The SLC16 gene family - structure, role and regulation in health and disease

Abstract

The SLC16 gene family has fourteen members. Four (SLC16A1, SLC16A3, SLC16A7, and SLC16A8) encode monocarboxylate transporters (MCT1, MCT4, MCT2, and MCT3, respectively) catalysing the proton-linked transport of monocarboxylates such as l-lactate, pyruvate and ketone bodies across the plasma membrane. SLC16A2 encodes a high affinity thyroid hormone transporter (MCT8) and SLC16A10 an aromatic amino acid transporter (TAT1). The substrates and roles of the remaining eight members are unknown. All family members are predicted to have 12 transmembrane helices (TMs) with intracellular C- and N-termini and a large intracellular loop between TMs 6 and 7. This topology has been confirmed for MCT1 and a three-dimensional structure has been modelled that suggests a plausible molecular mechanism. For correct plasma membrane expression and activity MCTs1-4, but not MCT8, require association with basigin or embigin; these are glycoproteins with a single TM and 2-3 extracellular immunoglobulin domains. SLC16 family members are involved in a wide range of metabolic pathways including energy metabolism of the brain, skeletal muscle, heart and tumour cells, gluconeogenesis, T-lymphocyte activation, bowel metabolism, spermatogenesis, pancreatic β-cell malfunction, thyroid hormone metabolism, and drug transport. MCTs 1-4 have distinct properties, tissue distribution and subcellular localisation that are appropriate for these metabolic roles. Their potential as pharmacological targets has been recognised with the discovery of potent and specific MCT1 inhibitors that act as immunosuppressant drugs by preventing proliferation of T-lymphocytes. It is suggested that the development of other drugs specifically targeting different MCT isoforms may provide a novel approach to cancer chemotherapy.