Lysine pyrrolation is a naturally-occurring covalent modification involved in the production of DNA mimic proteins

Abstract

Covalent modification of proteins exerts significant effects on their chemical properties and has important functional and regulatory consequences. We now report the identification and verification of an electrically-active form of modified proteins recognized by a group of small molecules commonly used to interact with DNA. This previously unreported property of proteins was initially discovered when the γ-ketoaldehydes were identified as a source of the proteins stained by the DNA intercalators. Using 1,4-butanedial, the simplest γ-ketoaldehyde, we characterized the structural and chemical criteria governing the recognition of the modified proteins by the DNA intercalators and identified Nε-pyrrolelysine as a key adduct. Unexpectedly, the pyrrolation conferred an electronegativity and electronic properties on the proteins that potentially constitute an electrical mimic to the DNA. In addition, we found that the pyrrolated proteins indeed triggered an autoimmune response and that the production of specific antibodies against the pyrrolated proteins was accelerated in human systemic lupus erythematosus. These findings and the apparent high abundance of Nε-pyrrolelysine in vivo suggest that protein pyrrolation could be an endogenous source of DNA mimic proteins, providing a possible link connecting protein turnover and immune disorders.

Inflammation, Immunity, and Hypertensive End-Organ Damage

“…These are products of fatty acid oxidation, which rapidly react with protein lysines. Recent evidence indicate that these oxidatively modified proteins are immunogenic, 95 and we find that isoketal protein adducts abundantly accumulate in DCs of mice made hypertensive by either angiotensin II or DOCA-salt hypertension. This is particularly evident in CD11c hi /CD11b + DCs, which are stimulated to express high levels of CD80 and CD86 when they form isoketal adducts.…”

Immune activation caused by vascular oxidation promotes fibrosis and hypertension

“…In particular, isoketals -alternatively referred to as isolevuglandins or γ-ketoaldehydes -are formed from fatty acid oxidation and react with protein lysines to form oxidized pyrrole adducts. These modified proteins become auto-antigens and can elicit antibody formation (17). We have recently shown that hypertension is associated with accumulation of isoketal-adducted Vascular oxidative injury accompanies many common conditions associated with hypertension.…”

Hypertension as an autoimmune and inflammatory disease

“…The modified self-proteins then behave as autoantigens and elicit an inflammatory reaction. 36 Wu et al 37 used a mouse model exhibiting excessive vascular production of ROS and observed that the animals developed vascular collagen deposition, aortic stiffening, renal dysfunction and hypertension with aging. Thus, increased oxidative stress may be a major culprit in the development of inflammatory infiltration, fibrosis and ensuing elevated blood pressures.…”