Student Theses and Dissertations
Date of Award
1984
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Anthony Cerami
Keywords
nonenzymatic protein modification, ketolic steroids, Heyns rearrangement, glucocorticoids, 16alpha-hydroxyestrone, hemoglobin
Abstract
A number of studies have demonstrated that small metabolites can react nonenzymatically with proteins to form covalent, addition products. An example of this type of reaction is the modification of hemoglobin A by glucose to form the minor species hemoglobin A1c. In this case, glucose reacts by forming a reversible Schiff base adduct with the N-terminal valine of the β-chain of hemoglobin. The Schiff base intermediate then slowly undergoes an Amadori rearrangement to produce a stable ketoamine addition product. The following studies investigate two novel aspects of nonenzymatic addition reactions. The first is the demonstration that ketolic steroids, i.e. steroids bearing a carbonyl function adjacent to a hydroxyl group, can react with protein amino groups to form stable Heyns rearrangement products. The second is the observation that reducing sugars can react with the nucleotides of DNA to form covalent adducts. The steroids which react with proteins include the glucocorticoids; such as Cortisol and prednisolone, which contain side-chain ketols, and the estrogen metabolite 16α-hydroxyestrone (16αOHE), which contains a ring ketol. The long-term therapeutic administration of glucocorticoids is associated with many toxic manifestations and it was reasoned that one of these effects, cataract formation, might be the result of the progressive accumulation of protein bound glucocorticoid adducts. 16α-hydroxyestrone on the other hand, has been reported to be present in elevated amounts in the autoimmune disease Systemic Lupus Erythematosus (SLE). Protein modification by this steroid might induce immune dysfunction by either hapten formation or by covalently modifying immunoregulatory proteins.
License and Reuse Information
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Bucala, Richard J., "The Nonenzymatic Modification of Proteins by Steroids and DNA by Reducing Sugars; In Vitro and In Vivo Studies" (1984). Student Theses and Dissertations. 585.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/585
Comments
A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy