Insulin sulfhydryl groups

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. 

We need a few words about the disulfide bonds that link the two chains of insulin. The side chain of Cys is —CH2—SH. The —SH group is termed the sulfhydryl group. If two of these side chains come together, the sulfhydryl groups can be linked together (oxidized) to form a disulfide bond ... 

Glutathione helps to maintain the sulfhydryl groups of proteins in a reduced state. An enzyme, protein-disulfide reductase, catalyzes sulfhydryl disulfide interchanges between glutathione and proteins. The reductase is important in insulin breakdown and may catalyze the reassortment of disulfide bonds during polypeptide chain folding. 

Another example of the usefullness of the new methods is the synthesis of the 6-11 fragment of insulin which bears a sulfhydryl group in addition to an -S-S-bridge (28b,3 ). This fragment (cf.fig.l2) could not have been synthesized in another way. 

Other possible mechanisms for insulin action have been proposed. It has been proposed that membrane phosphorylation regulates transport activity across membranes. Thus, if membrane phosphorylation decreases transport, it would be expected that dephosphorylation would enhance transport (Randle and Smith, 1958). However, insulin does not appear to phosphorylate plasma membrane proteins (Avruch et al., 1976b,c). The insulin activation of glucose transport in fat cells has been postulated to involve the oxidation of certain membrane sulfhydryl groups to the disulfide form (Czech, 1977). A rat liver plasma membrane subfraction has been isolated containing cAMP phosphodiesterase activity that could be stimulated by nanomolar amounts of... 

Fig. 6. Synthetic route to the S-sulfonated B chain of human insulin. Abbreviations Z, carbobenzoxy group (amino protector) Bz, benzyl group (sulfhydryl and imidazole protector) Tos, p-toluene-sulfonyl group ( -amino and guanido protector).

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