Monocarboxylate transporters (MCTs): Structure, roles, regulation and potential as therapeutic targets
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1
University of Bristol, School of Biochemistry, United Kingdom
Monocarboxylate transporters (MCTs) catalyse the proton-linked transport of monocarboxylates such as L-lactate, pyruvate and ketone bodies across the plasma membrane. They are members of the SLC16 family, which has fourteen members in total, all of which are predicted to have 12 transmembrane helices arranged in two 6 helix bundles that are linked by a large intracellular loop. Only four members of the family, MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8) and MCT4 (SLC16A3), have been confirmed to mediate proton-linked transport of monocarboxylates. They all require association with an ancillary proteins, either basigin or embigin, for their correct plasma membrane expression. Basigin and embigin are glycoproteins with a single transmembrane helix and 2-3 extracellular immunoglobulin domains.
MCT isoforms are involved in a wide range of metabolic pathways including energy metabolism of the brain, skeletal muscle, heart and tumour cells. In the latter they are essential for the removal of the lactici acid produced by the enhanced glycolysis oberved in tumour cells (The Warburg effect). Each isoform exhibits distinct properties, tissue distribution, subcellular localisation and regulation that are appropriate for these metabolic roles. MCT4 is up-regulated by hypoxia (mediated by HIF1-α) and is the dominant MCT isoform in aggressive tumours that over-express this transcription factor. Specific MCT1 inhibitors have been developed that act as immunosuppressant drugs by preventing proliferation of T-lymphocytes and the development of new drugs specifically targeting MCT4 isoforms may provide a novel approach to cancer chemotherapy. Recent work on the modelling the structure, mechanism and inhibitor binding sites of MCT1 and MCT4 will be described that may help in this process.
References
Halestrap, A. P. (2013) The SLC16 gene family structure, role and regulation in health and disease. Mol Aspects Med 34, 337–349.
Keywords:
Monocarboxylic Acid Transporters,
Lactate,
pH,
Basigin/CD147,
Warburg effect
Conference:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013.
Presentation Type:
Abstract
Topic:
2. Membrane transporter in intracellular and extracellular pH-control
Citation:
Halestrap
AP,
Nancolas
B and
Sessions
RB
(2014). Monocarboxylate transporters (MCTs): Structure, roles, regulation and potential as therapeutic targets.
Front. Pharmacol.
Conference Abstract:
4th Annual Meeting of the International Society of Proton Dynamics in Cancer.
doi: 10.3389/conf.fphar.2014.61.00019
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Received:
14 Jan 2014;
Published Online:
07 Feb 2014.
*
Correspondence:
Prof. Andrew P Halestrap, University of Bristol, School of Biochemistry, Bristol, BS8 1TD, United Kingdom, a.halestrap@bristol.ac.uk