Proton coupled amino acid transporter

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Proton-coupled amino acid transporters belong to the SLC26A5 family; they are protein receptors whose main function is the transmembrane movement of amino acids and their derivatives. This family of receptors is most commonly found within the luminal surface of the small intestine as well as in some lysosomes. The solute carrier family (SLC) of genes includes roughly 400 membrane proteins that are characterized by 66 families in total. The SLC36 family of genes maps to chromosome 11. The diversity of these receptors is vast, with the ability to transport both charged and uncharged amino acids along with their derivatives. In research and practice, SLC36A1/2 are both targets for drug-based delivery systems for a wide range of disorders.

Contents

Structure

The human protein acid transporter (hPAT1) is 5585 base pairs long and codes for a protein 476 amino acids long. The transporter has nine transmembrane regions where the amino terminus faces the cytoplasm. The rat protein acid transporter (rPAT1) has been widely studied and an 85% amino acid sequence match was found between hPAT1 and rPAT1. The hPAT1 gene is located on chromosome 5q31-33 and has 11 exons that are coding regions. Its translation site begins in exon 2 and exon 11 contains the termination site. [1]

Proton-coupled amino acid transporters 1 and 2

The molecular weight of Proton-coupled amino acid transporter 1 is 53.28 kDA; the molecular weight of Proton-coupled amino acid transporter 2 is 53.22 kDA. PAT1 has been found in lysosomes in brain neurons but also in the apical membrane of intestinal epithelial cells where it is associated with the brush border. Proton-coupled amino acid transporter 1 has a higher affinity for proline than it does for glycine and alanine Proton-coupled amino acid transporter 2 is found subcellularly in the kidneys, lungs, spinal cord, and brain and likely has a role in myelinating neurons. [2] It has an overall higher affinity for glycine, alanine, and proline than PAT1 but is more specific for what can inhibit it. [3] [4]

Biochemistry

Unlike most amino acid transporters in the exchange of Na+ with amino acid symporters, proton-coupled amino acid transporters function as H+ with amino acid symporters. They are located within the luminal surface of the small intestine and within lysosomes, so their action functions in absorption in the intestine and in the efflux pathway after intralysosomal digestion. Unlike typical mammalian amino acid transporters which function in exchanging Na+/amino acid symporters, these- transporters function in exchanging H+/amino acid symporters. The activity of transporters, such as Proton-coupled amino acid transporter 1 and Proton-coupled amino acid transporter 2 can be measured at the apical membrane of the human epithelial layer of cells which are loaded with pH sensitive dyes. The change in membrane potential can be measured by the absorption of pH sensitive dyes and the associated influx of H+ ions. The proteins involved in these transporters are consider anion exchangers

Function

The function of proton-coupled amino acid transporters is the transmembrane movement of amino acids and their derivatives for absorption by the luminal surface of the small intestine or digestion by intralysosomal proteins. In Drosophila models, the expression of SLC family genes that code for proton-coupled amino acid transporters is directly linked to the nutrient-dependent growth. In humans, similar expression patterns are observed and their function correlates to their location anatomically. Being located within the lamina of the small intestine allows for functional absorption of transported amino acids and derivatives. The majority of nutrient absorption takes place within this region of the intestines, and makes sense that these transporters are located throughout this tissue.

Non-functional proton coupled amino acid transporter

In hereditary disease iminoglycinuria, there is a defect in the human proton-coupled amino acid transporter 1 and 2 genes which results in a defect in the absorption of proline and glycine. Iminoglycinuria is an autosomal recessive disorder of the renal tubular. Lack of glycine and proline absorption leads to excess urinary excretions containing amino acids. If the transporters are not working properly, a drug that they usually help gain entry in to the cell might not be absorbed [3] Their function can also be inhibited by tryptophan derivatives and allow for exploration into the function of hPAT1 and hPAT2. Additionally, mutations that lead to structural changes in amino acid binding sites play a role in their functional transport. [5]

Biosynthesis

The DNA sequence of these transporters is transcribed in the nucleus of the cell by RNA polymerase and undergoes splicing and capping before it travels to the cytoplasm. In the cytoplasm, translation begins via a sequence in exon 2 of the mRNA. Subsequently, protein folding and packaging insert the transporter into the membrane. The protein has a signal recognition particle that is recognized as it leaves the ribosome. N-glycosylation at various sites on hPAT1 is necessary for its transport function. Three of its extracellular residues are glycosylated and determine transport efficacy. [6]

Clinical significance

PAT1 mRNA is expressed in the GI tract between the stomach and descending colon, but is generally absent in the esophagus, caecum, and rectum. This allows for different treatments that affect the affinity of the carrier protein for its substrates, giving the potential to treat various amino-acid related diseases. HPAT1 and HPAT2 are important in the absorption of certain drugs, especially pharmaceutically active amino acids derivatives. [3] They have also been targeted with medications used as anticonvulsants, for prostate cancer, and for bladder cancer. [7] HPAT1 and 2 are integral to the central nervous system because they transport GABA and its analogues which can induce and inhibitory and excitatory effect in the brain. [1]

Related Research Articles

In cellular biology, active transport is the movement of molecules across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient.

Cotransporter

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

The solute carrier (SLC) group of membrane transport proteins include over 400 members organized into 66 families. Most members of the SLC group are located in the cell membrane. The SLC gene nomenclature system was originally proposed by the HUGO Gene Nomenclature Committee (HGNC) and is the basis for the official HGNC names of the genes that encode these transporters. A more general transmembrane transporter classification can be found in TCDB database.

The Na-K-Cl cotransporter (NKCC) is a protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.

Symporter

A symporter is an integral membrane protein that is involved in the transport of two different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the cell membrane at the same time, and is, therefore, a type of cotransporter. The transporter is called a symporter, because the molecules will travel in the same direction in relation to each other. This is in contrast to the antiport transporter. Typically, the ion(s) will move down the electrochemical gradient, allowing the other molecule(s) to move against the concentration gradient. The movement of the ion(s) across the membrane is facilitated diffusion, and is coupled with the active transport of the molecule(s).

SLC22A5

SLC22A5 is a membrane transport protein associated with primary carnitine deficiency. This protein is involved in the active cellular uptake of carnitine. It acts a symporter, moving sodium ions and other organic cations across the membrane along with carnitine. Such polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for the elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. Mutations in the SLC22A5 gene cause systemic primary carnitine deficiency, which can lead to heart failure.

Sodium/glucose cotransporter 1

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells. Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

Peptide transporter 1 Mammalian protein found in Homo sapiens

Peptide transporter 1 also known as solute carrier family 15 member 1 (SLC15A1) is a protein that in humans is encoded by SLC15A1 gene. PepT 1 is a solute carrier for oligopeptides. It functions in renal oligopeptide reabsorption and in the intestines in a proton dependent way, hence acting like a cotransporter.

A neurotransmitter sodium symporter (NSS) (TC# 2.A.22) is type of neurotransmitter transporter that catalyzes the uptake of a variety of neurotransmitters, amino acids, osmolytes and related nitrogenous substances by a solute:Na+ symport mechanism. The NSS family is a member of the APC superfamily. Its constituents have been found in bacteria, archaea and eukaryotes.

Proton-coupled amino acid transporter 1

Proton-coupled amino acid transporter 1 is a protein that in humans is encoded by the SLC36A1 gene.

An amino acid transporter is a membrane transport protein that transports amino acids. They are mainly of the solute carrier family.

GABA transporters (Gamma-Aminobutyric acid transporters) belong to the family of neurotransmitters known as sodium symporters, also known as solute carrier 6 (SLC6). These are large family of neurotransmitter which are Na+ concentration dependent. They are found in various regions of the brain in different cell types, such as neurons and astrocytes.

Iminoglycinuria Medical condition

Iminoglycinuria is an autosomal recessive disorder of renal tubular transport affecting reabsorption of the amino acid glycine, and the imino acids proline and hydroxyproline. This results in excess urinary excretion of all three acids.

Proton-coupled amino acid transporter 2

Proton-coupled amino acid transporter 2 is a protein which in humans is encoded by the SLC36A2 gene.

Sodium-solute symporter Group of transport proteins

Members of the Solute:Sodium Symporter (SSS) Family (TC# 2.A.21) catalyze solute:Na+ symport. The SSS family is within the APC Superfamily. The solutes transported may be sugars, amino acids, organo cations such as choline, nucleosides, inositols, vitamins, urea or anions, depending on the system. Members of the SSS family have been identified in bacteria, archaea and eukaryotes. Almost all functionally well-characterized members normally catalyze solute uptake via Na+ symport.

Dicarboxylic aminoaciduria is a rare form of aminoaciduria which is an autosomal recessive disorder of urinary glutamate and aspartate due to genetic errors related to transport of these amino acids. Mutations resulting in a lack of expression of the SLC1A1 gene, a member of the solute carrier family, are found to cause development of dicarboxylic aminoaciduria in humans. SLC1A1 encodes for EAAT3 which is found in the neurons, intestine, kidney, lung, and heart. EAAT3 is part of a family of high affinity glutamate transporters which transport both glutamate and aspartate across the plasma membrane.

Hereditary folate malabsorption Medical condition

Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder caused by loss-of-function mutations in the proton-coupled folate transporter (PCFT) gene, resulting in systemic folate deficiency and impaired delivery of folate to the brain.

Proton-coupled folate transporter

The proton-coupled folate transporter is a protein that in humans is encoded by the SLC46A1 gene. The major physiological roles of PCFTs are in mediating the intestinal absorption of folate, and its delivery to the central nervous system.

The amino acid-polyamine-organocation (APC) superfamily is the second largest superfamily of secondary carrier proteins currently known, and it contains several Solute carriers. Originally, the APC superfamily consisted of subfamilies under the transporter classification number. This superfamily has since been expanded to include eighteen different families.

Natural resistance-associated macrophage protein Family of transport proteins

Natural resistance-associated macrophage proteins (Nramps), also known as metal ion (Mn2+-iron) transporters (TC# 2.A.55), are a family of metal transport proteins found throughout all domains of life. Taking on an eleven-helix LeuT fold, the Nramp family is a member of the large APC Superfamily of secondary carriers. They transport a variety of transition metals such as manganese, cadmium, and manganese using an alternating access mechanism characteristic of secondary transporters.

References

  1. 1 2 Chen, Zhong; Fei, You‐Jun; Anderson, Catriona M. H.; Wake, Katherine A.; Miyauchi, Seiji; Huang, Wei; Thwaites, David T.; Ganapathy, Vadivel (January 2003). "Structure, function and immunolocalization of a proton‐coupled amino acid transporter (hPAT1) in the human intestinal cell line Caco‐2". The Journal of Physiology. 546 (2): 349–361. doi:10.1113/jphysiol.2002.026500. PMC   2342508 . PMID   12527723.
  2. ↑ Boll, Michael; Daniel, Hannelore; Gasnier, Bruno (1 February 2004). "The SLC36 family: proton-coupled transporters for the absorption of selected amino acids from extracellular and intracellular proteolysis". Pflügers Archiv: European Journal of Physiology. 447 (5): 776–779. doi:10.1007/s00424-003-1073-4. PMID   12748860. S2CID   25655241.
  3. 1 2 3 Pillai, Samyuktha Muralidharan; Meredith, David (28 January 2011). "SLC36A4 (hPAT4) Is a High Affinity Amino Acid Transporter When Expressed in Xenopus laevis Oocytes". The Journal of Biological Chemistry. 286 (4): 2455–2460. doi: 10.1074/jbc.M110.172403 . PMC   3024739 . PMID   21097500.
  4. ↑ Anderson, Catriona M.H.; Grenade, Danielle S.; Boll, Michael; Foltz, Martin; Wake, Katherine A.; Kennedy, David J.; Munck, Lars K.; Miyauchi, Seiji; Taylor, Peter M.; Campbell, Frederick Charles; Munck, Bjarne G.; Daniel, Hannelore; Ganapathy, Vadivel; Thwaites, David T. (November 2004). "H+/amino acid transporter 1 (PAT1) is the imino acid carrier: An intestinal nutrient/drug transporter in human and rat". Gastroenterology. 127 (5): 1410–1422. doi:10.1053/j.gastro.2004.08.017. PMID   15521011.
  5. ↑ Edwards, Noel; Anderson, Catriona M.H.; Gatfield, Kelly M.; Jevons, Mark P.; Ganapathy, Vadivel; Thwaites, David T. (January 2011). "Amino acid derivatives are substrates or non-transported inhibitors of the amino acid transporter PAT2 (slc36a2)". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1808 (1): 260–270. doi:10.1016/j.bbamem.2010.07.032. PMC   3000476 . PMID   20691150.
  6. ↑ Dorn, Madlen; Jaehme, Michael; Weiwad, Matthias; Markwardt, Fritz; Rudolph, Rainer; Brandsch, Matthias; Bosse-Doenecke, Eva (19 May 2009). "The role of N -glycosylation in transport function and surface targeting of the human solute carrier PAT1". FEBS Letters. 583 (10): 1631–1636. doi: 10.1016/j.febslet.2009.04.037 . PMID   19409386.
  7. ↑ Frølund, S; Holm, R; Brodin, B; Nielsen, CU (October 2010). "The proton-coupled amino acid transporter, SLC36A1 (hPAT1), transports Gly-Gly, Gly-Sar and other Gly-Gly mimetics". British Journal of Pharmacology. 161 (3): 589–600. doi:10.1111/j.1476-5381.2010.00888.x. PMC   2990157 . PMID   20880398.
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