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Monocarboxylic Acid Transport

Andrew P. Halestrap

10.1002/cphy.c130008

Source: Volume 3, Issue 4, October 2013

Published online: October 2013

Full Article on Wiley Online Library



Abstract

Monocarboxylates such as lactate, pyruvate, and the ketone bodies play major roles in metabolism and must be transported across both the plasma membrane and mitochondrial inner membrane. A family of five proton‐linked MonoCarboxylate Transporters (MCTs) is involved in the former and the mitochondrial pyruvate carrier (MPC) mediates the latter. In the intestine and kidney, two Sodium‐coupled MonoCarboxylate Transporters (SMCTs) provide active transport of monocarboxylates across the apical membrane of the epithelial cells with MCTs on the basolateral membrane transporting the accumulated monocarboxylate into the blood. The kinetics and substrate and inhibitor specificities of MCTs, SMCTs, and the MPC have been well characterized and the molecular identity of the MCTs and SMCTs defined unequivocally. The identity of the MPC is less certain. The MCTs have been extensively studied and the three‐dimensional structure of MCT1 has been modeled and a likely catalytic mechanism proposed. MCTs require the binding of a single transmembrane glycoprotein (either embigin or basigin) for activity. Regulation of MCT activity involves both transcriptional and posttranscriptional mechanisms, examples being upregulation of MCT1 by chronic exercise in red muscle (which oxidizes lactate) and in T‐lymphocytes upon stimulation. MCT4 has properties that make it especially suited for lactic acid export by glycolytic cells and is upregulated by hypoxia. Some disease states are associated with modulation of plasma membrane and mitochondrial monocarboxylate transport and MCTs are promising drug targets for cancer chemotherapy. They may also be involved in drug uptake from the intestine and subsequent transport across the blood brain barrier. © 2013 American Physiological Society. Compr Physiol 3:1611‐1643, 2013.

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Figure 1. Figure 1. Key metabolic pathways requiring monocarboxylate transport across the plasma and inner mitochondrial membranes. Note that the particular metabolic pathways operating within any cell will depend on the tissue. This Figure does not include monocarboxylate absorption from the lumen of the intestine or reabsorption from the kidney which are illustrated in Figure 10.
Figure 2. Figure 2. Conserved sequence motifs that define membership of the SLCA16 (MCT) family. Family members are defined by the presence of two highly conserved sequences, [D/E]G[G/S][W/F][G/A]W and YFxK[R/K][R/L]xLAx[G/A]xAxAG, which traverse the lead into TM1 and TM5 respectively as well as a conserved R and RP in the lead in to TMs 3 and 6. Sequence variation between different SLC16A family members is greatest in loops between helices and in the N‐ and C‐termini; the TM segments are more conserved. Members of the family known to transport monocarboxylates all contain a lysine (K) on the cytosolic side of TM1 and an aspartate (D but glutamate in MCT7) and arginine (R) in the centre of TM 8. These groups are believed to play a critical role in binding the proton and monocarboxylate anion during the translocation cycle.
Figure 3. Figure 3. Phylogenetic tree of members of the SLC16A family. Both the SLC and MCT nomenclature are given. Only four members are confirmed as proton‐linked monocarboxylate transporters with SCL16A6 (MCT7) the only other member likely to be so. Seven members of the family are currently of unknown function (orphan transporters).
Figure 4. Figure 4. MCTs follow an ordered kinetic mechanism. Transport is show for the lactate anion moving with a proton from the extracellular to the intracellular compartment, but all steps are freely reversible. The conformational change of the protein that translocates the lactate and proton occurs faster for the substrate bound carrier (k 1) than the unbound carrier (k 2) which accounts for why monocarboxylate exchange is faster than net movement of monocarboxylic acid.
Figure 5. Figure 5. Characterization of the properties of MCTs by expression in Xenopus laevis oocytes.
Figure 6. Figure 6. Schematic diagram showing key structural features of basigin and embigin which are essential ancillary proteins for MCT activity.
Figure 7. Figure 7. Basigin colocalizes with MCT1 in the heart and Islets of Langherhan. Data were obtained using confocal microscopy as described references 160 and 324, respectively.
Figure 8. Figure 8. The structure of MCT1 derived from molecular modeling is shown in the two conformations representing the two forms, “inside open” and “outside open,” with substrate binding sites on opposite sides of the membrane. The N‐terminal domain is colored red and the C‐terminal domain colored blue, while the intracellular loop connecting the two is not modeled and shown as a connecting line. Cross‐sections of the transporter are rendered with a solvent‐accessible surface. The position of K38 (green) and F360 (yellow) are shown as these are critical residues for the translocation cycle and substrate specificity, respectively. D302 and R306, which are also essential for activity, are not shown for clarity, but line the channel next to F360. Lysine residues (K45, K282, and K413) involved in DIDS binding are rendered magenta. The axis system used for the C‐terminal domain rotations to generate the open model is shown in the centre of the figure. The schematic diagram below the model structures illustrates how individual helices are proposed to move during the transformation between inward and outward facing conformations of MCT1. The Figure is based on the structure reported in Ref. 313.
Figure 9. Figure 9. Cartoon illustrating the proposed mechanism of lactic acid transport by MCT1. Lactic acid protonates K38 causing the channel to open. Lactate then moves into the open extracellular side of the pore and forms an ion pair with K38. In the next step, the proton on K38 is transferred to aspartate 302 (D‐) neutralizing the aspatate side chain (DH). This is followed by migration of lactate through the pore where it forms an ion pair with R306 (R+). Once K38 is deprotonated and lactate is occupying the specificity filter, the transporter relaxes back toward the closed state and releases lactic acid into the intracellular space. The cartoon is based on the mechanism reported in Ref. 313.
Figure 10. Figure 10. Monocarboxylate uptake from the intestinal and kidney tubules involves cooperation of SMCTs and MCTs on the apical and basolateral surfaces of epithelial cells. Note that as shown the process would cause the pH of the cell to rise as protons are move with the monocarboxylate across the basolateral membrane and this must be compensated for by pH regulatory mechanisms.
Figure 11. Figure 11. In the brain and muscle MCTs are used to transport lactic and ketone bodies from the blood into the tissue as to shuttle lactic acid between the glycolytic astrocytes and white muscle fibers to the neurons and red fibers that oxidize it. A similar lactic acid shuttle may operate in some tumors where the hypoxic centre of the tumor produces lactic acid that is oxidized by the normoxic peripheral cells.


Figure 1. Key metabolic pathways requiring monocarboxylate transport across the plasma and inner mitochondrial membranes. Note that the particular metabolic pathways operating within any cell will depend on the tissue. This Figure does not include monocarboxylate absorption from the lumen of the intestine or reabsorption from the kidney which are illustrated in Figure 10.


Figure 2. Conserved sequence motifs that define membership of the SLCA16 (MCT) family. Family members are defined by the presence of two highly conserved sequences, [D/E]G[G/S][W/F][G/A]W and YFxK[R/K][R/L]xLAx[G/A]xAxAG, which traverse the lead into TM1 and TM5 respectively as well as a conserved R and RP in the lead in to TMs 3 and 6. Sequence variation between different SLC16A family members is greatest in loops between helices and in the N‐ and C‐termini; the TM segments are more conserved. Members of the family known to transport monocarboxylates all contain a lysine (K) on the cytosolic side of TM1 and an aspartate (D but glutamate in MCT7) and arginine (R) in the centre of TM 8. These groups are believed to play a critical role in binding the proton and monocarboxylate anion during the translocation cycle.


Figure 3. Phylogenetic tree of members of the SLC16A family. Both the SLC and MCT nomenclature are given. Only four members are confirmed as proton‐linked monocarboxylate transporters with SCL16A6 (MCT7) the only other member likely to be so. Seven members of the family are currently of unknown function (orphan transporters).


Figure 4. MCTs follow an ordered kinetic mechanism. Transport is show for the lactate anion moving with a proton from the extracellular to the intracellular compartment, but all steps are freely reversible. The conformational change of the protein that translocates the lactate and proton occurs faster for the substrate bound carrier (k 1) than the unbound carrier (k 2) which accounts for why monocarboxylate exchange is faster than net movement of monocarboxylic acid.


Figure 5. Characterization of the properties of MCTs by expression in Xenopus laevis oocytes.


Figure 6. Schematic diagram showing key structural features of basigin and embigin which are essential ancillary proteins for MCT activity.


Figure 7. Basigin colocalizes with MCT1 in the heart and Islets of Langherhan. Data were obtained using confocal microscopy as described references 160 and 324, respectively.


Figure 8. The structure of MCT1 derived from molecular modeling is shown in the two conformations representing the two forms, “inside open” and “outside open,” with substrate binding sites on opposite sides of the membrane. The N‐terminal domain is colored red and the C‐terminal domain colored blue, while the intracellular loop connecting the two is not modeled and shown as a connecting line. Cross‐sections of the transporter are rendered with a solvent‐accessible surface. The position of K38 (green) and F360 (yellow) are shown as these are critical residues for the translocation cycle and substrate specificity, respectively. D302 and R306, which are also essential for activity, are not shown for clarity, but line the channel next to F360. Lysine residues (K45, K282, and K413) involved in DIDS binding are rendered magenta. The axis system used for the C‐terminal domain rotations to generate the open model is shown in the centre of the figure. The schematic diagram below the model structures illustrates how individual helices are proposed to move during the transformation between inward and outward facing conformations of MCT1. The Figure is based on the structure reported in Ref. 313.


Figure 9. Cartoon illustrating the proposed mechanism of lactic acid transport by MCT1. Lactic acid protonates K38 causing the channel to open. Lactate then moves into the open extracellular side of the pore and forms an ion pair with K38. In the next step, the proton on K38 is transferred to aspartate 302 (D‐) neutralizing the aspatate side chain (DH). This is followed by migration of lactate through the pore where it forms an ion pair with R306 (R+). Once K38 is deprotonated and lactate is occupying the specificity filter, the transporter relaxes back toward the closed state and releases lactic acid into the intracellular space. The cartoon is based on the mechanism reported in Ref. 313.


Figure 10. Monocarboxylate uptake from the intestinal and kidney tubules involves cooperation of SMCTs and MCTs on the apical and basolateral surfaces of epithelial cells. Note that as shown the process would cause the pH of the cell to rise as protons are move with the monocarboxylate across the basolateral membrane and this must be compensated for by pH regulatory mechanisms.


Figure 11. In the brain and muscle MCTs are used to transport lactic and ketone bodies from the blood into the tissue as to shuttle lactic acid between the glycolytic astrocytes and white muscle fibers to the neurons and red fibers that oxidize it. A similar lactic acid shuttle may operate in some tumors where the hypoxic centre of the tumor produces lactic acid that is oxidized by the normoxic peripheral cells.
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Article Title: Monocarboxylic Acid Transport
 

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Andrew P. Halestrap. Monocarboxylic Acid Transport. Compr Physiol 2013, 3: 1611-1643. doi: 10.1002/cphy.c130008