Phenol-Promoted Structural Transformation of Insulin in Solution

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Abstract
Phenolic additives widely used for the preservation of insulin preparations can have a profound effect on the hormone''s conformation in solution. m-Cresol, for instance, increases the circular dichroism in the far ultraviolet by 10-20%, corresponding to an increase in helix, and around 255 nm. The CD-spectral changes are strikingly similar to those brought about by halide ions which have been identified to reflect the 2Zn .fwdarw. 4Zn insulin transition. Its most prominent element is the helix formation at the B-chain N-terminus. In both cases the changes fail to occur with dimeric insulin in the absence of Zn2+ and with monomeric des-(B26-B30)-insulin. In the presence of Ni2+ which is unable to replace Zn2+ in 4Zn insulin for coordinative reasons, the effect of m-cresol is impeded. m-Cresol thus induces a transition identical with or closely similar to the 2Zn .fwdarw. 4Zn transformation. 2Zn insulin crystals, when soaked in m-cresol containing solvents, are destroyed. Crystals grown in the presence of m-cresol, however, are monoclinic and containing symmetrical hexamers of, notably, 4Zn conformation. Phenol, o-and p-cresol, m-nitrophenol, Nipagin M and benzene were further additives tested, all of them inducing largely the same spectral effects except for benzene. The results presented corroborate the close correspondence of insulin''s structure in solution and in the crystal as well as insulin''s capacity for structural variation.

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