Somatostatin structure

Somatostatin is a tetradecapeptide of the hypothalamus that inhibits the release of pituitary growth hormone Its ammo acid sequence has been determined by a combination of Edman degradations and enzymic hydrolysis expenments On the basis of the following data deduce the pnmary structure of somatostatin... 

High amounts of somatostatin are found in the CNS, the peripheral nervous system, the gut and the endocrine pancreas whereas the kidneys, adrenals, thyroid, submandibular glands, prostate and placenta produce rather low amounts. In particular, the hypothalamus, all limbic structures, the deeper layers of the cerebral cortex, the striatum, the periaqueductal central grey and all levels of the major sensoty pathway are brain areas that are especially rich in somatostatin. Eighty percent of the somatostatin immunoreactivity in the hypothalamus is found in cells of the anterior periventricular nucleus (Fig. 1, [1]). The gut 5 cells of the mucosa and neurons, which are intrinsic to the submucous and... 

Zhou HH, Ma RL, Sheng LS, Xiang BR, An DK. 2003. Determination of first-order structure of somatostatin by electrospray ionization mass spectrometry. Yao Xue Xue Bao 38 617 (article in Chinese). 

Examlnatloi of molecular models revealed that the desired two B-tum conformation might be restored by moving the N-methyl group from D-Ala to D-Phell in 4. This change would permit the key cis peptide bond to form in the proper location in the backbone and should as a result achieve better overall side chain correspondence with 3b. The resultant structure, cyclo- (N -Me-D-Phe-D-Thr-D-Lys-L-Trp-D-Phe-D-Ala) 5, was prepared and in fact, displayed a full biological response and had about 10) of the potency of 3b and 25 of somatostatin Itself. 

Scheme 11 Structures of the Naturally Occurring Cyclic Hexapeptides Segetalin A, 2781 Bouvardin, 279-2801 Pneumocandin b, 284-2861 and of a Synthetic Cyclic Somatostatin Analogue 2871...

Amino-acid abbreviations are spelled out in Appendix V. Through a series of structure-activity relationship studies, the bioactive conformation and peptide sequences that produce undesirable biologic responses were identihed. Also identified were sequences susceptible to proteolysis, and a working-model compound that eliminated these sequences was proposed (Figure 4.6). This allowed the rational design of optimized somatostatin analogues with desirable biologic characteristics and activity and increased stability. 

While small peptides, such as somatostatin, a tetradecapeptide, could be synthesized chemically, synthesis of larger molecules resulted in low yields of desired peptide, usually contaminated with peptides of similar structure. Examples of clinically useful peptides and protein hormones, their sources, and uses are listed in Table 8.1 and shown in Figure 8.1. 

Figure 30-3 Possible secondary structure of somatostatin with a beta turn at residues 7-10 and a disulfide bond between positions 3 and 14.

Hormones related to oxytocin and vasopressin occur in most vertebrates, the compound vasotocin shown in Fig. 30-4 being the most common. Substitution of phenylalanine for isoleucine at position 3 gives arginine vasopressin, the vasopressin found in our bodies. Structure of oxytocin and related hormones82 are also shown in Fig. 30-4. Like somatostatin, vasopressin and oxytocin may also form antiparallel pleated sheet structures with P turns. The structural requirements for hormone activity have been studied intensively. Both the macrocyclic hexapeptide ring and the tripeptide side chains are necessary for maximal activity.83... 

It has been suggested that y-turns are present in the solution structures of several peptides, and furthermore implicated in their bioactive conformations 101 including brady-kinin, 111 substance P,1121 cyclic somatostatin analogues, 131 cyclolinopeptide, 141 and the 6-opioid receptor bound conformation of enkephalin. 151 Yet, despite the fact that y-tums are frequently hypothesized to represent important features of secondary structure 161 based upon computational,1171 IR absorption,1181 NMR spectroscopic,119 201 and X-ray diffraction crystallographic determinations,1211 verification of the role of this predicted secondary structural element remains a difficult, but nonetheless critical step. 

The disulfide bridge in somatostatin is between cysteine 3 and cysteine 14. Thus, the primary structure is... 

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