Intrachain disulfide bridges

Disulfides. As shown in Figure 4, the and h-chains of insulin are connected by two disulfide bridges and there is an intrachain cycHc disulfide link on the -chain (see Insulin and other antidiabetic drugs). Vasopressin [9034-50-8] and oxytocin [50-56-6] also contain disulfide links (48). Oxidation of thiols to disulfides and reduction of the latter back to thiols are quite common and important in biological systems, eg, cysteine to cystine or reduced Hpoic acid to oxidized Hpoic acid. Many enzymes depend on free SH groups for activation—deactivation reactions. The oxidation—reduction of glutathione (Glu-Cys-Gly) depends on the sulfhydryl group from cysteine. 

FIGURE 5.6 Bovine pancreatic ribonuclease A contains 124 amino acid residues, none of which are tryptophan. Four intrachain disulfide bridges (S—S) form cross-links in this... 

A further development of the DMSO/H+ method for oxidation of cysteine peptides led to the cysteine-sulfoxide acid-catalyzed intermolecular disulfide formation with a second S-unprotected or acid-labile protected cysteine component as shown in Scheme 19. 1471 The protonation of the sulfoxide by TfOH in the case of 5(0)-Mob or TFA in the case of 5(0)-Acm derivatives provides electrophilicity to the sulfur atom to allow attack by the second S-unprotected cysteine component (formed by the fast deprotection of the 5-Mob group with TfOH in presence of dimethylsulfide) to generate in a site-directed manner the interchain disulfide bond. Although extensive experience with this method has not been accumulated for interchain disulfide bridging, it has been successfully applied for intrachain site-directed disulfide bond formation in chicken calcitonin-gene-related peptide.1 79 ... 

Among the methods established in cysteine chemistry for cleavage of the Mob group with concomitant formation of disulfide bridges, i.e. I2, Tl( III )trifluoroacetate140 and DMSO/ TFA,[411 only the DMSO/TFA procedure allows for clean deprotection of SeC(Mob) residues and for their concomitant oxidation to selenocystine dimers or intrachain cyclic structures. IP°33]... 

Formation of Disulfide Cross-Links After folding into their native conformations, some proteins form intrachain or interchain disulfide bridges between Cys residues. In eukaryotes, disulfide bonds are common in proteins to be exported from cells. The cross-links formed in this way help to protect the native conformation of the protein molecule from denaturation in the extracellular environment, which can differ greatly from intracellular conditions and is generally oxidizing. 

The disulfide bridges in some proteins are between different peptide chains. Insulin, for instance, has two interchain as well as one intrachain S—S bridges (Figure 25-8). 

Figure 25-15 Lysozyme from hen egg-white showing the amino-acid sequence (primary structure) and the four intrachain disulfide bridges. [Adapted from D. C. Phillips, Sc/. Amer. 5, 215 (1966).]...

The growth hormone (STH) or the human growth hormone 87) (HGH), a linear peptide hormone made up of 191 amino acids with 2 intrachain disulfide bridges, is formed under the control of somatostatin and influences the maturation process during the growth period (e.g. the increase in protein substance and in height). 

Diphtheria toxin, produced by Corynebacterium diphtheriae, is a single polypeptide (Mr = 63,000) with two intrachain disulfide bridges. A portion of the molecule, the A fragment (Mr = 21,000), must enter the cytoplasm of a cell to exert the toxic effect. Through a fairly complex mechanism, the larger molecule is cleaved into two on the membrane surface to yield A and B fragments. The latter facilitates entry of the A fragment into the... 

From a purely chemical point of view, the fundamental fact is that proteins contain covalent bonds which are split by rather drastic means and more labile, noncovalent bonds which may be split or at least altered by denaturation alone. Two types of covalent structures exist, involving peptide bonds and disulfide bridges respectively. Both structures should be clearly differentiated since they are destroyed by quite different chemical treatments (hydrolysis for the first, oxidation or reduction for the second). They will be called for this reason, respectively, the primary and the secondary structures. Conversely, several inter- or intrachain, noncovalent... 

BMG is the light or P-chain of the human leukocyte antigen and consists of a single polypeptide chain with one intrachain disulfide bridge it does not contain carbohydrate. Its small size allows BMG to pass through the glomerular membrane, but normally less than 1% of the filtered BMG is excreted in the urine the remainder is reabsorbed and catab-olized in the proximal tubules of the kidneys. It has a plasma half-life of only 107 minutes. 

Somatostatin(growth hormone release-inhibiting hormone) is a tetradecapeptide with an intrachain disulfide bridge. Somatostatin neurons are located in the parvi-cellular neurons of the PVN, the periventricular nuclei... 

The yeast enzyme has 8 86,378,379) to 9 368,399) free SH groups per subunit and is inhibited by thiol reagents. It may also be inactivated by oxidation to form intrachain disulfide bridges 399). Preparations may vary in SH content 366,399,408,. 09), although the number of cysteine residues reactive to iodoacetamide is constant 408,409). This type of variability seems reminiscent to that of the subfractions of rat liver alcohol dehydrogenase (Section II,A,3,a). 

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