Quantitative Analysis of Tetrahydrobiopterin Synthesis and Oxidation in eNOS Uncoupling

Abstract

The uncoupling of eNOS shifts the production from nitric oxide (NO) to (O2•−). The lack of availability of eNOS co‐factor tetrahydrobiopterin (BH4), which oxidizes to dihydrobiopterin (BH2) is the primary cause of eNOS uncoupling. In an earlier study, we showed that biopterin ratio (BH4:total biopterin) is an important determinant of the extent of eNOS uncoupling. However, it is not clear whether the synthesis of BH4 can lead to a significant change in the biopterin ratio. In this study, we developed a computational model based on the eNOS biochemical pathways for NO and O2•− production with provisions for changing concentration of different forms of biopterin and BH4 synthesis. The key results from the study include (i) The biopterin ratio remains unchanged under normal conditions and reduces under oxidative stress conditions, (ii) Under normal conditions eNOS uncoupling can still be restored by BH4 synthesis and (iii) Increased oxidative stress conditions significantly reduces eNOS based NO production and increases eNOS based O2•− production. The results thus show that oxidative stress and BH4 synthesis can play a regulatory role in eNOS catalysis. Supported by NIH R01 HL084337.