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Quantitative Analysis of Tetrahydrobiopterin Synthesis and Oxidation in eNOS Uncoupling
Author(s) -
Kar Saptarshi,
Kavdia Mahendra
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1142.12
Subject(s) - biopterin , tetrahydrobiopterin , enos , chemistry , nitric oxide , oxidative stress , medicine , oxidative phosphorylation , endocrinology , biochemistry , nitric oxide synthase , biology
The uncoupling of eNOS shifts the production from nitric oxide (NO) to (O 2 •− ). The lack of availability of eNOS co‐factor tetrahydrobiopterin (BH 4 ), which oxidizes to dihydrobiopterin (BH 2 ) is the primary cause of eNOS uncoupling. In an earlier study, we showed that biopterin ratio (BH 4 :total biopterin) is an important determinant of the extent of eNOS uncoupling. However, it is not clear whether the synthesis of BH 4 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 O 2 •− production with provisions for changing concentration of different forms of biopterin and BH 4 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 BH 4 synthesis and (iii) Increased oxidative stress conditions significantly reduces eNOS based NO production and increases eNOS based O 2 •− production. The results thus show that oxidative stress and BH 4 synthesis can play a regulatory role in eNOS catalysis. Supported by NIH R01 HL084337.