4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating Hormone: a Highly Potent Alpha-melanotropin with Ultralong Biological Activity

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1980 Oct 1

PMID 6777774

Citations 159

Authors

T K Sawyer

P J Sanfilippo

V J Hruby

M H Engel

C B Heward

J B Burnett

M E Hadley

Affiliations

Soon will be listed here.

Abstract

alpha-Melanocyte-stimulating hormone (alpha-MSH) reversibly darkens frog skins by stimulating melanosome movement (dispersion) within melanophores. Heat-alkali treatment of alpha-MSH results in prolonged biological activity of the hormone. Quantitative gas chromatographic analysis of the hydrolyzed heat-alkali-treated peptide revealed partial racemization particularly at the 4(methionine) and 7(phenylalanine) positions. [Nle4]-alpha-MSH, a synthetic analogue of alpha-MSH, reversibly darkens frog skins and also exhibits prolonged activity after heat-alkali treatment. Synthesis of [Nle4, D-Phe7]-alpha-MSH provided an analogue with prolonged biological activity identical to that observed with heat-alkali-treated alpha-MSH or [Nle4]-alpha-MSH. [Nle4, D-Phe7]-alpha-MSH was resistant to enzymatic degradation by serum enzymes. In addition, this peptide exhibited dramatically increased biological activity as determined by frog skin bioassay, activation of mouse melanoma adenylate cyclase, and stimulation of mouse melanoma cell tyrosinase activity. This Nle4, D-Phe7 synthetic analogue of alpha-MSH is a very porent melanotropin, 26 times as potent as alpha-MSH in the adenylate cyclase assay. The resistance of the peptide to enzymatic degradation and its extraordinarily potent and prolonged biological activity should make this analogue of alpha-MSH an important molecular probe for studying the melanotropin receptors of both normal and abnormal (melanoma) melanocytes.

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References

Pollock G, FROMMHAGEN L . The extent of racemization of some amino acids in dilute alkali-treated protein and soil humic and fulvic acid. Anal Biochem. 1968; 24(1):18-26. DOI: 10.1016/0003-2697(68)90055-9. View

Bregman M, Sawyer T, Hadley M, Hruby V . Adenosine and divalent cation effects on S-91 melanoma adenylate cyclase. Arch Biochem Biophys. 1980; 201(1):1-7. DOI: 10.1016/0003-9861(80)90480-4. View

Silman R, Chard T, LANDON J, Lowry P, Smith I, Young I . ACTH and MSH peptides in the human adult and fetal pituitary gland. Front Horm Res. 1977; 4:179-87. DOI: 10.1159/000400364. View

Lemaire S, Yamashiro D, Li C . Synthesis and biological activity of camel and bovine beta-melanotropins. J Med Chem. 1976; 19(3):373-6. DOI: 10.1021/jm00225a006. View

Pert C, Pert A, Chang J, Fong B . (D-Ala2)-Met-enkephalinamide: a potent, long-lasting synthetic pentapeptide analgesic. Science. 1976; 194(4262):330-2. DOI: 10.1126/science.968485. View

Heward C, Yang Y, Sawyer T, Bregman M, Fuller B, Hruby V . Iodination associated inactivation of beta-melanocyte stimulating hormone. Biochem Biophys Res Commun. 1979; 88(1):266-73. DOI: 10.1016/0006-291x(79)91725-x. View

Yang Y, Hruby V, Heward C, Hadley M . Synthesis of alpha- and beta-melanocyte stimulating hormones. Int J Pept Protein Res. 1980; 15(2):130-8. View

Heward C, Yang Y, Ormberg J, Hadley M, Hruby V . Effects of chloramine T and iodination on the biological activity of melanotropin. Hoppe Seylers Z Physiol Chem. 1979; 360(12):1851-9. DOI: 10.1515/bchm2.1979.360.2.1851. View

van der Gugten A, Waters M, Murthy G, Friesen H . Studies on the irreversible nature of prolactin binding to receptors. Endocrinology. 1980; 106(1):402-11. DOI: 10.1210/endo-106-1-402. View

10.

Huntington T, Hadley M . Evidence against mass action direct feedback control of melanophore-stimulating hormone (MSH) release. Endocrinology. 1974; 95(2):472-9. DOI: 10.1210/endo-95-2-472. View

11.

Noll B, Jarboe C, HASS L . Kinetic studies on the alkali-catalyzed hydrolysis and epimerization of model alkyl and hydroxyalkyl di- and tripeptides. Biochemistry. 1974; 13(25):5164-9. DOI: 10.1021/bi00722a018. View

12.

Smith G, DE Sol B . Racemization of Amino Acids in Dipeptides Shows COOH > NH2 for Non-Sterically Hindered Residues. Science. 1980; 207(4432):765-7. DOI: 10.1126/science.207.4432.765. View

13.

Salomon Y, Londos C, Rodbell M . A highly sensitive adenylate cyclase assay. Anal Biochem. 1974; 58(2):541-8. DOI: 10.1016/0003-2697(74)90222-x. View

14.

Fuller B, Viskochil D . The role of RNA and protein synthesis in mediating the action of MSH on mouse melanoma cells. Life Sci. 1979; 24(26):2405-15. DOI: 10.1016/0024-3205(79)90448-x. View

15.

SHIZUME K, LERNER A, Fitzpatrick T . In vitro bioassay for the melanocyte stimulating hormone. Endocrinology. 1954; 54(5):553-60. DOI: 10.1210/endo-54-5-553. View

16.

Kriausakul N, Mitterer R . Isoleucine epimerization in peptides and proteins: kinetic factors and application to fossil proteins. Science. 1978; 201(4360):1011-4. DOI: 10.1126/science.201.4360.1011. View

17.

Wright M, LERNER A . On the movement of pigment granules in frog melanocytes. Endocrinology. 1960; 66:599-609. DOI: 10.1210/endo-66-4-599. View

18.

Williams K, Smith G . A critical evaluation of the application of amino acid racemization to geochronology and geothermometry. Orig Life. 1977; 8(2):91-144. DOI: 10.1007/BF00927978. View

19.

Engel M, Zumberge J, Nagy B . Kinetics of amino acid racemization in Sequoiadendron giganteum heartwood. Anal Biochem. 1977; 82(2):415-22. DOI: 10.1016/0003-2697(77)90179-8. View

20.

Lee T, BUETTNER-JANUSCH V . On the mechanism of sodium hydroxide modification of alpha-melanocyte-stimulating hormone. J Biol Chem. 1963; 238:2012-5. View