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Chemical Compound Review

alanine     (2S)-2-aminopropanoic acid

Synonyms: Alaninum, alanina, polyalanine, L-Alanin, L-alanine, ...
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Disease relevance of L-alanine

  • Eighteen hypoglycemic patients with severe malnutrition had been ill longer than 26 better-nourished patients with hypoglycemia (median duration of illness, 18 vs. 10 hours; P = 0.023) and had lower median plasma concentrations of lactate (1.9 vs. 3.9 mmol per liter; P = 0.021) and alanine (173 vs. 293 micromol per liter; P = 0.040) [1].
  • Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome [2].
  • Plasma concentrations of insulin and C peptide were inappropriately high, and lactate and alanine concentrations were significantly higher than in patients with falciparum malaria who were normoglycemic (P less than 0.05) [3].
  • Gene deletions show that much of Escherichia coli alanine tRNA synthetase is dispensable for each of three activities and that these activities appear to require specific domains arranged linearly along the polypeptide [4].
  • Here we show that treatment with arimoclomol, a coinducer of heat shock proteins (HSPs), significantly delays disease progression in mice expressing a SOD1 mutant in which glycine is substituted with alanine at position 93 (SOD1(G93A)) [5].

Psychiatry related information on L-alanine

  • CONCLUSIONS: Homozygosity for alanine in the mitochondrial targeting sequence of manganese superoxide does not modify alcohol consumption and the risk of macrovacuolar steatosis in alcoholics but is a major risk factor for severe alcoholic liver disease [6].
  • More recently, expansions of alanine tracts, particularly in transcription factor genes, have been shown to cause at least nine human conditions, including mental retardation and malformations of the brain, digits and other structures [7].
  • Mutation of residues that directly hydrogen bond glucose hydroxyls (Asn-204, Glu-256, and Glu-290) to alanine resulted in enzymes that did not exhibit cooperative behavior, but mutation of Lys-56 or other residues that do not directly contact glucose had no effect on the Hill coefficient [8].
  • Study of Al3+ binding and conformational properties of the alanine-substituted C-terminal domain of the NF-M protein and its relevance to Alzheimer's disease [9].
  • Among non-treatment reasons, alcoholism (P = 0.001), drug-addiction (P = 0.04) and escaping monitoring (P = 0.04) were more frequent in males than in females, whereas normal alanine transferase was more frequent in females than in males (P = 0.004) [10].

High impact information on L-alanine

  • Replacement of bulky hydrophobic residues in the alpha helix with alanine yields Sar1p mutants that are unable to generate highly curved membranes and are defective in vesicle formation from native ER membranes despite normal recruitment of coat and cargo proteins [11].
  • By contrast, aphidicolin-treated extracts containing mutants of Claspin with alanine substitutions at positions 906 or 934 (T906A or S934A) are unable to undergo adaptation [12].
  • Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein [13].
  • Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei [14].
  • This 566C-->T mutation, predicting an alanine to valine substitution, is located in exon 7 of the FSHR gene, in the region encoding the extracellular domain of the receptor molecule [15].

Chemical compound and disease context of L-alanine


Biological context of L-alanine

  • Using alanine-scanning mutagenesis, we have found that microtubule-interacting kinesin residues are located in three loops that cluster in a patch on the motor surface [21].
  • Here we report the in vitro and in vivo consequences of converting these sites to alanine residues, which eliminates phosphorylation at these positions, or to aspartate residues, which mimics the negative charge state of the phosphorylated molecule [22].
  • Cultured NIH 3T3 cells devoid of endogenous EGF receptors were transfected with cDNA constructs encoding either the human EGF receptor or an EGF receptor mutant in which Lys721, a key residue in the ATP binding site, was replaced with an alanine residue [23].
  • Hypoglycemia was associated with low plasma insulin concentrations and with elevated plasma concentrations of lactate, alanine, and 5'-nucleotidase--a finding that suggests that impaired hepatic gluconeogenesis but not hyperinsulinemia contributes to the pathogenesis of pretreatment hypoglycemia [24].
  • Complete nucleotide sequence analysis of this cloned alanine tRNA gene and its primary transcript shows that transcription initiates three nucleotides away from the mature tRNA2Ala 5' end and terminates in a U cluster 22 nucleotides beyond the last encoded 3' nucleotide of the mature species [25].

Anatomical context of L-alanine

  • We compared the presentation of peptide antigens and superantigens by a panel of mutant-presenting cell lines, each displaying an A kappa alpha chain with a single alanine replacement along the alpha helix proposed to form one face of the groove [26].
  • T-cell development is normal in transgenic mice that express a dominant-negative form of CREB (CREBA119, with alanine at position 119) under the control of the T-cell-specific CD2 promoter/enhancer [27].
  • PABPN1 with an expanded polyalanine tract forms aggregates consisting of tubular filaments within the nuclei of skeletal muscle fibers [28].
  • Recently, we showed that the myristoylated, alanine-rich C-kinase substrate (MARCKS) protein is required for mucus secretion by human bronchial epithelial cells in culture [29].
  • Primary rat embryo fibroblasts were transformed by a p53 mutant (alanine to valine change at amino acid 135) plus ras [30].

Associations of L-alanine with other chemical compounds


Gene context of L-alanine

  • Substitution of Ser-51 with alanine eliminates phosphorylation of eIF-2 alpha by GCN2 in vivo and in vitro and abolishes increased expression of GCN4 and amino acid biosynthetic genes under its control in amino acid-starved cells [36].
  • We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14 [37].
  • However, unlike many polypeptide hormones (including EGF), cleavage of the 50-amino acid TGF-alpha from the larger form does not occur at paired basic residues, but rather between alanine and valine residues, suggesting the role of a novel protease [38].
  • Here, it is demonstrated that synpolydactyly, an inherited human abnormality of the hands and feet, is caused by expansions of a polyalanine stretch in the amino-terminal region of HOXD13 [39].
  • The complementary DNA for hPRL was cloned, expressed in Escherichia coli, and mutated to introduce sequentially those substitutions from hGH that were predicted by alanine-scanning mutagenesis and other studies to be most critical for binding to the hGH receptor from human liver [40].

Analytical, diagnostic and therapeutic context of L-alanine


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  2. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Amiel, J., Laudier, B., Attié-Bitach, T., Trang, H., de Pontual, L., Gener, B., Trochet, D., Etchevers, H., Ray, P., Simonneau, M., Vekemans, M., Munnich, A., Gaultier, C., Lyonnet, S. Nat. Genet. (2003) [Pubmed]
  3. Severe hypoglycemia and hyperinsulinemia in falciparum malaria. White, N.J., Warrell, D.A., Chanthavanich, P., Looareesuwan, S., Warrell, M.J., Krishna, S., Williamson, D.H., Turner, R.C. N. Engl. J. Med. (1983) [Pubmed]
  4. Modular arrangement of functional domains along the sequence of an aminoacyl tRNA synthetase. Jasin, M., Regan, L., Schimmel, P. Nature (1983) [Pubmed]
  5. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Kieran, D., Kalmar, B., Dick, J.R., Riddoch-Contreras, J., Burnstock, G., Greensmith, L. Nat. Med. (2004) [Pubmed]
  6. Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dismutase and risk for severe alcoholic liver disease. Degoul, F., Sutton, A., Mansouri, A., Cepanec, C., Degott, C., Fromenty, B., Beaugrand, M., Valla, D., Pessayre, D. Gastroenterology (2001) [Pubmed]
  7. Alanine tracts: the expanding story of human illness and trinucleotide repeats. Brown, L.Y., Brown, S.A. Trends Genet. (2004) [Pubmed]
  8. Site-directed mutagenesis studies on the determinants of sugar specificity and cooperative behavior of human beta-cell glucokinase. Xu, L.Z., Zhang, W., Weber, I.T., Harrison, R.W., Pilkis, S.J. J. Biol. Chem. (1994) [Pubmed]
  9. Study of Al3+ binding and conformational properties of the alanine-substituted C-terminal domain of the NF-M protein and its relevance to Alzheimer's disease. Shen, Z.M., Perczel, A., Hollósi, M., Nagypál, I., Fasman, G.D. Biochemistry (1994) [Pubmed]
  10. Is the management of hepatitis C patients appropriate? A population-based study. Hatem, C., Minello, A., Bresson-Hadni, S., Jooste, V., Evrard, P., Obert, B., Lepage, C., Bonithon-Kopp, C., Faivre, J., Monnet, E., Miguet, J.P., Hillon, P. Aliment. Pharmacol. Ther. (2005) [Pubmed]
  11. Sar1p N-terminal helix initiates membrane curvature and completes the fission of a COPII vesicle. Lee, M.C., Orci, L., Hamamoto, S., Futai, E., Ravazzola, M., Schekman, R. Cell (2005) [Pubmed]
  12. Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase. Yoo, H.Y., Kumagai, A., Shevchenko, A., Shevchenko, A., Dunphy, W.G. Cell (2004) [Pubmed]
  13. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Strømme, P., Mangelsdorf, M.E., Shaw, M.A., Lower, K.M., Lewis, S.M., Bruyere, H., Lütcherath, V., Gedeon, A.K., Wallace, R.H., Scheffer, I.E., Turner, G., Partington, M., Frints, S.G., Fryns, J.P., Sutherland, G.R., Mulley, J.C., Gécz, J. Nat. Genet. (2002) [Pubmed]
  14. Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. Brais, B., Bouchard, J.P., Xie, Y.G., Rochefort, D.L., Chrétien, N., Tomé, F.M., Lafrenière, R.G., Rommens, J.M., Uyama, E., Nohira, O., Blumen, S., Korczyn, A.D., Heutink, P., Mathieu, J., Duranceau, A., Codère, F., Fardeau, M., Rouleau, G.A., Korcyn, A.D. Nat. Genet. (1998) [Pubmed]
  15. Men homozygous for an inactivating mutation of the follicle-stimulating hormone (FSH) receptor gene present variable suppression of spermatogenesis and fertility. Tapanainen, J.S., Aittomäki, K., Min, J., Vaskivuo, T., Huhtaniemi, I.T. Nat. Genet. (1997) [Pubmed]
  16. Crystal structure and function of the isoniazid target of Mycobacterium tuberculosis. Dessen, A., Quémard, A., Blanchard, J.S., Jacobs, W.R., Sacchettini, J.C. Science (1995) [Pubmed]
  17. Conversion of a T cell antagonist into an agonist by repairing a defect in the TCR/peptide/MHC interface: implications for TCR signaling. Baker, B.M., Gagnon, S.J., Biddison, W.E., Wiley, D.C. Immunity (2000) [Pubmed]
  18. Mapping the energy of superantigen Staphylococcus enterotoxin C3 recognition of an alpha/beta T cell receptor using alanine scanning mutagenesis. Churchill, H.R., Andersen, P.S., Parke, E.A., Mariuzza, R.A., Kranz, D.M. J. Exp. Med. (2000) [Pubmed]
  19. Glucose and alanine metabolism in children with maple syrup urine disease. Haymond, M.W., Ben-Galim, E., Strobel, K.E. J. Clin. Invest. (1978) [Pubmed]
  20. Epstein-Barr virus-induced autoimmune responses. I. Immunoglobulin M autoantibodies to proteins mimicking and not mimicking Epstein-Barr virus nuclear antigen-1. Vaughan, J.H., Valbracht, J.R., Nguyen, M.D., Handley, H.H., Smith, R.S., Patrick, K., Rhodes, G.H. J. Clin. Invest. (1995) [Pubmed]
  21. Microtubule interaction site of the kinesin motor. Woehlke, G., Ruby, A.K., Hart, C.L., Ly, B., Hom-Booher, N., Vale, R.D. Cell (1997) [Pubmed]
  22. Dictyostelium myosin heavy chain phosphorylation sites regulate myosin filament assembly and localization in vivo. Egelhoff, T.T., Lee, R.J., Spudich, J.A. Cell (1993) [Pubmed]
  23. Point mutation at the ATP binding site of EGF receptor abolishes protein-tyrosine kinase activity and alters cellular routing. Honegger, A.M., Dull, T.J., Felder, S., Van Obberghen, E., Bellot, F., Szapary, D., Schmidt, A., Ullrich, A., Schlessinger, J. Cell (1987) [Pubmed]
  24. Blood glucose levels in Malawian children before and during the administration of intravenous quinine for severe falciparum malaria. Taylor, T.E., Molyneux, M.E., Wirima, J.J., Fletcher, K.A., Morris, K. N. Engl. J. Med. (1988) [Pubmed]
  25. The primary transcription product of a silkworm alanine tRNA gene: identification of in vitro sites of initiation, termination and processing. Hagenbüchle, O., Larson, D., Hall, G.I., Sprague, K.U. Cell (1979) [Pubmed]
  26. Superantigens interact with MHC class II molecules outside of the antigen groove. Dellabona, P., Peccoud, J., Kappler, J., Marrack, P., Benoist, C., Mathis, D. Cell (1990) [Pubmed]
  27. Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB. Barton, K., Muthusamy, N., Chanyangam, M., Fischer, C., Clendenin, C., Leiden, J.M. Nature (1996) [Pubmed]
  28. Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice. Davies, J.E., Wang, L., Garcia-Oroz, L., Cook, L.J., Vacher, C., O'Donovan, D.G., Rubinsztein, D.C. Nat. Med. (2005) [Pubmed]
  29. A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Singer, M., Martin, L.D., Vargaftig, B.B., Park, J., Gruber, A.D., Li, Y., Adler, K.B. Nat. Med. (2004) [Pubmed]
  30. Cellular localization and cell cycle regulation by a temperature-sensitive p53 protein. Martinez, J., Georgoff, I., Martinez, J., Levine, A.J. Genes Dev. (1991) [Pubmed]
  31. Effects of oral alanine feeding on blood glucose, plasma glucagon and insulin concentrations in small-for-gestational-age infants. Williams, P.R., Fiser, R.H., Sperling, M.A., Oh, W. N. Engl. J. Med. (1975) [Pubmed]
  32. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Freund, C.L., Gregory-Evans, C.Y., Furukawa, T., Papaioannou, M., Looser, J., Ploder, L., Bellingham, J., Ng, D., Herbrick, J.A., Duncan, A., Scherer, S.W., Tsui, L.C., Loutradis-Anagnostou, A., Jacobson, S.G., Cepko, C.L., Bhattacharya, S.S., McInnes, R.R. Cell (1997) [Pubmed]
  33. A tyrosine-based signal targets H/K-ATPase to a regulated compartment and is required for the cessation of gastric acid secretion. Courtois-Coutry, N., Roush, D., Rajendran, V., McCarthy, J.B., Geibel, J., Kashgarian, M., Caplan, M.J. Cell (1997) [Pubmed]
  34. Prevention of human diabetic ketoacidosis by somatostatin. Evidence for an essential role of glucagon. Gerich, J.E., Lorenzi, M., Bier, D.M., Schneider, V., Tsalikian, E., Karam, J.H., Forsham, P.H. N. Engl. J. Med. (1975) [Pubmed]
  35. A simple structural feature is a major determinant of the identity of a transfer RNA. Hou, Y.M., Schimmel, P. Nature (1988) [Pubmed]
  36. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Dever, T.E., Feng, L., Wek, R.C., Cigan, A.M., Donahue, T.F., Hinnebusch, A.G. Cell (1992) [Pubmed]
  37. A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex. Hovnanian, A., Pollack, E., Hilal, L., Rochat, A., Prost, C., Barrandon, Y., Goossens, M. Nat. Genet. (1993) [Pubmed]
  38. Cloning and sequence analysis of a cDNA for rat transforming growth factor-alpha. Lee, D.C., Rose, T.M., Webb, N.R., Todaro, G.J. Nature (1985) [Pubmed]
  39. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Muragaki, Y., Mundlos, S., Upton, J., Olsen, B.R. Science (1996) [Pubmed]
  40. Engineering human prolactin to bind to the human growth hormone receptor. Cunningham, B.C., Henner, D.J., Wells, J.A. Science (1990) [Pubmed]
  41. Restriction of glycolipids to the outer half of a plasma membrane: concanavalin A labeling of membrane halves in Acanthamoeba castellanii. Barbosa, M.L., Pinto da Silva, P. Cell (1983) [Pubmed]
  42. High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Cunningham, B.C., Wells, J.A. Science (1989) [Pubmed]
  43. The cytomegalovirus DNA polymerase subunit UL44 forms a C clamp-shaped dimer. Appleton, B.A., Loregian, A., Filman, D.J., Coen, D.M., Hogle, J.M. Mol. Cell (2004) [Pubmed]
  44. The V beta complementarity determining region 1 of a major histocompatibility complex (MHC) class I-restricted T cell receptor is involved in the recognition of peptide/MHC I and superantigen/MHC II complex. Bellio, M., Lone, Y.C., de la Calle-Martin, O., Malissen, B., Abastado, J.P., Kourilsky, P. J. Exp. Med. (1994) [Pubmed]
  45. Ig beta tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization. Gazumyan, A., Reichlin, A., Nussenzweig, M.C. J. Exp. Med. (2006) [Pubmed]
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