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Chemical Compound Review

NORLEUCINE     (2S)-2-aminohexanoic acid

Synonyms: Caprine, Glycoleucine, L-Norleucine, H-Nle-OH, PubChem21410, ...
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Disease relevance of NORLEUCINE

  • The X-ray crystal structures of an anti-p24 (HIV-1) monoclonal antibody Fab fragment alone and in complexes with the epitope peptide GATPQDLNTnL (n = norleucine), an epitope-homologous peptide GATPEDLNQKLAGN, as well as two unrelated peptides GLYEWGGARITNTD and efslkGpllqwrsG (D-peptide), are presented to a maximum resolution of 2.6 A [1].
  • The structure of a complex between a peptide inhibitor with the sequence N-acetyl-Thr-Ile-Nle-psi[CH2-NH]-Nle-Gln-Arg.amide (Nle, norleucine) with chemically synthesized HIV-1 (human immunodeficiency virus 1) protease was determined at 2.3 A resolution (R factor of 0.176) [2].
  • Biosynthesis of a protein containing a nonprotein amino acid by Escherichia coli: L-2-aminohexanoic acid at position 21 in human epidermal growth factor [3].
  • This was also true for the D and L forms of the non-utilisable isomer of Leu, norleucine (nLeu) [4].
  • Norleucine accumulation by a norleucine-resistant mutant of Serratia marcescens [5].

High impact information on NORLEUCINE


Chemical compound and disease context of NORLEUCINE

  • Incorporation of norleucine at methionine positions in recombinant human macrophage colony stimulating factor (M-CSF, 4-153) expressed in Escherichia coli: structural analysis [11].
  • To understand the processing of the CA-p2 site, we have determined the structure of HIV-1 protease complexed with an analog of the CA-p2 site, the reduced peptide inhibitor Arg-Val-Leu-r-Phe-Glu-Ala-Ahx-NH2 [r denotes the reduced peptide bond and Ahx 2-aminohexanoic acid (norleucine), respectively] [12].

Biological context of NORLEUCINE


Anatomical context of NORLEUCINE


Associations of NORLEUCINE with other chemical compounds

  • We have developed a radioiodinated photoaffinity label, N-formyl-Nle-Leu-Phe-Nle-125I-Tyr-Lys-N-6-(4'-azido-2'-nitrophenylamino) hexanoate (where Nle represents norleucine) (125I-PAL), which forms a covalent complex with the formyl peptide chemotactic receptor of living human neutrophils [23].
  • We have examined the impact of C-H...pi and hydrophobic interactions in the diagonal position of a beta-hairpin peptide through comparison of the interaction of Phe, Trp, or Cha (cyclohexylalanine) with Lys or Nle (norleucine) [24].
  • Randomization at three positions considered to be important for proteinase specificity (P2, P1 and P'2) with the genetically coded amino acids (minus cysteine) plus norleucine generated 8000 permutations [25].
  • The RNA site is specific, discriminating against branched side chains of different size (valine--one methylene smaller than isoleucine) by at least 1.3 kcal/mol and against the shape (linear) of norleucine by 0.6 kcal/mol [26].
  • The pH optimum for the enzymatic activity was 5.0 with elastin-Congo red as the substrate, and the activity was not significantly inhibited by pepstatin A, diazoacetyl norleucine methylester, and 1,2-epoxy-3-(p-nitrophenoxy) propane [27].

Gene context of NORLEUCINE

  • Furthermore, this study reveals that these events were completely abrogated in cells exposed to Abeta peptides in which methionine 35 was substituted by a norleucine residue [28].
  • Mutations of the metK gene encoding S-adenosylmethionine synthetase, which is involved in Met metabolism, were detected in 12 norleucine-resistant mutants [29].
  • We have attempted to label the GRF receptor by chemically coupling the 125I-GRF analog [His1, Nle27]-hGRF(1-32)-NH2 (GRFa) (where Nle is norleucine) to plated rat anterior pituitary cells with the protein cross-linker disuccinimidyl suberate (DSS) (0.1 mM) [30].
  • We have purified a 30-kDa serine protease (designated RNK-Met-1) from the granules of the rat large granular lymphocyte leukemia cell line (RNK-16) that hydrolytically cleaves model peptide substrates after methionine, leucine, and norleucine (Met-ase activity) [31].
  • METHODS: Screening of combinatorial libraries has led to identification of D-Trp-Nle-NH2 (Nle, norleucine) and D-Trp-Arg-NH2 as the smallest structures known to antagonize the amphibian MCR (1) [32].

Analytical, diagnostic and therapeutic context of NORLEUCINE


  1. Crystallographic analysis of anti-p24 (HIV-1) monoclonal antibody cross-reactivity and polyspecificity. Keitel, T., Kramer, A., Wessner, H., Scholz, C., Schneider-Mergener, J., Höhne, W. Cell (1997) [Pubmed]
  2. Structure of complex of synthetic HIV-1 protease with a substrate-based inhibitor at 2.3 A resolution. Miller, M., Schneider, J., Sathyanarayana, B.K., Toth, M.V., Marshall, G.R., Clawson, L., Selk, L., Kent, S.B., Wlodawer, A. Science (1989) [Pubmed]
  3. Biosynthesis of a protein containing a nonprotein amino acid by Escherichia coli: L-2-aminohexanoic acid at position 21 in human epidermal growth factor. Koide, H., Yokoyama, S., Kawai, G., Ha, J.M., Oka, T., Kawai, S., Miyake, T., Fuwa, T., Miyazawa, T. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  4. Chirality differences in amino acid retention and release from acid-extractable pool of cultured mammalian cells. Wheatley, D.N., Slater, J., Love, E.M., Miseta, A. Int. J. Biochem. Cell Biol. (1996) [Pubmed]
  5. Norleucine accumulation by a norleucine-resistant mutant of Serratia marcescens. Kisumi, M., Sugiura, M., Chibata, I. Appl. Environ. Microbiol. (1977) [Pubmed]
  6. Crystal structure of a catalytic antibody with a serine protease active site. Zhou, G.W., Guo, J., Huang, W., Fletterick, R.J., Scanlan, T.S. Science (1994) [Pubmed]
  7. Corticotropin-releasing factor receptors in rat forebrain: autoradiographic identification. De Souza, E.B., Perrin, M.H., Insel, T.R., Rivier, J., Vale, W.W., Kuhar, M.J. Science (1984) [Pubmed]
  8. Synthesis and biological evaluation of antagonists of growth hormone-releasing hormone with high and protracted in vivo activities. Varga, J.L., Schally, A.V., Csernus, V.J., Zarándi, M., Halmos, G., Groot, K., Rékási, Z. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  9. Synthesis and biological evaluation of superactive agonists of growth hormone-releasing hormone. Izdebski, J., Pinski, J., Horvath, J.E., Halmos, G., Groot, K., Schally, A.V. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  10. Development of potent gastrin-releasing peptide antagonists having a D-Pro-psi(CH2NH)-Phe-NH2 C terminus. Leban, J.J., Kull, F.C., Landavazo, A., Stockstill, B., McDermed, J.D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  11. Incorporation of norleucine at methionine positions in recombinant human macrophage colony stimulating factor (M-CSF, 4-153) expressed in Escherichia coli: structural analysis. Randhawa, Z.I., Witkowska, H.E., Cone, J., Wilkins, J.A., Hughes, P., Yamanishi, K., Yasuda, S., Masui, Y., Arthur, P., Kletke, C. Biochemistry (1994) [Pubmed]
  12. Crystallographic analysis of human immunodeficiency virus 1 protease with an analog of the conserved CA-p2 substrate -- interactions with frequently occurring glutamic acid residue at P2' position of substrates. Weber, I.T., Wu, J., Adomat, J., Harrison, R.W., Kimmel, A.R., Wondrak, E.M., Louis, J.M. Eur. J. Biochem. (1997) [Pubmed]
  13. Potent and sustained satiety actions of a cholecystokinin octapeptide analogue. Moran, T.H., Sawyer, T.K., Seeb, D.H., Ameglio, P.J., Lombard, M.A., McHugh, P.R. Am. J. Clin. Nutr. (1992) [Pubmed]
  14. A comparison of the crystallographic structures of two catalytic antibodies with esterase activity. Buchbinder, J.L., Stephenson, R.C., Scanlan, T.S., Fletterick, R.J. J. Mol. Biol. (1998) [Pubmed]
  15. Uterine relaxing action of parathyroid hormone: effect of oxidation and methionine substitution. Shew, R.L., Kenny, A.D., Pang, P.K. Proc. Soc. Exp. Biol. Med. (1984) [Pubmed]
  16. Leucine is a direct-acting nutrient signal that regulates protein synthesis in adipose tissue. Lynch, C.J., Patson, B.J., Anthony, J., Vaval, A., Jefferson, L.S., Vary, T.C. Am. J. Physiol. Endocrinol. Metab. (2002) [Pubmed]
  17. Inhibition by L-valine and L-norleucine of 3-phenylpyruvate-induced insulin release. Sener, A., Malaisse, W.J. Biochimie (1984) [Pubmed]
  18. The dynamics of ligand-receptor interactions. Real-time analyses of association, dissociation, and internalization of an N-formyl peptide and its receptors on the human neutrophil. Sklar, L.A., Finney, D.A., Oades, Z.G., Jesaitis, A.J., Painter, R.G., Cochrane, C.G. J. Biol. Chem. (1984) [Pubmed]
  19. Discovery of a high affinity radioligand for the human orphan receptor, bombesin receptor subtype 3, which demonstrates that it has a unique pharmacology compared with other mammalian bombesin receptors. Mantey, S.A., Weber, H.C., Sainz, E., Akeson, M., Ryan, R.R., Pradhan, T.K., Searles, R.P., Spindel, E.R., Battey, J.F., Coy, D.H., Jensen, R.T. J. Biol. Chem. (1997) [Pubmed]
  20. Identification of neurite outgrowth active sites on the laminin alpha4 chain G domain. Ichikawa, N., Kasai, S., Suzuki, N., Nishi, N., Oishi, S., Fujii, N., Kadoya, Y., Hatori, K., Mizuno, Y., Nomizu, M., Arikawa-Hirasawa, E. Biochemistry (2005) [Pubmed]
  21. Studies on amino acid inhibition of monosaccharide exit from anuran small intestinal epithelium. Boyd, C.A. J. Physiol. (Lond.) (1979) [Pubmed]
  22. Tissue-specific effects of chronic dietary leucine and norleucine supplementation on protein synthesis in rats. Lynch, C.J., Hutson, S.M., Patson, B.J., Vaval, A., Vary, T.C. Am. J. Physiol. Endocrinol. Metab. (2002) [Pubmed]
  23. Formyl peptide chemotactic receptor. Evidence for an active proteolytic fragment. Dolmatch, B., Niedel, J. J. Biol. Chem. (1983) [Pubmed]
  24. Comparison of C-H...pi and hydrophobic interactions in a beta-hairpin peptide: impact on stability and specificity. Tatko, C.D., Waters, M.L. J. Am. Chem. Soc. (2004) [Pubmed]
  25. Selection of chymotrypsin inhibitors from a conformationally-constrained combinatorial peptide library. McBride, J.D., Freeman, N., Domingo, G.J., Leatherbarrow, R.J. J. Mol. Biol. (1996) [Pubmed]
  26. Isoleucine:RNA sites with associated coding sequences. Majerfeld, I., Yarus, M. RNA (1998) [Pubmed]
  27. Molecular cloning of the cDNA and gene for an elastinolytic aspartic proteinase from Aspergillus fumigatus and evidence of its secretion by the fungus during invasion of the host lung. Lee, J.D., Kolattukudy, P.E. Infect. Immun. (1995) [Pubmed]
  28. Substitution of methionine 35 inhibits apoptotic effects of Abeta(31-35) and Abeta(25-35) fragments of amyloid-beta protein in PC12 cells. Clementi, M.E., Misiti, F. Med. Sci. Monit. (2005) [Pubmed]
  29. Effects of deregulation of methionine biosynthesis on methionine excretion in Escherichia coli. Usuda, Y., Kurahashi, O. Appl. Environ. Microbiol. (2005) [Pubmed]
  30. Cross-linking of a growth hormone releasing factor-binding protein in anterior pituitary cells. Zysk, J.R., Cronin, M.J., Anderson, J.M., Thorner, M.O. J. Biol. Chem. (1986) [Pubmed]
  31. Purification and cloning of a novel serine protease, RNK-Met-1, from the granules of a rat natural killer cell leukemia. Smyth, M.J., Wiltrout, T., Trapani, J.A., Ottaway, K.S., Sowder, R., Henderson, L.E., Kam, C.M., Powers, J.C., Young, H.A., Sayers, T.J. J. Biol. Chem. (1992) [Pubmed]
  32. Structure-based search for peptide ligands that cross-react with melanocortin receptors. Quillan, J.M., Sadée, W. Pharm. Res. (1996) [Pubmed]
  33. Conservative replacement of methionine by norleucine in Escherichia coli adenylate kinase. Gilles, A.M., Marlière, P., Rose, T., Sarfati, R., Longin, R., Meier, A., Fermandjian, S., Monnot, M., Cohen, G.N., Bârzu, O. J. Biol. Chem. (1988) [Pubmed]
  34. Separation and characterization of modified variants of recombinant human insulin-like growth factor I derived from a fusion protein secreted from Escherichia coli. Forsberg, G., Palm, G., Ekebacke, A., Josephson, S., Hartmanis, M. Biochem. J. (1990) [Pubmed]
  35. Amino acids of the Murchison meteorite: I. Six carbon acyclic primary alpha-amino alkanoic acids. Cronin, J.R., Gandy, W.E., Pizzarello, S. J. Mol. Evol. (1981) [Pubmed]
  36. Identification of unusual replacement of methionine by norleucine in recombinant interleukin-2 produced by E. coli. Lu, H.S., Tsai, L.B., Kenney, W.C., Lai, P.H. Biochem. Biophys. Res. Commun. (1988) [Pubmed]
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