Oxytocin 8-isoleucine

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 known for many years, however, that the (3-branched amino acids, especially valine and isoleucine, cause problems in synthesis,14,5] and special care and additional reaction time are required when -substituted amino acids are added to a growing peptide chain in synthesis. For example, in the synthesis of [2,4-diisoleucine]oxytocin efforts to couple the isoleucine to isoleucine by the azide method failed and only the rearranged product was obtained 61 Also, it is much more difficult to hydrolyze peptide bonds formed between two or more contiguous -substituted amino adds using standard 6M HC1 conditions. For example, in the hydrolysis of [2,4-diisoleucine]oxytocin (3 isoleucine residues adjacent to each other) complete hydrolysis takes 60 hours. 

As the 7] values of the secondary butyl group of isoleucine are similar to those in the free amino acid [855] the mobility of the side chain of He seems not to be influenced by other residues of the oxytocin molecule. 

When the unusual bromine cleavage of oxytocin and vasopressin, reported by du Vigneaud and his associates, was repeated with a simplified tripeptide model, N-carbobenzyloxy-(S-benzyl-L-cysteinyl-L-tyrosyl-L-iso-leucine (CXV) (Ressler and du Vigneaud, 1957), bromine or NBS liberated a ninhydrin-reactive material in 40% yield. Paper chromatography proved isoleucine to be the sole ninhydrin-reactive substance present. The ultraviolet spectrum of the reaction mixture showed the characteristic 260 mM absorption for a dienone (CXVI). 

AVP), except in the pig which has a Lys residue (iysine vasopressin). Oxytocin differs from vasopressin in having leucine at position 8 and isoleucine at position 3. Vasopressin and oxytocin analogues with some degree of receptor subtype selectivity that have been synthesized have ANTIDIURETIC or vasoconstrictor or OXYTOCIC (uterine-contracting) activity. See VASOPRESSIN RECEPTOR AGONISTS VASOPRESSIN RECEPTOR ANTAGONISTS. 

With the exception of two amino acids, vasopressin resembles oxytocin in stracture. Oxytocin contains leucine and isoleucine, and vasopressin contains phenylalanine and arginine. The sites of synthesis, storage, and release of vasopressin are identical to those described for oxytocin. Many agents alter the secretion or action of vasopressin, and these are listed in Figures 101 and 102. 

Oxytocin has an isoleucine at position 3 and a leucine at position 8 it stimulates smooth muscle contraction in the uterus during labor and in the mammary glands during lactation. Vasopressin has a phenylalanine at position 3... 

Schaker W, Sterba G, Ambrosius H (1967) Der immunologische Nachweis von Isoleucin -Leucin -Oxytocin nach Immunisierung mit einem Oxytocin-Carboxymethyldextran-Komplex. Pfiuegers Arch 297 166-173... 

Even this brief discussion of oxytocin analogs can not be concluded without pointing out that Nature experimented with hormone analogs well before organic chemists undertook the synthesis of such compounds. Thus, 8-isoleucine oxytocin (mesotocin) was discovered in the frog [56], 4 serine-8-isoleucine oxytocin (isotocin) in teleost fishes [57] and 4-serine-8-glutamine oxytocin (glumitocin) in the ray [58]. 

In the course of the isolation of oxytocin, the second principal hormone of the pituitary gland, vasopressin, a peptide with pressor and antidiuretic effects, was similarly secured in pure form. Porcine glands yielded a vasopressin that contained lysine, while an arginine containing peptide was obtained from the neurohypophysis of cattle. Structure elucidation [63,64] revealed that the two vasopressins are quite analogous to oxytocin, except that isoleucin in position 3 of oxytocin is replaced by phenylalanine and position 8 is occupied by one of the basic amino acids, lysine or arginine, rather than by leucine ... 

R. Acher, J. Chauvet, M.T. Chauvet, D. Crepy, Phylogeny of peptides of the neurohypophysis. Isolation of mesotocin (8-iso-leudne oxytocin) of the frog, intermediate between 4-serine-8-isoleucine oxytocin of the bony fish and manunahan oxytocin. Biochim. Biophys. Acta 90 613-615 (1964)... 

Oxytocin and vasopressin (Fig. 24.6) are two rather small polypeptides with strikingly similar structures (where oxytocin has leucine, vasopressin has arginine, and where oxytocin has isoleucine, vasopressin has phenylalanine). In spite of the similarity of their... 

Position 3. The isoleucine residue in position 3 bears two asymmetric carbon atoms. Inversion of the second centre of asymmetry yields alloisoleucine -oxytocin which is considerably less active than oxytocin. Studies of other compounds show... 

Position 3. Replacement of phenylalanine by tyrosine abolishes all activity. Introduction of an isoleucine residue gives vasotocin, a compound already described in the oxytocin series. 

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