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Modification of sialyl residues of gonadotropic hormones by reductive amination. Influence on biological activity and circulating half-life
Authors:Marianne C Murray  V P Bhavanandan  Eugene A Davidson
Institution:(1) Department of Biological Chemistry, The Milton S Hershey Medical Center, The Pennsylvania State University, 17033 Hershey, PA, USA;(2) The Cell and Molecular Biology Center, The Milton S Hershey Medical Center, The Pennsylvania State University, 17033 Hershey, PA, USA;(3) Present address: Rockefeller University, 1230 York Avenue, Box 282, 10021 New York, NY, USA;(4) Present address: Department of Biochemistry, Georgetown University, 3900 Reservoir Rd., NW, 20007 Washington, DC, USA
Abstract:The sialic acid residues of human chorionic gonadotropin, human lutropin and human follitropin were quantitatively modified by introduction of an amino compound. In radioreceptor assays, the modified chorionic gonadotropin, lutropin and follitropin saturated the receptors. However, in the low nanogram range, the gonadotropic binding was higher for the control compared to the modified sample.The hormonal activity of the chorionic gonadotropin was testedin vitro. The modified preparations were four- to thirteen-fold less stimulatory compared to the control but elicited the same maximal response. The biological activity of follitropin was determinedin vivo. In this case, the modified preparations were four- to five-fold less stimulatory than the control. Both the modified chorionic gonadotropin and follitropin preparations were found to act as agonists. Modification of the gonadotropin hormones did not significantly alter the immune recognition of these glycoproteins.The apparent circulating half-life in rats of the modified chorionic gonadotropin and follitropin was increased six- to nine-fold compared to that of native hormones; this might be a consequence of resistance of the modified sialyl residues to sialidases and the resultant slower exposure of terminal galactosyl residues; the plasma half-life of modified lutropin remained the same as that of the native hormone.Abbreviations hCG human chorionic gonadotropin - hLH human lutropin or luteinizing hormone - hFSF human follitropin or follicle stimulating hormone - mala methyl ester of alanine - hCG(ala, mala, etc.) human chorionic gonadotropin modified on sialicacid by reductive amination with alanine, methyl ester of alanine, etc. - IRP-HMG intact rat prostrate-human menopausal gonadotropin
Keywords:glycoprotein hormones  sialyl modification  reductive amination
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