) have been demonstrated experimentally to catalyse the proton-linked transport of metabolically important monocarboxylates such as lactate, pyruvate and ketone bodies. SLC16A10 (T-type amino-acid transporter-1, TAT1) is an aromatic amino acid transporter whilst the other members await characterization. MCTs have 12 transmembrane domains (TMDs) with intracellular N- and C-termini and… 

The monocarboxylate transporter family—Structure and functional characterization

Site‐directed mutagenesis has identified key residues required for catalysis and inhibitor binding and enabled the development of a molecular model of MCT1 in both inward and outward facing conformations, which suggests a likely mechanism for the translocation cycle.

The SLC16 monocaboxylate transporter family

The MCT proteins have the typical twelve transmembrane-spanning domain (TMD) topology of membrane transporter proteins, and their structure–function relationship is discussed, especially in relation to the future impact of the single nucleotide polymorphism (SNP) databases and, given their ability to transport pharmacologically relevant compounds, the potential impact for pharmacogenomics.

Overview of the Proton-coupled MCT (SLC16A) Family of Transporters: Characterization, Function and Role in the Transport of the Drug of Abuse γ-Hydroxybutyric Acid

Emerging evidence suggests that in addition to endogenous substrates, MCTs are involved in the transport of pharmaceutical agents, including γ-Hydroxybuytrate (GHB), 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), salicylic acid, and bumetanide.

The monocarboxylate transporter family—Role and regulation

The recent discovery of potent and specific MCT1 inhibitors that prevent proliferation of T‐lymphocytes confirms that MCTs may be promising pharmacological targets including for cancer chemotherapy.

Monocarboxylic acid transport.

Some disease states are associated with modulation of plasma membrane and mitochondrial monocarboxylate transport and MCTs are promising drug targets for cancer chemotherapy and may also be involved in drug uptake from the intestine and subsequent transport across the blood brain barrier.

Role of monocarboxylate transporters in drug delivery to the brain.

This review will focus on utilization of MCTs as potential targets for drug delivery into the brain including their role in the treatment of malignant brain tumors and the physiological role of these transporters in the brain.

Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease

A summary of the current literature focusing on the characterization, function, and regulation of the MCT family isoforms and on their roles in drug disposition and in health and disease is provided.

Monocarboxylate transporters as targets and mediators in cancer therapy response.

MCTs can act as "Trojan horses", as their elevated expression in cancer cells can mediate the entry of this chemotherapeutic agent into the cells and selectively kill cancer cells, and their expression can be used as a molecular marker to predict response to chemotherapy.

Monocarboxylate transporters: past, present, and future.

The 14 members of the Monocarboxylate transporter family (MCTs), their relationship based on sequence homology is reviewed, and several candidate or proven genetic diseases that have arisen from MCT mutations are noted.

Monocarboxylate transporters in the central nervous system: distribution, regulation and function

New data indicate that MCT expression is regulated at the translational level by neurotransmitters, suggesting a particular role of monocarboxylates and their transporters in synaptic transmission.



The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation.

There is still much work to be done to characterize the properties of the different MCT isoforms and their regulation, which may have wide-ranging implications for health and disease.

The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells.

Rat MCT4 was identified as the major isoform of white muscle cells, mediating lactate efflux out of glycolytically active myocytes and was sensitive to inhibition by the thiol reagent p-chloromercuribenzoesulphonic acid.

Human Monocarboxylate Transporter 2 (MCT2) Is a High Affinity Pyruvate Transporter*

The finding that co-expression of human MCT1 and MCT2 at the mRNA level in human cancer cell lines, including the hematopoietic lineages HL60, K562, MOLT-4, and Burkitt’s lymphoma Raji, andSolid tumor cells such as SW480, A549, and G361, suggest that the two monocarboxylate transporters have distinct biological roles.

Determination of transport kinetics of chick MCT3 monocarboxylate transporter from retinal pigment epithelium by expression in genetically modified yeast.

MCT3 was highly resistant to a number of "classical" inhibitors of lactate transport, and studies with diethyl pyrocarbonate and p-chloromercuribenzenesulfonate set limitations on the locus of potential residues involved in the critical site of lactates translocation.

Characterisation of human monocarboxylate transporter 4 substantiates its role in lactic acid efflux from skeletal muscle

The characterisation of MCT4 expressed in Xenopus oocytes shows that the protein was correctly targeted to the plasma membrane and rates of substrate transport were determined from the rate of intracellular acidification monitored with the pH‐sensitive dye 2′,7′‐bis‐( carboxyethyl)‐5(6)‐carboxyfluorescein (BCECF).

Transport of lactate and other monocarboxylates across mammalian plasma membranes.

There are distinct Na(+)-monocarboxylate cotransporters on the luminal surface of intestinal and kidney epithelia, which enable active uptake of lactate, pyruvate, and ketone bodies in these tissues.

Characterization of the high-affinity monocarboxylate transporter MCT2 in Xenopus laevis oocytes.

It is suggested that cells which express MCT2 preferentially use lactate and ketone bodies as energy sources, and could be inhibited by alpha-cyano-4-hydroxycinnamate, anion-channel inhibitors and flavonoids.

Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past.

The identification of new human MCT homologues in the database of expression sequence tags and the cloning and sequencing of four new full-length MCT-like sequences from human cDNA libraries are reported, which are denoted MCT3, MCT4, M CT5 and MCT6.