SLC16 Family: From Atomic Structure to Human Disease

The solute carrier 16 (SLC16) family is a diverse group of monocarboxylate transporters (MCTs). This is reflected in the diversity of transported substrates (e.g., L-lactate, pyruvate, ketone bodies, drugs, metabolites, aromatic amino acids, hormones). Changes in the functionality and loss of function of certain family members are associated with severe health disorders (e.g., cancer, diabetes, neurological disorders, eye diseases). The substrate-bound X-ray structure of the L-lactate-transporting SfMCT represents the first structural information on the SLC16 family and provides insights into the molecular working mechanism of L-lactate-transporting family members. The pharmacologically relevant outward-open conformation of the SfMCT structure can be used as a template for homology modelling of human MCTs. The L-lactate-transporting MCT1 and 4 are important in the metabolism of certain tumors and represent validated drug targets. The solute carrier 16 (SLC16) family represents a diverse group of membrane proteins mediating the transport of monocarboxylates across biological membranes. Family members show a variety of functional roles ranging from nutrient transport and intracellular pH regulation to thyroid hormone homeostasis. Changes in the expression levels and transport function of certain SLC16 transporters are manifested in severe health disorders including cancer, diabetes, and neurological disorders. L-Lactate-transporting SLC16 family members play essential roles in the metabolism of certain tumors and became validated drug targets. This review illuminates the SLC16 family under a new light using structural information obtained from a SLC16 homolog. Furthermore, the role of these transporters in cancer metabolism and how their inhibition can contribute to anticancer therapy are discussed. The solute carrier 16 (SLC16) family represents a diverse group of membrane proteins mediating the transport of monocarboxylates across biological membranes. Family members show a variety of functional roles ranging from nutrient transport and intracellular pH regulation to thyroid hormone homeostasis. Changes in the expression levels and transport function of certain SLC16 transporters are manifested in severe health disorders including cancer, diabetes, and neurological disorders. L-Lactate-transporting SLC16 family members play essential roles in the metabolism of certain tumors and became validated drug targets. This review illuminates the SLC16 family under a new light using structural information obtained from a SLC16 homolog. Furthermore, the role of these transporters in cancer metabolism and how their inhibition can contribute to anticancer therapy are discussed. a variety of congenital (i.e., from birth on) disorders in which hypoglycemia is caused by excessive secretion of insulin. Congenital versions of hyperinsulinism-induced hypoglycemia can be transient or persistent and mild or severe. an oxygen-independent metabolic pathway comprising ten enzyme-catalyzed reactions that convert one mole of glucose into two moles of pyruvate. The released free energy is utilized to generate high-energy molecules of ATP and reduced NADH. members of a large class of eukaryotic receptors; membrane proteins comprising seven transmembrane spanning α-helices. GPCRs convert and amplify an extracellular chemical or physical stimulus into various intracellular signaling cascades, depending on which G protein is bound to the GPCR. a 3D structural model of a protein that is generated in silico based on a template with a known structure that shares sufficient sequence identity with the target protein. If experimentally derived structures of a target protein are not available, homology models can be used; for example, for structure-based drug discovery projects. a pathological condition characterized by the biosynthesis of large amounts of L-lactate in the body. It is associated with an excessively low pH in the bloodstream. It can result from the accumulation of L-lactate due to its excessive production or impaired oxidative metabolism. a pathological metabolic state caused by increased production or impaired clearance of ketone bodies (e.g., acetoacetate, R-3-hydroxybutyrate), which results in lowered blood pH. a heterogeneous superfamily of membrane transport proteins mediating the transport of solutes across biological membranes as a function of electrochemical gradients. In the family there are uniporters (i.e., substrate transport down the electrochemical gradient), symporters (i.e., transport of substrate down an electrochemical substrate gradient coupled to the transport of another substrate against its electrochemical gradient in the same direction) and antiporters (i.e., transport of substrate down an electrochemical substrate gradient coupled to the uphill transport of another substrate in the opposite direction). Most of the MFS members share a common fold, which is characterized by twelve transmembrane spanning α-helices that are arranged in an amino- and carboxy-terminal six helix bundle. low-frequency substitution of a single nucleotide occurring at a specific position in the genome. a group of membrane transport proteins in humans that are organized into 65 families. Within a SLC family, members have a sequence identity of >20%. The SLC families include facilitated transporters (i.e., transport down the electrochemical substrate gradient) and secondary active transporters (i.e., transport of substrate down an electrochemical gradient coupled to the transport of another substrate against its electrochemical gradient).