Peptide prohormones

Plants do not only possess the tools for the perception of peptide signals, they also have enzymes potentially involved in the processing of peptide prohormones. The existence of such enzymes provides additional indirect evidence for a general role of peptide hormones in plant signal transduction processes. 

Like all neuropeptides, NT is synthesized as part of a larger precursor that also contains neuromedin N (NN), a 6 amino acid neurotensin-like peptide (Table 1). Pro-NT/NN is processed in the regulated secretory pathway of neuroendocrine cells by prohormone convertases PCI, PC2 and PC5-A that belong to a larger family of proprotein convertases. Due to differential cleavage specificity and tissue distribution of the convertases, pro-NT/NN processing gives rise to approximately a 1 1 and a 5 1 ratio of NT over NN content in the brain and gut, respectively. The peptides are stored in secretory vesicles and released from neuroendocrine cells in a Ca2+-dependent manner. NT and NN actions are terminated by desensitization of the... 

The mu, kappa, and delta opioid receptors have been found to interact with endogenous peptide ligands that share certain pharmacologic properties with opioid drugs. These peptide ligands are derived from at least three different prohormones located in both... 

The third prohormone from which opioid peptides are derived is pro-opiomelanocortin, which yields a number of nonopioid and opioid peptide products (O Donohue and Dorsa 1982). Of these products, beta-endorphin, an untriakontapeptide isolated from camel pituitary gland by Li and Chung (1976)) is thought to interact primarily with mu and delta receptors. 

The term polyproteins is used for two different types of entity. The first refers to precursor polypeptides which are cleaved post-translationally into biologically active proteins or peptides of quite different functions. Examples of these include polyproteins of viruses and some prohormones of vertebrates (reviewed in Kennedy, 2000b). The other type is large proproteins which comprise tandem repetitions of identical or similar polypeptides that are post-translationally cleaved into multiple copies of biochemically similar functional entities. The nematode polyprotein allergens/antigens (NPAs) fall into this class (Fig. 16.1). 

FIGURE 18-7 Processing of the proopiomelanocortin (POMC) precursor proceeds in an ordered, stepwise fashion. Cleavage of the POMC precursor occurs at seven sites, with some of the reactions being tissue-specific. The circled numbers indicate the temporal order of cleavage in tissues where these proteolytic events occur. ACTH, adrenocorticotropic hormone CLIP, corticotropin-like intermediate lobe peptide JP, joining peptide LPH, lipotropin MSH, melanocyte-stimulating hormone PC, prohormone convertase. 

Laurent, V., Jaubert-Miazza, L., Desjardins, R., Day, R. and Lindberg, I. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Endocrinology 145 519-528, 2004. 

As would be expected of active protein secreting cells, glandular epithelial tissue, the cytokine secreting cells of the immune system and the blood vessel endothelium, have an extensive internal structure consisting of rough endoplasmic reticulum and numerous mitochondria. Peptide hormones, growth factors and cytokines like all proteins are synthesized by DNA transcription and mRNA translation. The primary transcript of the mRNA may code for an inactive prohormone which requires careful proteolysis to produce the active hormone, as for example in the case of insulin. Adrenocorticotropic hormone (ACTH) is particularly interesting in this respect because... 

P cells of the pancreatic islets in combination with atoms of zinc, but when required to regulate blood glucose concentration, the prohormone is cleaved and functional insulin is released into the circulation along with the C-peptide. This example of post-translational processing is mediated by peptidases which are contained in the vesicles along with the proinsulin. The fusion of the secretory vesicles with the cell membrane and activation of the peptidase prior to exocytosis of the insulin are prompted by an influx of calcium ions into the P-cell in response to the appropriate stimulus. Similarly, catecholamines are synthesized and held within the cell by attachment to proteins called chromogranins. 

Cleavage of the signal peptide and other modifications in the ER (formation of disulfide bonds, glycosylation, phosphorylation) give rise to the mature prohormone ( pro-POMC ). 

Angiotensin I is a prohormone that is formed as a result of the action of renin on a peptide substrate produced by the liver. 

Peptide Hormones Peptide hormones may have from 3 to 200 or more amino acid residues. They include the pancreatic hormones insulin, glucagon, and somatostatin, the parathyroid hormone, calcitonin, and all the hormones of the hypothalamus and pituitary (described below). These hormones are synthesized on ribosomes in the form of longer precursor proteins (prohormones),... 

In some cases, prohormone proteins yield a single peptide hormone, but often several active hormones are carved out of the same prohormone. Pro-opiomelano-cortin (POMC) is a spectacular example of multiple hormones encoded by a single gene. The POMC gene encodes a large polypeptide that is progressively carved up into at least nine biologically active peptides (Fig. 23-6). The terminal residues of peptide hormones are often modified, as in TRH (Fig. 23-2). 

Many secreted proteins, as well as smaller peptide hormones, are acted upon in the endoplasmic reticulum by tryptases and other serine proteases. They often cut between pairs of basic residues such as KK, KR, or RR.214-216 A substilisin-like protease cleaves adjacent to methionine.217 Other classes of proteases (e.g., zinc-dependent carboxypeptidases) also participate in this processing. Serine carboxypeptidases are involved in processing human prohormones.218 Among the serine carboxypeptidases of known structure is one from wheat219 and carboxypeptidase Y, a vacuolar enzyme from yeast.220 Like the pancreatic metallocarboxypeptidases discussed in Section 4, these enzymes remove one amino acid at a time, a property that has made carboxypeptidases valuable reagents for determination of amino acid sequences. Carboxypeptidases may also be used for modification of proteins by removal of one or a few amino acids from the ends. 

Further support for the occurrence and activity of neuropeptides in flatworms stems from the presence of enzymes necessary for the production of the mature peptides. For example, the first step in the generation of a mature neuropeptide is often the excision of a propeptide from a longer pre-propeptide. This is achieved by the activity of prohormone convertases, and a number of putative platyhelminth convertase-encoding cDNAs are represented within the EST databases. 

Anterior pituitary hormones include growth hormone (GH), thyrotropin (TSH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), and adrenocorticotropin (ACTH). Another peptide, B-lipotropin (B-LPH), is derived from the same prohormone, proopiomelanocortin, as ACTH. B-LPH is secreted from the pituitary (along with ACTH), and is a precursor of the opioid peptide B-endorphin (see Chapter 31 Opioid Analgesics Antagonists). 

Relaxin is another peptide that can be extracted from the ovary. The three-dimensional structure of relaxin is related to that of growth-promoting peptides and is similar to that of insulin. Although the amino acid sequence differs from that of insulin, this hormone, like insulin, consists of two chains linked by disulfide bonds, cleaved from a prohormone. It is found in the ovary, placenta, uterus, and blood. Relaxin synthesis has been demonstrated in luteinized granulosa cells of the corpus luteum. 

Similar to mammalian prohormones, all opioid peptides in amphibian skin precursors are flanked by paired dibasic amino acids (Lys-Arg). Moreover, the precursor sequence contains an additional Gly residue at its carboxyl terminus this extra residue is required for the carboxamidation of the mature heptapeptide [20]. 

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