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Amino Acid Transport Across the Mammalian Intestine

Stefan Bröer, Stephen J. Fairweather

10.1002/cphy.c170041

Source: Volume 9, Issue 1, January 2019

Published online: December 2018

Full Article on Wiley Online Library



ABSTRACT

The small intestine mediates the absorption of amino acids after ingestion of protein and sustains the supply of amino acids to all tissues. The small intestine is an important contributor to plasma amino acid homeostasis, while amino acid transport in the large intestine is more relevant for bacterial metabolites and fluid secretion. A number of rare inherited disorders have contributed to the identification of amino acid transporters in epithelial cells of the small intestine, in particular cystinuria, lysinuric protein intolerance, Hartnup disorder, iminoglycinuria, and dicarboxylic aminoaciduria. These are most readily detected by analysis of urine amino acids, but typically also affect intestinal transport. The genes underlying these disorders have all been identified. The remaining transporters were identified through molecular cloning techniques to the extent that a comprehensive portrait of functional cooperation among transporters of intestinal epithelial cells is now available for both the basolateral and apical membranes. Mouse models of most intestinal transporters illustrate their contribution to amino acid homeostasis and systemic physiology. Intestinal amino acid transport activities can vary between species, but these can now be explained as differences of amino acid transporter distribution along the intestine. © 2019 American Physiological Society. Compr Physiol 9:343‐373, 2019.

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Figure 1. Figure 1. Transporters involved in amino acid absorption in the human small intestine. The apical membrane is shown at the top, the basolateral membrane at the bottom. Arrows indicate preferential direction of transport. Transporter acronyms are shown. Import transporters in the basolateral membrane, such as GlyT1A, EAAT2, SNAT2, BGT1, Cat1, etc. have been omitted. Claudins are indicated as channel‐like structures between cells. AA0, neutral amino acids, AA+, cationic amino acids, AA−, anionic amino acids. Tau, taurine; β, beta‐amino acids, P, proline; G, glycine.
Figure 2. Figure 2. Transporters involved in amino acid absorption in the human colon. The apical membrane is shown at the top, the basolateral membrane at the bottom. Arrows indicate preferential direction of transport. For explanations, see text. Transporter acronyms are shown. AA0, neutral amino acids, AA+, cationic amino acids, AA−, anionic amino acids. Tau, taurine; β, beta‐amino acids, P, proline; G, glycine.
Figure 3. Figure 3. Expression of amino acid transporters along the mouse intestine. Expression data were extracted from microarray data deposited in GEO datasets GDS 521, 522, and 524 (218). A log2 scale is used for transporter expression due to large differences in mRNA abundance. B0AT1, b0,+AT, y+LAT1, LAT2, rBAT, SIT1, and PAT1 show the typical signature for transporters primarily involved in amino acid absorption (high in the small intestine, low in colon). ATB0,+ and ASCT2 show the opposite distribution. EAAT3 and TauT1 show a more even distribution along the intestine.
Figure 4. Figure 4. Typical shapes of amino acid transporters involved in amino acid absorption. Known amino acid transporters belong to four different classes and three different structural folds. The SLC6 family contains several epithelial amino acid transporters, such as B0AT1, ATB0,+, SIT, GlyT1, and TauT. These are structurally very similar to LeuT. B0AT1 in addition forms a complex with angiotensin converting enzyme 2 (Ace2), but there is no structural information about this interaction available. It is shown next to B0AT1 for size comparison. The APC (amino acid, polyamine, organo‐cation) family of transporters have a structure that is also closely related to LeuT, but do not translocate Na+‐ions. Some of these transporters (b0,+AT, LAT2, y+LAT1) form covalent heterodimers with heavy subunits (rBAT, 4F2hc). The figure depicts the structural arrangement between LAT2 and 4F2hc. The rBAT‐b0,+AT heterodimer in addition forms a heterotetramer, which can be visualized by adding a second heterodimer mirror image to the right of the depicted molecule. Glutamate transporters and ASCT2 form a bowel‐shaped trimer in the membrane. TAT1 and LAT4 belong to the multifacilitator superfamily (MFS). Structures used to represent class: LeuT related (2A65), Ace 2 (1R42), APC (3OB6, chain A), 4F2hc (2DH2), GltPh (2NWW), and MFS (5CFY).
Figure 5. Figure 5. Structural features of LeuT. The scaffold‐forming helices are shown in gold, while the rocking bundle is colored magenta. In the outward open conformation (PDB: 3TT1) amino acids can enter the transporter through the gap between the scaffold and the bundle from top. Substrate and Na+‐ion binding (green spheres) causes the transporter to interact with the substrates and ions and to close up (occlusion). In the inward‐open conformation (PDB: 3TT3) the bundle has moved inward and the loop blocks access from the outside. Helix 1 and 6 perform a rocker‐switch like motion allowing the release of the substrate on the inside.
Figure 6. Figure 6. Structural features of glutamate transporters. Glutamate transporters form a trimer of independently operating subunits. The scaffold‐forming helices are shown in gold, mobile structures are magenta or green. In contrast to LeuT, the mobile elements perform an elevator‐like movement instead of a rocking motion. The gates, colored in green, will allow or restrict access of the substrate. In the depicted outward‐open conformation (pdb: 2NWW) the green gate on the right will close over the substrate. Subsequently, the mobile parts perform an elevator‐like downward shift relative to the scaffold and the gate on the left opens to release the substrate.


Figure 1. Transporters involved in amino acid absorption in the human small intestine. The apical membrane is shown at the top, the basolateral membrane at the bottom. Arrows indicate preferential direction of transport. Transporter acronyms are shown. Import transporters in the basolateral membrane, such as GlyT1A, EAAT2, SNAT2, BGT1, Cat1, etc. have been omitted. Claudins are indicated as channel‐like structures between cells. AA0, neutral amino acids, AA+, cationic amino acids, AA−, anionic amino acids. Tau, taurine; β, beta‐amino acids, P, proline; G, glycine.


Figure 2. Transporters involved in amino acid absorption in the human colon. The apical membrane is shown at the top, the basolateral membrane at the bottom. Arrows indicate preferential direction of transport. For explanations, see text. Transporter acronyms are shown. AA0, neutral amino acids, AA+, cationic amino acids, AA−, anionic amino acids. Tau, taurine; β, beta‐amino acids, P, proline; G, glycine.


Figure 3. Expression of amino acid transporters along the mouse intestine. Expression data were extracted from microarray data deposited in GEO datasets GDS 521, 522, and 524 (218). A log2 scale is used for transporter expression due to large differences in mRNA abundance. B0AT1, b0,+AT, y+LAT1, LAT2, rBAT, SIT1, and PAT1 show the typical signature for transporters primarily involved in amino acid absorption (high in the small intestine, low in colon). ATB0,+ and ASCT2 show the opposite distribution. EAAT3 and TauT1 show a more even distribution along the intestine.


Figure 4. Typical shapes of amino acid transporters involved in amino acid absorption. Known amino acid transporters belong to four different classes and three different structural folds. The SLC6 family contains several epithelial amino acid transporters, such as B0AT1, ATB0,+, SIT, GlyT1, and TauT. These are structurally very similar to LeuT. B0AT1 in addition forms a complex with angiotensin converting enzyme 2 (Ace2), but there is no structural information about this interaction available. It is shown next to B0AT1 for size comparison. The APC (amino acid, polyamine, organo‐cation) family of transporters have a structure that is also closely related to LeuT, but do not translocate Na+‐ions. Some of these transporters (b0,+AT, LAT2, y+LAT1) form covalent heterodimers with heavy subunits (rBAT, 4F2hc). The figure depicts the structural arrangement between LAT2 and 4F2hc. The rBAT‐b0,+AT heterodimer in addition forms a heterotetramer, which can be visualized by adding a second heterodimer mirror image to the right of the depicted molecule. Glutamate transporters and ASCT2 form a bowel‐shaped trimer in the membrane. TAT1 and LAT4 belong to the multifacilitator superfamily (MFS). Structures used to represent class: LeuT related (2A65), Ace 2 (1R42), APC (3OB6, chain A), 4F2hc (2DH2), GltPh (2NWW), and MFS (5CFY).


Figure 5. Structural features of LeuT. The scaffold‐forming helices are shown in gold, while the rocking bundle is colored magenta. In the outward open conformation (PDB: 3TT1) amino acids can enter the transporter through the gap between the scaffold and the bundle from top. Substrate and Na+‐ion binding (green spheres) causes the transporter to interact with the substrates and ions and to close up (occlusion). In the inward‐open conformation (PDB: 3TT3) the bundle has moved inward and the loop blocks access from the outside. Helix 1 and 6 perform a rocker‐switch like motion allowing the release of the substrate on the inside.


Figure 6. Structural features of glutamate transporters. Glutamate transporters form a trimer of independently operating subunits. The scaffold‐forming helices are shown in gold, mobile structures are magenta or green. In contrast to LeuT, the mobile elements perform an elevator‐like movement instead of a rocking motion. The gates, colored in green, will allow or restrict access of the substrate. In the depicted outward‐open conformation (pdb: 2NWW) the green gate on the right will close over the substrate. Subsequently, the mobile parts perform an elevator‐like downward shift relative to the scaffold and the gate on the left opens to release the substrate.
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Teaching Material

S. Brӧer, S. J. Fairweather. Amino Acid Transport Across the Mammalian Intestine. Compr Physiol 9: 2019, 373-403.

Didactic Synopsis

Enterocytes of the intestine are endowed with a suite of amino acid transporters on their apical membrane. These ensure the efficient removal of all groups of amino acids from the lumen of the intestine. Broadly specific transporters are found for neutral amino acids, cationic amino acids, anionic amino acids, imino acids, and β-amino acids. A different set of transporters is found in the basolateral membrane, allowing amino acids to be released into the blood stream after nutrient intake. Expression levels of these transporters are high in the small intestine, where the bulk of nutrient absorption occurs. Rare diseases of amino acid absorption have contributed significantly to the elucidation of amino acid transport in the intestine and the related transporters found in kidney.

Major Teaching Points:

  1. Amino acid transporters show a specific distribution along the intestine.
  2. Amino acid transporters select amino acids with specific side-chain characteristics.
  3. Transport mechanisms in the apical and basolateral membrane are different allowing vectorial transfer.
  4. Transport is energized by ion and amino acid gradients.
  5. Different evolutionary principles are used to mediate transport across membranes.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: Amino acid transporters accept amino acids with similar biophysical properties, such as neutral amino acids (AA0), cationic amino acids (AA+), anionic amino acids (AA−), β-amino acids (β), proline (P), and glycine (G). To remove these amino acids efficiently from the lumen of the intestine, different mechanisms are used, such as cotransport with Na+ or H+ or the uptake of a cationic amino acid in exchange for a neutral amino acid. Neutral amino acids are recaptured by cotransport with Na+. Due to the length of the small intestine > 95% of amino acids are absorbed even at a high protein load. Release of amino acids across the basolateral membrane makes use of uniporters and exchangers. Net transfer from luminal to serosal compartments (vectorial transport) is achieved by ion gradients established by the Na+/K+-ATPase.

Figure 2 Teaching points: Only a small fraction of amino acids is absorbed in the distal jejunum and colon. These are mostly generated by bacteria from endogenous proteins. Similar transport mechanisms are used as in the small intestine, but the actual transporters are different. Net transfer from luminal to serosal compartments is achieved by ion gradients established by the Na+/K+-ATPase.

Figure 3 Teaching points: This image shows expression data from microarrays that experimentally demonstrate the changes of amino acid transporter expression along the longitudinal axis of the intestine (Duodenum/Jejunum/Ileum/Colon). Experiments like this support the data depicted in Figures and .

Figure 4 Teaching points: Rendition of transporter molecules that mediate the absorption of amino acids. Only a limited number of transporter designs are used to mediate absorption of amino acids. The principal protein folds are shown in Figure ; however, APC and LeuT-related transporters use the same structural principles reducing the number of transporter designs to three. All structures span the lipid bilayer and can pass amino acids from the lumen to the cytosol or in the opposite direction.

Figure 5 Teaching points: To illustrate the transport mechanism of LeuT related transporters (see Figure 4), a different depiction is used. Secondary structures are shown in particular the α-helices spanning the membrane bilayer. In the outside-open conformation, a gap can be seen between the scaffold helices (gold) and the rocking helices (magenta). The rocking helices tilt during amino acid absorption thereby opening a gap on the cytosolic side of the transporter (inside open). At the same time, access to the lumen is closed. The substrate first diffuses into the center of the transporter (green in the outside-open structure). After the conformational changes, the substrate is released to the cytosol.

Figure 6 Teaching points: A different translocation mechanism is used by the intestinal glutamate transporter. The transporter also has a scaffold domain (gold) and a mobile domain (magenta), but instead of a rocker motion, an elevator-like movement is used to translocate the substrate across the membrane. Glutamate transporters assemble as trimers, but each individual unit operates independently. One unit is shown on the right with the elevator domain facing upwards (lumen). A gate (green to the right) encloses the substrate. After movement of the elevator domain towards the cytosol, a second gate (green to the left) opens to release the substrate.

 


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Article Title: Amino Acid Transport Across the Mammalian Intestine
 

How to Cite

Stefan Bröer, Stephen J. Fairweather. Amino Acid Transport Across the Mammalian Intestine. Compr Physiol 2018, 9: 343-373. doi: 10.1002/cphy.c170041