engleski

Reaction mechanism of biologically relevant reactive aldehydes with different amino acids

Reactive aldehydes, such as 4-hydroxy-2E- nonenal (HNE) and 4-oxo-2E-nonenal (ONE) are formed during oxidative stress in cellular membranes. They readily react with membrane proteins and lipids in phospholipid bilayersin turn modifying cellular function. In order to understand the details of chemical reactions relevant in biological membranes, we performed model calculations in inert solvent dichloromethane using SMD/MP2/6- 311++G(d, p)//B3LYP/6-31G(d) level of theory. In particular, we present a detailed reaction mechanism of reaction between HNE and ONE with four different amino acids (lysine, arginine, histidine and cysteine). Two different mechanisms between nucleophilic amino acids and electrophilic reactive aldehydes are identified - Michael addition and Schiff base formation. Michael addition mechanism has three steps: zwitterion formation, proton transfer and cyclization to a hemiacetal derivative resulting in thermodynamically stable products. On the other hand, Schiff base formation occurs in two steps with elimination of water as a rate determining step. Overall, free energy reaction barriers for Schiff base formation are larger as compared to those in Michael addition reaction. Interestingly, both HNE and ONE have similar free energy barriers in both reaction pathways with a single exception in Michael addition of ONE and arginine amino group, where a substantial decrease of free energy reaction barrier is predicted in agreement with experiments.

reactive aldehydes ; amino acids ; Michael addition ; Schiff base formation

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