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.
","abstract_html":"<p>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 A<sub>1c</sub>. 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.</p>","abstract_has_math":false,"creators":["Bucala, Richard J"],"institution":null,"degree_name":"Doctor of Philosophy (PhD)","degree_level":"Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Anthony Cerami"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":1984,"date_issued":"1984-01-01T08:00:00Z","date_published":"1984-01-01T08:00:00Z","updated_at":"2026-07-24T04:11:45Z","subjects":["nonenzymatic protein modification","ketolic steroids","Heyns rearrangement","glucocorticoids","16alpha-hydroxyestrone","hemoglobin","Life Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/585","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Anthony Cerami"]},{"key":"dc:creator","label":"Author","values":["Bucala, Richard J"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"thesis:degree_level","label":"Degree Level","values":["Thesis"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["nonenzymatic protein modification","ketolic steroids","Heyns rearrangement","glucocorticoids","16alpha-hydroxyestrone","hemoglobin","Life Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/585"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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.
"]},{"key":"dc:title","label":"Title","values":["The Nonenzymatic Modification of Proteins by Steroids and DNA by Reducing Sugars; In Vitro and In Vivo Studies"]}]}],"canonical_facts":{"dc:contributor":["Anthony Cerami"],"dc:creator":["Bucala, Richard J"],"dc:description.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.
"],"dc:identifier":["https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/585"],"dc:subject":["nonenzymatic protein modification","ketolic steroids","Heyns rearrangement","glucocorticoids","16alpha-hydroxyestrone","hemoglobin","Life Sciences"],"dc:title":["The Nonenzymatic Modification of Proteins by Steroids and DNA by Reducing Sugars; In Vitro and In Vivo Studies"],"thesis:degree_level":["Thesis"],"thesis:degree_name":["Doctor of Philosophy (PhD)"]},"updated_at":"2026-07-24T04:11:45Z"}