Peptide hormones, synthesis

See also Maintaining Blood Glucose Levels, Response to Starvation, Action of Insulin, Action of Glucagon, Peptide Hormone Synthesis... 

In light of the importance of the / -turn motif in peptide and protein recognition, and the design and synthesis of bioactive small molecules, / -turn mimetics has attracted considerable attention. Seebach and coworkers have shown recently that low molecular weight open-chain / - and y-peptides designed to promote turn formation can be used as templates for mimicking the a-peptide hormone somatostatin. 

Steroid hormones and thyroid hormone carry out their effects by way of gene activation. In contrast to the protein/peptide hormones, which alter existing enzyme activity, these hormones induce the synthesis of new enzymes that then influence cellular metabolism. 

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action. Hormones act either via cell-surface or intracellular receptors. Peptide hormones and amino-acid derivatives, such as epinephrine, act on cell-surface receptors that do such things as open ion-channels, cause rapid electrical responses and facilitate exocytosis of hormones or neurotransmitters. Alternatively, they activate second-messenger systems at the cell membrane, such as those involving cAMP, Ca2+/ calmodulin or phosphoinositides (see Chs 20 and 24), which leads to phosphorylation of proteins inside various parts of the target cell (Fig. 52-2A). Steroid hormones and thyroid hormone, on the other hand, act on intracellular receptors in cell nuclei to regulate gene expression and protein synthesis (Fig. 52-2B). Steroid hormones can also affect cell-surface events via receptors at or near the cell surface. 

Adipose tissue, fat, is usually thought of as a metabolically sluggish energy reservoir and mechanical and thermal insnlator. It has proved to be much more than that. Adipose tissue influences the body weight, the inunnne response, the control of blood pressure, hemostasis, bone mass, and the fnnctions of thyroid and reproductive glands. It does these things largely on the basis of synthesis and release of a family of adipocyte peptide hormones. 

The peptide hormone insulin (see Box 13.1) is produced by the pancreas and plays a key role in the regulation of carbohydrate, fat, and protein metabolism, hi particular, it has a hypoglycaemic effect, lowering the levels of glucose in the blood. A malfunctioning pancreas may produce a deficiency in insulin synthesis or secretion, leading to the condition known as diabetes mellitus. This results in increased amounts of glucose in the blood and urine, diuresis, depletion of carbohydrate stores, and subsequent breakdown of fat and protein. Incomplete breakdown of fat leads to the accumulation of ketones in the blood, severe acidosis, coma, and death. 

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 biosynthesis of peptide hormones and proteohormones, as well as their secretion, is controlled by higher-order regulatory systems (see p. 372). Calcium ions are among the substances involved in this regulation as second messengers an increase in calcium ions stimulates synthesis and secretion. 

The final step in thyroid hormone synthesis is the coupling of two iodotyrosines within a single peptide chain of Tg to form the iodothyronine T4 or T3. Both the coupling of two DITs to form T4 and the coupling of a MIT with a DIT to form T3 are catalyzed by the enzyme TPO. 

The methods of peptidic synthesis, in the liquid phase as well as in the solid phase, have led to the preparation of numerous polypeptides that contain a fluorinated amino acid. Most of the examples concern peptidic hormones and neuropeptides, with replacement of either (1) a phenylalanine (or of a tyrosine) by an analogue containing a... 

An alternative to the synthesis of proteins by classical fragment synthesis in solution or by solid-phase synthesis on a support is the use of enzyme-catalyzed condensation of amino acids or peptides. This possibility was first demonstrated in 1938 91 with the synthesis of poorly soluble benzoyl-leucyl-leucine anilide by papain catalysis. After many years, this approach was extended to the preparation of peptide hormones such as Leu-enkephalin 92 and dynorphin(l -8).[93 This was made possible by the use of highly purified enzymes and by careful control of reaction conditions. The basic principles of protease-catalyzed peptide bond formation have been discussed.194 ... 

The synthesis of peptides of known sequence in the laboratory is extremely important to biochemical research. For example, we might want to know how the effects of a peptide hormone are altered by replacement of one amino acid in a particular position by another. The synthetic methods must be precise294-298 and because there are so many steps the yield should... 

Figure 30-1 (A) Median sagittal section of the human brain. From Maya Pines.15 (B) Drawing illustrating the synthesis of peptide hormones in the hypothalamus and transport via portal blood vessels into the anterior lobe of the pituitary gland or via nerve tracts into the posterior lobe.16...

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