title: The monocarboxylate transporter family--Structure and functional characterization.
abstract: Monocarboxylate transporters (MCTs) catalyze the proton-linked transport of monocarboxylates such as L-lactate, pyruvate, and the ketone bodies across the plasma membrane. There are four isoforms, MCTs 1-4, which are known to perform this function in mammals, each with distinct substrate and inhibitor affinities. They are part of the larger SLC16 family of solute carriers, also known as the MCT family, which has 14 members in total, all sharing conserved sequence motifs. The family includes a high-affinity thyroid hormone transporter (MCT8), an aromatic amino acid transporter (T-type amino acid transporter 1/MCT10), and eight orphan members yet to be characterized. MCTs were predicted to have 12 transmembrane helices (TMs) with intracellular C- and N-termini and a large intracellular loop between TMs 6 and 7, and this was confirmed by labeling studies and proteolytic digestion. 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. This suggests a likely mechanism for the translocation cycle. Although MCT family members are not themselves glycosylated, MCTs1-4 require association with a glycosylated ancillary protein, either basigin or embigin, for their correct translocation to the plasma membrane. These ancillary proteins have a single transmembrane domain and two to three extracellular immunoglobulin domains. They must remain closely associated with MCTs1-4 to maintain transporter activity. MCT1, MCT3, and MCT4 bind preferentially to basigin and MCT2 to embigin. The choice of binding partner does not affect substrate specificity or kinetics but can influence inhibitor specificity.
authors: School of Biochemistry, Medical Sciences Building, University of Bristol, Bristol, UK. a.halestrap@bristol.ac.uk
authors: Andrew P
authors: AP
authors: Halestrap
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D006801:Humans; D027501:Monocarboxylic Acid Transporters / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D002264:Carboxylic Acids; D027501:Monocarboxylic Acid Transporters