Prohormones, peptide hormones

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... 

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. 

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. 

Kourounakis Rekka ADVANCED DRUG DESIGN AND DEVELOPMENT Labaune HANDBOOK OF PHARMACOKINETICS The Toxicity Asssessment of Chemicals Macheras, Reppas Dressman BIOPHARMACEUTICS OF ORALLY ADMINISTERED DRUGS Martinez PEPTIDE HORMONES AS PROHORMONES Rainsford ANTI-RHEUMATIC DRUGS Actions and Side Effects... 

Neuropeptides are derived from larger protein precursors known as proneuropeptides or prohormones. Proneuropeptides refers to protein precursors of peptide neurotransmitters as well as peptide hormones, whereas prohormones refers primarily to... 

Studies have shown that, in addition to the conventional peptide hormones of pancreatic islets (insulin, glucagon, somatostatin, and pancreatic polypeptide), these tumors can also secrete (and express) ectopic peptides, in particular gastrin and VIP (vasoactive intestinal peptide),but on occasion also ACTH (adrenal corticotropic hormone),antidiuretic hormone (ADH), MSH (melanocyte-stimulating hormone), calcitonin, neurotensin, secretoneurin, 754-356 PTH (parathyroid hormone-like peptide),growth hormone and growth hormone releasing factor, secretogranin inhibin/activin, i prohormone... 

The concept that thymic hormones exist is now well accepted. However, many controversies still persist because of the multiplicity of different thymic products that have been isolated from thymus tissue over the past several decades. Many of the peptides appear to fulfill at least some of the accepted criteria for categorization as true thymic hormones. However, it is still unclear whether the various thymic polypeptides are components of a single thymic hormone (prohormone) that is capable of exhibiting the complete gamut of biologic properties ascribed to all of the different thymic peptides or whether each peptide alone or in certain combinations with other factors, at both intrathymic and extrathymic locations, regulates specific steps of T cell maturation. In this section we will review the biologic properties attributable to thymic factors in both animals and man. 

Dockray, G.I., Dimaline, R., Pauwels, S. Varro, A. (1980) in Peptide Hormones as Prohormones - Processing, Biological Activiies, Pharmacology (Martinez, J. ed.) pp. 245-284, Ellis Horword, Chichester. 

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. 

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. 

One of the highly characterized prohormones is the pro-opiomelanocortin (POMC) also known as proadrenocorticotropin and 31 K ACTH/endorphin. The POMC family consists of peptides which act as hormones (ACTH, LPH, MSH) and others which may serve as neurotransmitters or neuromodulators (endorphins). POMC is synthesized as a precursor molecule of about 285 amino acids and is processed differently in various regions of the pituitary. One gene is responsible for POMC expression. 

Insulin [IN suh lin] is a small protein consisting of two polypeptide chains that are connected by disulfide bonds. It is synthesized as a precursor protein (pro-insulin) that undergoes proteolytic cleavage to form insulin and peptide C, both of which are secreted by the p-cells of the pancreas.4 [Note Normal individuals secrete less pro-insulin than insulin, whereas NIDDM patients secrete high levels of the prohormone. Since radioimmunoassays do not distinguish between the two insulin types, NIDDM patients may have lower levels of the active hormone than the assay indicates. Thus measurement of circulating C peptide provides a better index of insulin levels.]... 

Proteases are essential for the conversion of inactive proprotein precursors into the active neuropeptides. Two main protease pathways have been elucidated for processing proneuropeptides and hormones the recently discovered cysteine protease cathepsin L with aminopeptidase B and the well-established subtilisin-like serine proteases that consist of prohormone con-vertases 1 and 2 followed by carboxypeptidase E/H. Endogenous regulators modulate these two protease pathways as endogenous peptide inhibitors, activators, and in vivo secretory vesicle proteins. Neuropeptides in CSE (cerebrospinal fluid) in neurological diseases can monitor brain nervous activity because neuropeptides represent active neurotransmission (93, 94). 

T, Peters C, Bogyo M. Cathepsin L and Arg/Lys aminopepti-dase a distinct prohormone processing pathway for the biosynthesis of peptide neurotransmitters and hormones. Biol. Chem. 2004 385 473-480. 

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