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      Pro-Gonadotropin-Releasing Hormone Protein Is Processed within Hypothalamic Neurosecretory Granules

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          Abstract

          Peptide-hormones are synthesized as higher-molecular-weight precursor proteins which must undergo numerous posttranslational modifications to yield the bioactive peptide(s) which may include limited endoproteolysis, limited exopeptidase digestion, and C-terminal amidation. Three different enzymes which are likely to be the physiologically relevant processing enzymes of bovine pro-gonadotropin-releasing hormone (pro-GnRH) precursor protein have been colocalized to, and purified from, hypothalamic neurosecretory granules. Gonadotropin-releasing-hormone-associated-peptide-releasing enzyme initiates processing by endoproteolysis of the pro-hormone exclusively at the Argl3-Aspl4 bond in the sequence, -Gly6-Leu-Arg-Pro-Gly10-Gly-Lys12-Arg13-Asp-, which overlaps the sequence for GnRH (1–10) and GAP(14–69) within the pro-protein. Hypothalamic carboxypeptidase E then sequentially removes the -Lysl2-Argl3- doublet from the newly formed peptide before peptidyl glycine α-amidating monooxygenase catalyzes the formation of amidated GnRH. Carboxypeptidase E activity is stimulated in vitro by cobalt ion and removes the Lys and Arg residues with equal facility. The residue which acts as the amide nitrogen donor for the α-amidating enzyme must be present as the free C-terminal residue of a substrate; the enzyme does not recognize peptide substrates with C-terminal extensions. Based on the mandatory ordered events for processing pro-GnRH and the relative pH profiles displayed by these enzyms, our results are consistent with the idea that endoproteolysis of the pro-hormone occurs upon formation of the secretory granule at the Golgi apparatus and that the processed pep tides are the storage form within the secretory vesicles.

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          Author and article information

          Journal
          NEN
          Neuroendocrinology
          10.1159/issn.0028-3835
          Neuroendocrinology
          S. Karger AG
          0028-3835
          1423-0194
          1991
          1991
          04 April 2008
          : 53
          : 1
          : 20-28
          Affiliations
          Department of Biochemistry and Molecular Biophysics, Virginia Commonwealth University, Richmond, Va., USA
          Article
          125692 Neuroendocrinology 1991;53:20–28
          10.1159/000125692
          2046858
          © 1991 S. Karger AG, Basel

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          Page count
          Pages: 9
          Categories
          Original Paper

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