Pflügers Archiv

, Volume 451, Issue 4, pp 511–517 | Cite as

The molecular basis of neutral aminoacidurias

  • Angelika Bröer
  • Juleen A. Cavanaugh
  • John E. J. Rasko
  • Stefan Bröer
Invited Review


Recent success in the molecular cloning and identification of apical neutral amino acid transporters has shed a new light on inherited neutral amino acidurias, such as Hartnup disorder and Iminoglycinuria. Hartnup disorder is caused by mutations in the neutral amino acid transporter B0 AT1 (SLC6A19). The transporter is found in kidney and intestine, where it is involved in the resorption of all neutral amino acids. The molecular defect underlying Iminoglycinuria has not yet been identified. However, two transporters, the proton amino acid transporter PAT1 (SLC36A1) and the IMINO transporter (SLC6A20) appear to play key roles in the resorption of glycine and proline. A model is presented, involving all three transporters that can explain the phenotypic variability of iminoglycinuria.


Iminoglycinuria Hartnup disorder SLC6A19 SLC6A20 SLC36A1 neurotransmitter transporter Proton amino acid transporter 


  1. 1.
    Anderson CM et al (2004) H+/amino acid transporter 1 (PAT1) is the imino acid carrier: an intestinal nutrient/drug transporter in human and rat. Gastroenterology 127:1410–1422PubMedGoogle Scholar
  2. 2.
    Avissar NE, Ryan CK, Ganapathy V, Sax HC (2001) Na(+)-dependent neutral amino acid transporter ATB(0) is a rabbit epithelial cell brush-border protein. Am J Physiol Cell Physiol 281:C963–C971PubMedGoogle Scholar
  3. 3.
    Baron DN, Dent CE, Harris H, Hart EW, Jepson JB (1956) Hereditary pellagra-like skin rash with temporary cerebellar ataxia, constant renal aminoaciduria and other bizarre biochemical features. Lancet 2:421–428CrossRefGoogle Scholar
  4. 4.
    Bohmer C et al (2005) Characterization of mouse amino acid transporter B 0AT1 (slc6a19). Biochem J (in press)Google Scholar
  5. 5.
    Boll M, Foltz M, Rubio-Aliaga I, Kottra G, Daniel H (2002) Functional characterization of two novel mammalian electrogenic proton-dependent amino acid cotransporters. J Biol Chem 277:22966–22973CrossRefPubMedGoogle Scholar
  6. 6.
    Boll M et al (2003) Substrate recognition by the mammalian proton-dependent amino acid transporter PAT1. Mol Membr Biol 20:261–269CrossRefPubMedGoogle Scholar
  7. 7.
    Broer A et al (1999) The astroglial ASCT2 amino acid transporter as a mediator of glutamine efflux. J Neurochem 73:2184–2194PubMedGoogle Scholar
  8. 8.
    Broer A, Wagner C, Lang F, Broer S (2000) Neutral amino acid transporter ASCT2 displays substrate-induced Na+ exchange and a substrate-gated anion conductance. Biochem J 346 Pt 3:705–710CrossRefPubMedGoogle Scholar
  9. 9.
    Broer A, Klingel K, Kowalczuk S, Rasko JE, Cavanaugh J, Broer S (2004) Molecular cloning of mouse amino acid transport system B0, a neutral amino acid transporter related to Hartnup disorder. J Biol Chem 279:24467–24476CrossRefPubMedGoogle Scholar
  10. 10.
    Chesney RW (2001) Iminoglycinuria. In: Scriver CH, Beaudet AL, Sly WS, Valle D (eds) The metabolic & molecular bases of inherited diseases, 8th edn. McGraw-Hill, NY, pp 4971–4982Google Scholar
  11. 11.
    Curran PF, Schultz SG, Chez RA, Fuisz RE (1967) Kinetic relations of the Na-amino acid interaction at the mucosal border of intestine. J Gen Physiol 50:1261–1286CrossRefPubMedGoogle Scholar
  12. 12.
    Daniel H (2004) Molecular and integrative physiology of intestinal peptide transport. Annu Rev Physiol 66:361–384CrossRefPubMedGoogle Scholar
  13. 13.
    del Castillo JR, Sulbaran-Carrasco MC, Burguillos L (2002) Glutamine transport in isolated epithelial intestinal cells. Identification of a Na+-dependent transport mechanism, highly specific for glutamine. Pflugers Arch 445:413–422CrossRefPubMedGoogle Scholar
  14. 14.
    Doyle FA, McGivan JD (1992) The bovine renal epithelial cell line NBL-1 expresses a broad specificity Na(+)-dependent neutral amino acid transport system (System Bo) similar to that in bovine renal brush border membrane vesicles. Biochim Biophys Acta 1104:55–62PubMedGoogle Scholar
  15. 15.
    Evers J, Murer H, Kinne R (1976) Phenylalanine uptake in isolated renal brush border vesicles. Biochim Biophys Acta 426:598–615PubMedGoogle Scholar
  16. 16.
    Fass SJ, Hammerman MR, Sacktor B (1977) Transport of amino acids in renal brush border membrane vesicles. Uptake of the neutral amino acid l-alanine. J Biol Chem 252:583–590PubMedGoogle Scholar
  17. 17.
    Foltz M, Mertl M, Dietz V, Boll M, Kottra G, Daniel H (2005) Kinetics of bidirectional H+ and substrate transport by the proton-dependent amino acid symporter PAT1. Biochem J 386:607–616CrossRefPubMedGoogle Scholar
  18. 18.
    Ganapathy V, Roesel RA, Howard JC, Leibach FH (1983) Interaction of proline, 5-oxoproline, and pipecolic acid for renal transport in the rabbit. J Biol Chem 258:2266–2272PubMedGoogle Scholar
  19. 19.
    Goodman SI, McIntyre CA Jr, O’Brien D (1967) Impaired intestinal transport of proline in a patient with familial iminoaciduria. J Pediatr 71:246–249PubMedGoogle Scholar
  20. 20.
    Green BJ, Lee CS, Rasko JE (2004) Biodistribution of the RD114/mammalian type D retrovirus receptor, RDR. J Gene Med 6:249–259CrossRefPubMedGoogle Scholar
  21. 21.
    Hajjar JJ, Curran PF (1970) Characteristics of the amino acid transport system in the mucosal border of rabbit ileum. J Gen Physiol 56:673–691CrossRefPubMedGoogle Scholar
  22. 22.
    Hammerman MR, Sacktor B (1977) Transport of amino acids in renal brush border membrane vesicles. Uptake of l-proline. J Biol Chem 252:591–595PubMedGoogle Scholar
  23. 23.
    Hillman RE, Albrecht I, Rosenberg LE (1968) Identification and analysis of multiple glycine transport systems in isolated mammalian renal tubules. J Biol Chem 243:5566–5571PubMedGoogle Scholar
  24. 24.
    Hoyer J, Gogelein H (1991) Sodium-alanine cotransport in renal proximal tubule cells investigated by whole-cell current recording. J Gen Physiol 97:1073–1094CrossRefPubMedGoogle Scholar
  25. 25.
    Jonas AJ, Butler IJ (1989) Circumvention of defective neutral amino acid transport in Hartnup disease using tryptophan ethyl ester. J Clin Invest 84:200–204PubMedGoogle Scholar
  26. 26.
    Jorgensen KE, Kragh-Hansen U, Sheikh MI (1990) Transport of leucine, isoleucine and valine by luminal membrane vesicles from rabbit proximal tubule. J Physiol 422:41–54PubMedGoogle Scholar
  27. 27.
    Kleta R et al (2004) Mutations in SLC6A19, encoding B0AT1, cause Hartnup disorder. Nat Genet 36:999–1002CrossRefPubMedGoogle Scholar
  28. 28.
    Kowalczuk S, Broer A, Munzinger M, Tietze N, Klingel K, Broer S (2005) Molecular cloning of the mouse IMINO system: an Na+- and Cl -dependent proline transporter. Biochem J 386:417–422CrossRefPubMedGoogle Scholar
  29. 29.
    Kragh-Hansen U, Sheikh MI (1984) Serine uptake by luminal and basolateral membrane vesicles from rabbit kidney. J Physiol 354:55–67PubMedGoogle Scholar
  30. 30.
    Kragh-Hansen U, Roigaard-Petersen H, Jacobsen C, Sheikh MI (1984) Renal transport of neutral amino acids. Tubular localization of Na+-dependent phenylalanine- and glucose-transport systems. Biochem J 220:15–24PubMedGoogle Scholar
  31. 31.
    Levy LL (2001) Hartnup disorder. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic & molecular bases of inherited diseases, 8th edn. McGraw-Hill, NY, pp 4957–4969Google Scholar
  32. 32.
    Lynch AM, McGivan JD (1987) Evidence for a single common Na+-dependent transport system for alanine, glutamine, leucine and phenylalanine in brush-border membrane vesicles from bovine kidney. Biochim Biophys Acta 899:176–184PubMedGoogle Scholar
  33. 33.
    Maenz DD, Patience JF (1992) l-threonine transport in pig jejunal brush border membrane vesicles. Functional characterization of the unique system B in the intestinal epithelium. J Biol Chem 267:22079–22086PubMedGoogle Scholar
  34. 34.
    McNamara PD, Ozegovic B, Pepe LM, Segal S (1976) Proline and glycine uptake by renal brushborder membrane vesicles. Proc Natl Acad Sci USA 73:4521–4525PubMedGoogle Scholar
  35. 35.
    Morikawa T, Tada K, Ando T, Yoshida T, Yokoyama Y, Arakawa T (1966) Prolinuria: defect in intestinal absorption of imino acids and glycine. Tohoku J Exp Med 90:105–116PubMedGoogle Scholar
  36. 36.
    Munck BG, Munck LK (1994a) Phenylalanine transport in rabbit small intestine. J Physiol 480(Pt 1):99–107PubMedGoogle Scholar
  37. 37.
    Munck LK, Munck BG (1994b) Amino acid transport in the small intestine. Physiol Res 43:335–345PubMedGoogle Scholar
  38. 38.
    Munck LK, Munck BG (1994c) Chloride-dependent intestinal transport of imino and beta-amino acids in the guinea pig and rat. Am J Physiol 266:R997–1007PubMedGoogle Scholar
  39. 39.
    Munck LK, Munck BG (1995) Transport of glycine and lysine on the chloride-dependent beta-alanine (B0,+) carrier in rabbit small intestine. Biochim Biophys Acta 1235:93–99PubMedGoogle Scholar
  40. 40.
    Munck BG, Munck LK (1999) Effects of pH changes on systems ASC and B in rabbit ileum. Am J Physiol 276:G173–G184PubMedGoogle Scholar
  41. 41.
    Munck BG, Munck LK, Rasmussen SN, Polache A (1994) Specificity of the imino acid carrier in rat small intestine. Am J Physiol 266:R1154–R1161PubMedGoogle Scholar
  42. 42.
    Munck LK, Grondahl ML, Thorboll JE, Skadhauge E, Munck BG (2000) Transport of neutral, cationic and anionic amino acids by systems B, b(o,+), X(AG), and ASC in swine small intestine. Comp Biochem Physiol A Mol Integr Physiol 126:527–537CrossRefPubMedGoogle Scholar
  43. 43.
    Nakanishi T et al (2001) Na+- and Cl -coupled active transport of carnitine by the amino acid transporter ATB(0,+) from mouse colon expressed in HRPE cells and Xenopus oocytes. J Physiol 532:297–304CrossRefPubMedGoogle Scholar
  44. 44.
    Nozaki J et al (2001) Homozygosity mapping to chromosome 5p15 of a gene responsible for Hartnup disorder. Biochem Biophys Res Commun 284:255–260CrossRefPubMedGoogle Scholar
  45. 45.
    Obermuller N, Kranzlin B, Verma R, Gretz N, Kriz W, Witzgall R (1997) Renal osmotic stress-induced cotransporter: expression in the newborn, adult and post-ischemic rat kidney. Kidney Int 52:1584–1592PubMedGoogle Scholar
  46. 46.
    Palacin M, Goodyer P, Nunes V, Gasparini P (2001) Cystinuria. In: Scriver CR, Beaudet AL, Sly SW, Valle D (eds) Metabolic and molecular basis of inherited diseases, 9th edn. McGraw-Hill, NY, pp 4909–4932Google Scholar
  47. 47.
    Quan H et al (2004) Hypertension and impaired glycine handling in mice lacking the orphan transporter XT2. Mol Cell Biol 24:4166–4173CrossRefPubMedGoogle Scholar
  48. 48.
    Rajendran VM, Barry JA, Kleinman JG, Ramaswamy K (1987) Proton gradient-dependent transport of glycine in rabbit renal brush-border membrane vesicles. J Biol Chem 262:14974–14977PubMedGoogle Scholar
  49. 49.
    Roigaard-Petersen H, Jacobsen C, Iqbal Sheikh M (1987) H+-l-proline cotransport by vesicles from pars convoluta of rabbit proximal tubule. Am J Physiol 253:F15–F20PubMedGoogle Scholar
  50. 50.
    Samarzija I, Fromter E (1982) Electrophysiological analysis of rat renal sugar and amino acid transport. III. Neutral amino acids. Pflugers Arch 393:119–209PubMedGoogle Scholar
  51. 51.
    Scriver CR (1968) Renal tubular transport of proline, hydroxyproline, and glycine. 3. Genetic basis for more than one mode of transport in human kidney. J Clin Invest 47:823–835PubMedGoogle Scholar
  52. 52.
    Scriver CR, Efron ML, Schafer IA (1964) Renal tubular transport of proline, hydroxyproline, and glycine in health and in familial hyperprolinemia. J Clin Invest 43:374–385PubMedGoogle Scholar
  53. 53.
    Scriver CR et al (1987) The Hartnup phenotype: Mendelian transport disorder, multifactorial disease. Am J Hum Genet 40:401–412PubMedGoogle Scholar
  54. 54.
    Seow HF et al (2004) Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genet 36:1003–1007CrossRefPubMedGoogle Scholar
  55. 55.
    Sepulveda FV, Smith MW (1978) Discrimination between different entry mechanisms for neutral amino acids in rabbit ileal mucosa. J Physiol 282:73–90PubMedGoogle Scholar
  56. 56.
    Silbernagl S, Foulkes EC, Deetjen P (1975) Renal transport of amino acids. Rev Physiol Biochem Pharmacol 74:105–167PubMedGoogle Scholar
  57. 57.
    Sloan JL, Mager S (1999) Cloning and functional expression of a human Na(+) and Cl(−)-dependent neutral and cationic amino acid transporter B(0+). J Biol Chem 274:23740–23745CrossRefPubMedGoogle Scholar
  58. 58.
    Stevens BR, Kaunitz JD, Wright EM (1984) Intestinal transport of amino acids and sugars: advances using membrane vesicles. Annu Rev Physiol 46:417–433CrossRefPubMedGoogle Scholar
  59. 59.
    Stevens BR, Ross HJ, Wright EM (1982) Multiple transport pathways for neutral amino acids in rabbit jejunal brush border vesicles. J Membr Biol 66:213–225CrossRefPubMedGoogle Scholar
  60. 60.
    Stevens BR, Wright EM (1985a) Kinetic model of the brush-border proline/sodium (IMINO) cotransporter. Ann N Y Acad Sci 456:115–117PubMedGoogle Scholar
  61. 61.
    Stevens BR, Wright EM (1985b) Substrate specificity of the intestinal brush-border proline/sodium (IMINO) transporter. J Membr Biol 87:27–34CrossRefPubMedGoogle Scholar
  62. 62.
    Stevens BR, Wright EM (1987) Kinetics of the intestinal brush border proline (Imino) carrier. J Biol Chem 262:6546–6551PubMedGoogle Scholar
  63. 63.
    Takanaga H, Mackenzie B, Suzuki Y, Hediger MA (2005) Identification of Mammalian proline transporter SIT1 (SLC6A20) with characteristics of classical system imino. J Biol Chem 280:8974–8984CrossRefPubMedGoogle Scholar
  64. 64.
    Utsunomiya-Tate N, Endou H, Kanai Y (1996) Cloning and functional characterization of a system ASC-like Na+-dependent neutral amino acid transporter. J Biol Chem 271:14883–14890CrossRefPubMedGoogle Scholar
  65. 65.
    Verrey F, Closs EI, Wagner CA, Palacin M, Endou H, Kanai Y (2004) CATs and HATs: the SLC7 family of amino acid transporters. Pflugers Arch 447:532–542CrossRefPubMedGoogle Scholar
  66. 66.
    Verrey F, Meier C, Rossier G, Kuhn LC (2000) Glycoprotein-associated amino acid exchangers: broadening the range of transport specificity. Pflugers Arch 440:503–512PubMedGoogle Scholar
  67. 67.
    Wilcken B, Yu JS, Brown DA (1977) Natural history of Hartnup disease. Arch Dis Child 52:38–40PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Angelika Bröer
    • 1
  • Juleen A. Cavanaugh
    • 2
  • John E. J. Rasko
    • 3
  • Stefan Bröer
    • 1
  1. 1.School of Biochemistry and Molecular BiologyAustralian National UniversityCanberraAustralia
  2. 2.Medical Genetics Research Unit, ANU Medical SchoolThe Canberra HospitalWodenAustralia
  3. 3.Gene and Stem Cell Therapy, Centenary Institute of Cancer Medicine and Cell BiologyUniversity of Sydney and Sydney Cancer Centre, Royal Prince Alfred HospitalNewtownAustralia

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