Peptide hormones inactivation

In contrast to glucagon, the peptide hormone insulin (see p. 76) increases glycogen synthesis and inhibits glycogen breakdown. Via several intermediates, it inhibits protein kinase GSK-3 (bottom right for details, see p. 388) and thereby prevents inactivation of glycogen synthase. In addition, insulin reduces the cAMP level by activating cAMP phosphodiesterase (PDE). 

The half-life of most peptide hormones is less than 30 minutes rapid inactivation results from the concerted action of various endo- and exopeptidases... 

Insulin, a peptide hormone produced in the islets of Langerhans in the pancreas, is essential for glucose metabolism in the body and is the key for diabetes treatment. It is primarily administered as an injection, as it is inactivated by proteolytic enzymes by the oral route. Moreover, its high molecular weight and lower lipophilic character result in poor absorption of the drug in vivo, leading to lower oral bioavailability. This makes insulin unsuitable for oral administration. 

Because of the metabolic lability of peptide bonds, metabolic inactivation is likely to play a particularly important role in the overall action of the peptide hormones. Structural alterations in the hormone molecule which increase metabolic stability would be expected to increase the duration of hormone action. Oxytocin is well known to be inactivated by an enzyme present in the serum of pregnant primates ( serum oxytocinase" see (1) but also more generally by homogenates of various tissues including the kidneys and liver. The major pathway of oxytocin inactivation by liver cell-sap has been shown to involve reductive fission of the disulphide bond followed by aminopeptidase degradation of the peptide chain (2). In an effort to obtain peptides resistant to aminopeptidase action we introduced D-hemicystine and N-methylhemicystine into the amino terminal position of... 

Zhang, P., Jobert, A. S., Couvineau, A., and Silve, C. (1998) Homozygous inactivating mutation in the parathyroid hormone parathyroid hormone-related peptide receptor causing Blomstrand chondrodysplasia. J. Clin. Endocrinol. Metab. 83, 3365-3368. 

The hormone-hke peptide incretin stimulates the release of insuhn by a feedback process that involves cleaving the molecule to an inactive form. The protease enzyme dipeptidal peptidase (DPP) in turn cleaves incretin, in effect inactivating this enzyme. Inhibition of DPP consequently extends the action of incretin. This inhibition thus prevents the increased levels of blood glucose that mark diabetes. The protease inhibitor vidagliptin, which is modeled in part on the terminal sequence in DPP, has been found to sustain levels of insulin in Type II diabetics. The inhibition is apparently reversible in spite of the presence in the structure of the relatively reactive a-aminonitrile function. Construction of one intermediate in the convergent synthesis comprises the reaction of amino adamantamine (21-1) with a mixture of nitric and... 

Many tests substances change the secretion of hypothalamic hormones, either by direct action or more generally by a feedback effects at the hypothalamic level. Under these conditions, the tissue concentration in hypothalamic specimens of treated rats is of interest, especially because several hypothalamic peptide assays are available and can be measured in the same specimen. In contrast to the tissue concentration, for many hypothalamic hormones it is difficult to measure the circulating concentrations, due to analytical problems of low concentration and rapid inactivation by enzymes. Circulating concentrations would also change immediately due to the interference of anesthesia and of the autopsy procedure. It is therefore recommended to take samples of hypothalamic tissue, and control samples of cerebral cortical tissue. 

Microencapsulation has also been used medically for the encapsulation of live cells and vaccines. Biocompatibility can be improved by the encapsulation of artificial cells and biomolecules such as peptides, proteins, and hormones, which can prevent unwanted immunological reactions that would lead to inactivation or rejection. Microspheres are used for isolating materials until their activity is needed. The biotechnology industry employs microspheres to contain organisms and their recombinant products to aid in the isolation of these products. ... 

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