Original ContributionModeling of biopterin-dependent pathways of eNOS for nitric oxide and superoxide production
Section snippets
Model description
Using known biochemical pathways for eNOS, NO production was modeled for a single endothelial cell [41], [42]. For eNOS uncoupling and O2•− production, we used the biochemical pathway described by Berka and co-workers [43], [44]. In brief, the electron transport from the reductase to the oxygenase domain in eNOS occurs after biopterin binds to the enzyme [1]. After the binding of biopterin, l-arginine, and CaM to the NOS dimer, the heme in the oxygenase domain undergoes a series of redox
NO production decreases and O2•− production increases nonlinearly with a reduction in tetrahydrobiopterin availability
Under normal physiological conditions, a small amount (5–10%) of total biopterin is in oxidized biopterin (BH2 and BH3) form [23], [25]. However, the amount of oxidized biopterin can increase as much as 90% in endothelial cell dysfunction [23], [25]. To understand the impact of BH4 availability on the NO and O2•− production from eNOS, six cases were simulated with a [BH4]/[TBP] ratio from 0.99 to 0.05. A high value for the ratio indicates that the majority of TBP is in the reduced form BH4
Discussion
In this study, we developed a computational model for eNOS biochemical pathways for the production of NO and O2•− to understand the eNOS uncoupling and related endothelial dysfunction mechanism. We analyzed the effects of [BH4]/[TBP] ratio, total biopterin, eNOS concentration, and feedback inhibition of NO consumption on NO and O2•− production.
Acknowledgment
This study was funded by National Institutes of Health Grant NIH R01 HL084337.
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