Defective function of y+LAT1 causes lysinuric protein intolerance as a transport defect in the basolateral membrane of epithelial cells where it normally mediates the influx of neutral amino acids together with sodium ions in exchange for cationic amino acids from cells. Two recent reviews are recommended for further reading that provide a comprehensive description of the structural and functional aspects of this class of amino acid exchangers (Verrey et al., 2000; Chillaron et al., 2001).
The system N amino acid transporters have been cloned recently (Chaudry et al., 1999; Nakanishi et al., 2001). The most important substrate for this class of amino acid transporters is glutamine. Its central role in interorgan metabolism as a carrier for carbon and nitrogen and its coupling to acid-base metabolism brings glutamine transporters and their regulation into the focus of a variety of metabolic processes. Moreover, as glutamine is the precursor of neuronal glutamate and is taken up efficiently by neurons, system N transporters are also interesting in view oftransmitter metabolism. A novelty is the ionic coupling of glutamine influx to cation fluxes. Glutamine uptake mediated by the transporters SN1 and SN2 is sodium dependent but electro-neutral. This is caused by the co-transport of a sodium (or lithium) ion together with glutamine and the concomitant efflux of a proton from the cell, that, in turn, causes an intracellular alkalinization. However, glutamine fluxes can also be electrogenic, as SN1 shows an intrinsic proton conductance, allowing proton efflux either coupled to or uncoupled from glutamine uptake (Chaudry et al., 2001). This close functional coupling of glutamine transport to cellular acid-base balance is a key to understanding the metabolic adaptations in glutamine metabolism in states of metabolic acidosis and alkalosis. SN1 and SN2 can transport almost all zwitterionic amino acids (glycine, serine, alanine, asparagine and histidine but not methyl-aminobutyric acid) in addition to glutamine. The transporter SN1 shows prominent expression in hepatocytes of both the periportal and the perivenous regions, and in brain restricted to astrocytes. SN2 mRNA is present in liver and brain but also in kidney, spleen and testis, and appears to have splice variants (Nakanishi et al., 2001).
Although transport of the cationic amino acids arginine, lysine and ornithine has already been described as an exchange process mediated by the heterodimeric exchangers, the most important transport proteins for these amino acids are the CAT family members initially identified as ecotropic retrovirus receptors (Kim et al., 1991; Wang et al, 1991). In the CAT family, at least three genes encode four different isoforms (CAT-1, CAT-2(A), CAT-2(B) and CAT-3), but there might also be a CAT-4 transporter. They all represent proteins of approximately 70 kDa with 12-14 TM segments. Despite their structural similarity, they differ in tissue distribution, kinetics and regulatory properties. System y+ (CAT transporters) and thus cellular uptake of the cationic amino acids is driven by the inside negative membrane potential in a uniport process. CAT proteins deliver cationic amino acids for growth and development but also for specialized cellular functions such as creatine, carnitine and polyamine synthesis or the delivery ofarginine for the different nitric oxide synthases (Closs, 2002).
The anionic amino acids glutamate and aspartate are substrates for the XaG and Xc transport systems (Gadea and Lopez-Colome, 2001a). Four isoforms of the XAG system in the brain belong to the family of Na+-dependent amino acid transporters that can - depending on the isoform -operate in an electrogenic mode with movement of more than one sodium during translocation, or in an electroneutral mode. Some show a potassium efflux during sodium-dependent glutamate influx. These excitatory amino acid transporters (EAATs) have their most important role in the inactivation ofglutamatergic neurotransmission in brain by removal of glutamate from the synaptic cleft, but they also seem to be important for the synthesis of glutathione. All EAATs show a very high specificity for the anionic amino acids, with a very high affinity in the micromolar range that is required for efficient and complete removal of glutamate from the synaptic cleft. Although predominantly found in brain, EAAT3 and EAAT4 are also found in a variety of other tissues, and
EAAT5 appears to be expressed ubiquitously. Transporters of the ASC family, namely ASCT1 and ASCT2, also possess the capability for transport of anionic amino acids, although they predominantly take zwitterionic amino acids (alanine, cysteine, serine, glutamine, leucine, isoleucine and valine). These transporters operate in a sodium-dependent manner and are either electrogenic or electroneutral (Utsunomiya-Tate et al., 1996).
Other amino acid transporters include the GLYT carriers that show a preference for glycine with various isoforms and splice variants. They mediate cellular uptake of glycine in co-transport with two Na+ and one Cl- ion, and possess 12 putative TM domains (Gadea and Lopez-Colome, 2001b). Very recently, the first proton-dependent electrogenic amino acid transporters have been discovered in mammals (Sagne et al., 2001). They may represent the first lysosomal efflux carriers for amino acids with short side chains (glycine, alanine, serine and proline) by coupling of amino acid flux to the movement of protons. Such proton-dependent transport pathways for small neutral amino acids have also been identified in the apical membrane of intestinal and renal epithelial cells. By their mode of action, one might speculate that these transporters resemble the mammalian roots of archaic proton-coupled amino acid transport pathways as found in prokaryotes, yeast and plants.
Although the two thyroid hormones T4 and T3 are not amino acids but tyrosine derivatives, their transport across the cell membrane involves amino acid transporters and plays a very important role in thyroid hormone metabolism. Based on their high lipophilicity, it was believed originally that thyroid hormones enter cells by passive diffusion. Based on the kinetics of transport and particularly its stereoselectivity, it became clear that specific binding and carrier-mediated processes must be involved. A low-capacity transport mechanism with affinities for T4 and T3 in the nanomolar range and another system characterized by high binding and transport capacity but lower affinities in the micromolar range have been identified. Uptake of T4 and T3 by the high-affinity sites was energy, temperature and often
Na+ dependent, and most probably represents the translocation of thyroid hormone across the plasma membrane by both Na+-dependent and Na+-independent mechanisms (Hennemann et al., 2001).
In a variety of tissues and cells (erythrocytes, pituitary cells, astrocytes, the blood-brain barrier and the choroid plexus), uptake of T4 and T3 appears to be mediated by system L or T (aromatic amino acids) transporters. Efflux of T3 - but not of T4 - from some cell types is also saturable (Hennemann et al., 2001). As the liver plays an important role in clearance of thyroid hormones and their conversion, hepatic transport processes are essential for metabolism of thyroid hormones. Hormone uptake in human liver cells is ATP-dependent and appears to be rate limiting for subsequent iodothyronine metabolism. In conditions of starvation, T4 uptake in the liver is decreased probably by inhibition by non-esterified fatty acids, and bilirubin or ATP depletion, resulting in lowered plasma T3 levels as a consequence ofreduced conversion. Recently, several organic anion transporters have also been identified as carriers of thyroid hormones (Friesema et al., 1999).
Uptake of amino acids in peptide-bound form is a biological phenomenon found throughout nature. Bacteria, yeast and fungi as well as specialized cells of plants, invertebrates and vertebrates express membrane proteins for uptake of dipeptides and tripeptides. Some species (but not mammals) additionally have transporters that also accept larger oligopeptides (>4 amino acid residues). Based on their molecular and functional characteristics, the membrane peptide transporters have been grouped into the PTR family ofproton-dependent oligopeptide transporters (Steiner et al., 1995). In mammals, two genes have been identified that express transport activity for di- and tripeptides: PEPT1 and PEPT2, corresponding to SLC15A1 and SLC15A2 (Fei et al, 1994; Ramamoorthy et al, 1995; Boll et al, 1996). A third protein may be a histidine transporter that also can transport dipeptides (PHT-1) (Yamashita et al, 1997). The human PEPT1 and PEPT2 represent proteins with 708 (PEPT1) and 729 (PEPT2) amino acids residues, 12 TM domains and with N- and
C-terminal ends facing the cytoplasm. The mammalian peptide carriers couple peptide movement across the membrane to movement of protons (H3O+) along an inwardly directed electrochemical proton gradient that allows transport of peptides to occur against a substrate gradient. By coupling to proton flux, transport - regardless of the net charge of the substrate - occurs electro-genically and causes intracellular acidification (Amasheh et al., 1997). The required proton gradient for peptide influx is mainly, but not exclusively, provided by electroneutral proton/ cation exchangers such as the Na+/H+ antiporters that export protons again in exchange for Na+ ions entering the cells. However, the main driving force for peptide transport is the inside negative membrane potential. Normal dipeptides taken up into the cells are hydrolysed rapidly by a multitude ofpeptidases present in the cytoplasm that possess a high affinity for di- and tripeptides and a high capacity for hydrolysis. Free amino acids are then delivered into the circulation or are used within the cell for protein synthesis or other purposes.
It is of course tempting to speculate with regards to the advantages for evolutionary conservation of the peptide transporters considering that a large number of amino acid transporters have emerged during evolution. Obviously, transport of a package of amino acids in one transport step requires less cellular energy compared with that required for the individual transport of single amino acids. Moreover, the ability of peptide carriers to transport all possible di- and tripeptides indicates that there is no discrimination either with respect to essential and non-essential amino acids or with respect to the physicochemical characteristics of the substrates, possessing molecular masses of 96.2 Da (di-glycine) to 522.6 Da (tri-tryptophan). Whereas nutritional needs with provision ofamino acids for growth, development and metabolism may explain the primary role of peptide transporters, there is evidence that they also may serve special functions in more complex organisms where the transporters are expressed only in specialized cells.
PEPT1 shows highest expression in the apical membrane ofintestinal epithelial cells and appears to be responsible for uptake of bulk quantities of di-and tripeptides as end-products of the luminal and membrane-associated digestion of dietary proteins. PEPT1 is also found in renal tubular cells. The predominant peptide transporter expressed in kidney, however, is PEPT2 (Daniel and Herget, 1997). When compared with the intestinal PEPT1 isoform, kidney PEPT2 shows about 50% identity and 70% homology in amino acid sequence, with the highest levels of identity in the TM regions. When in situ hybridization experiments in rabbit kidney were performed with PEPT2-specific antisense probes, high expression of the PEPT2 mRNA was found in proximal tubular cells, with expression levels higher in S1 and S2 than in S3 segments (Smith et al., 1998). Reverse trans-cription-polymerase chain reaction (RT-PCR), Northern blot analysis and immunodetection identified a variety of extrarenal tissues that express PEPT2, with particularly high expression in brain, choroid plexus, lung epithelium and epithelial cells of the mammary gland (Doring et al., 1998; Berger and Hediger, 1999). The biological role of peptide transport in these tissues has not yet been determined.
The main role of PEPT2 in the apical membrane of renal tubular cells is the reabsorption and conservation of amino acid nitrogen. The amount of peptide-bound amino acids in circulation increases after ingestion of a protein meal, and di-and tripeptides are produced constantly by degradation of endogenous proteins and oligopeptides in circulation and/or are released from various tissues. Although individual di- or tripeptides can be identified in plasma, the total concentration of all circulating short chain peptides in peripheral blood is still not known. Studies in a variety of animals suggest that about 50% of circulating plasma amino acids are peptide bound and that the majority represent di- and tripeptides (Seal and Parker, 1991). In addition to short chain peptides entering the tubular system by filtration, the presence of a variety of renal brush border membrane-bound peptide hydrolases with high catalytic activity could provide considerable quantities of dipeptides and tripeptides by hydrolysis of larger oligopeptides filtered in the glomerulum. Since PEPT2 is a high-affinity transport system (Km values depending on the peptide >5 to <250 |M), it can remove di- and tripeptides efficiently from the tubular fluids.
Transport by PEPT1 and PEPT2 is stereoselective, with peptides containing L-enantiomers of amino acids possessing a higher affinity for transport than those containing D-enantiomers. Peptides consisting solely of D-amino acids do not show any relevant affinity for transport. The ability of mammalian peptide transporters to transport a variety of peptidomimetics, such as antibiotics of the aminocephalosporin and aminopenicillin classes, or selected peptidase inhibitors, such as bestatin or captopril, makes peptide transporters interesting for drug delivery and pharmacokinetic analyses. The excellent oral bioavailability of these drugs is mediated by PEPT1 in the intestinal epithelium (Adibi, 1997). The renal transporter PEPT2 increases the plasma half-life of these drugs by reabsorption of the compounds after they have been filtered in the glomerulum.
The clinical importance of PEPT1 has been demonstrated in a variety ofstudies including studies in humans. Here, dipeptides have been shown to be superior to free amino acids for fast intestinal absorption and are also more useful for enteral nutrition as they provide a lower osmolarity of the nutrition solution. Moreover, in a variety of gastrointestinal diseases, the peptide transporter has been found to be less affected by the pathophysiology than the amino acid transporters, and enables delivery of amino acid nitrogen even in states of impaired mucosal function (Adibi, 1997). Figure 3.5 summarizes the different transport pathways for peptides and free amino acids in epithelial cells that mediate, in concert, the transcellular absorption of amino acid nitrogen.
Some cells in the body need a very high membrane permeability for water. For example in the kidney, the apical membrane of epithelial cells requires a water permeability that can be adjusted to maintain water homeostasis and that is under hormonal - mainly vasopressin - control. Malfunction of the system demonstrates the quantitative importance of the membrane transport pathways for water. For example, diabetes insipidus, a heriditary disorder, causes decreased capability of renal reabsorption of water that leads to the loss of huge quantities of primary urine (Kwon et al., 2001). Depending on the severity of the disease,
the renal losses of water may account for up to 50 l per day. The underlying defect is in the signalling pathways that control the incorporation and proper function of specialized membrane water channels, the aquaporins (Sansom and Law, 2001). When aquaporins are expressed and inserted into the brush border membrane of tubular cells, a water conductance of the membrane is achieved that allows a large water flow from the lumen to the blood side, that in turn concentrates the urine and conserves water.
Aquaporins (AQPs) are integral membrane proteins that are expressed in a variety of tissues and specialized cells in humans and are also found in bacteria, plants and animals. APQproteins are subdivided into the AQP proper family, with the human genome containing at least ten related family members, and the aquaglyceroporins, which have a very similar structure but show a permeability for glycerol (Borgnia et al., 1999). These proteins have a channel-like core structure forming a pore. High-resolution X-ray structures of bacterial AQPs and medium-resolution electron microscopy of human AQPs provide detailed insights into the structure and functions of these membrane proteins. They consist of six membrane-spanning helices and two half-TM helices that are only partly inserted into the membrane bilayer. The central pore shows a length of 20 A and an internal width of 2 A that account for the water and glycerol permeability (Nollert et al., 2001). In the case of aquaporin proper (AQP1), a single protein molecule allows movement of 109 water molecules per second.
Mammalian transport proteins that mediate vitamin uptake or efflux across the plasma cell membranes have - with the exception of vitamin B12 — only been identified on a molecular basis very recently. Although the various processes had been analysed in various cell systems by flux measurements and with regard to regulatory processes, the molecular identity of the responsible proteins long remained unknown. As it is not possible to cover all aspects of vitamin transport here, some of the most important recent findings and novel processes will be briefly addressed. Figure 3.6 summarizes the systems involved in transport of vitamins that will be addressed here and the proposed mode of how they mediate TM translocation.
Based on the physicochemical characteristics of the different water-soluble vitamins, different classes oftransporters are required to allow neutral,
anionic or cationic (thiamine) compounds to be transported into a cellular compartment that provides an inside negative membrane potential. In the case of the anionic vitamins such as ascorbic acid, folic acid, pantothenic acid and biotin, cellular uptake requires the co-transport of sodium ions or protons to cause electroneutral transport or a different coupling ratio (excess sodium or protons) to induce an electrogenic process.
The ascorbic acid-transporting proteins SVCT1 and SVCT2 (SLC23A2 and SLC23A1) were identified in 1999 by expression cloning (Tsukaguchi et al., 1999). At that time, it was known that cellular ascorbic acid uptake was saturable and sodium dependent whereas the transport of dehydroascorbic acid had been shown to be mediated by sodium-independent processes involving the GLUT transporters (GLUT-1-GLUT-4), followed by rapid intracellular reduction to ascorbate. The sodium-dependent electrogenic human ascorbate transporter SVCT1 consists of 598 amino acids and has an affinity for ascorbate of approximately 250 | M, whereas SVCT2 has 650 amino acids and represents the high-affinity-type (Km ~20 ||M) transporter. Both are sodium-dependent co-transporters that mediate accumulation of cellular vitamin C but show quite distinct expression patterns (Liang et al., 2001).
A unique transporter that mediates the uptake of pantothenic acid, biotin and lipoate was cloned and designated SMVT for sodium-dependent multivitamin transporter (SLC5A6) (Prasad et al., 1998). The human SMVT represents a 635 amino acid protein with 12 putative TM domains encoded on chromosome 2p23. The SMVT protein transports the substrates with a coupling ratio oftwo Na+ ions to one substrate molecule, and is therefore an electrogenic carrier. The protein is expressed in apical membranes of polarized epithelial cells where it mediates uptake of dietary vitamins in intestine and contributes to reabsorption in renal tubular epithelium. Northern blot analysis shows that SMVT transcripts are also present in a variety of other cells and tissues. Protein database comparisons show significant sequence similarity between SMVT and known members of the Na+-dependent glucose transporter family (Prasad and Ganapathy, 2000).
A number of transporters for reduced folates have also been cloned and characterized recently (Matherly, 2001). Whereas the folic acid-binding proteins a and b were known for some time, the first identified mammalian membrane folate carrier was the RFC-1 (SLC19A1). It mediates a sodium-independent but strongly pH-dependent folic acid uptake process, as already identified functionally in intact tissues prior to cloning. Cellular uptake of reduced folic acid, methyl-tetrahydrofolate and methotrexate increases with decreasing extracellular pH, suggesting a folate-proton symport or an anion-exchange process with folate anions exchanged for intracellular hydroxyl ions. A comparison of the amino acid sequence of human RFC-1 with other protein sequences identifies human ThTr1, the thiamin transporter (SLC19A2), as the closest relative with a sequence identity of40% and similarity of55% at the amino acid level (Dutta et al., 1999). Very recently, a third member ofthis family ofproteins was cloned from human and mouse (SLC19A3) and identified as a second thiamine transporter (Rajgopal etal., 2001). The unique feature of thiamine as a water-soluble vitamin is its cationic character. Depending on the pH, it may carry one or two positive charges, and this would suggest that thiamine serves as a substrate of the organic cation transporters that have been identified in large numbers. However, it appears that most of the cation transporters of the OCT family do not transport thiamine. Instead, ThTr1, cloned from human placenta, induces specific thiamine influx in transfected cells that shows the characteristics of a thiamine-proton exchange process. Influx of thiamine into cells accordingly would be coupled to efflux of protons and so thiamine transport shows a pronounced pH dependence with reduced rates of influx at acidic extracellular pH values. A base deletion in the high-affinity thiamine transporter ThTr1 (287delG) was identified recently as the cause of the thiamine-responsive megaloblastic anaemia (TRMA) syndrome that is associated with diabetes and deafness (Diaz et al., 1999). Two patients suffering from TRMA were homozygous for the mutation at nucleotide 287 of the cDNA, relative to the translation start site. The genetic alteration results in a frameshift and a premature stop codon. Fibroblasts of the patients showed almost completely abolished thiamine uptake (Neufeld et al, 2001).
Although not all transport proteins that mediate the influx and efflux ofthe different water-soluble vitamins have been identified at a molecular level, substantial progress has been made in recent years, and the genes and proteins known so far are already interesting targets for systematic analysis of their associations with inborn errors of vitamin metabolism and screening for genetic heterogeneity in view of functional differences.
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