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Peroxynitrite modifications of cyclooxygenase‐1 are regulated by arachidonic acid
Author(s) -
Deeb Ruba S.,
Upmacis Rita K.,
Cheung Cynthia,
Hajjar David P.
Publication year - 2007
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.21.6.a748-a
Subject(s) - peroxynitrite , arachidonic acid , chemistry , nitration , heme , nitric oxide , biochemistry , cyclooxygenase , peroxynitrous acid , prostaglandin h2 , pharmacology , superoxide , enzyme , biology , organic chemistry
Cyclooxygenase (COX)‐derived prostaglandins (PGs) and nitric oxide (NO) play physiological and pathological roles in many processes e.g. vasodilation/vasoconstriction. In fact, PG and NO synthetic pathways converge to regulate PG production essential to vascular function. Recently, we showed that differential nitration and aggregation of COX‐1 by peroxynitrite (ONOO − ) occurs. We found that nitration at tyrosine 385 (essential to catalysis) is heme‐driven and leads to COX deactivation. The following study assesses ONOO − ‐modifications to COX‐1 and its activity in physiological bicarbonate levels, in the presence and absence of heme, arachidonic acid, aspirin and the hydroperoxide scavenger glutathione peroxidase. When heme in COX‐1 was substituted with Co III ‐protoporphyrinIX, ONOO − ‐treatment caused minimal nitration and aggregation, confirming the role of the Fe center in deactivation processes. Physiological bicarbonate levels markedly increased nitration levels in apoCOX‐1 and holoCOX‐1 compared to other buffers, without altering apoCOX‐1 function. This result supports specific and heme‐decisive tyrosine nitration that leads to COX‐1 inactivation. Results also indicate that while arachidonic acid protects against nitration by ONOO − , aggregation is driven by arachidonic acid‐hydroperoxides suggesting that ONOO − ‐induced COX‐1 modifications are regulated by arachidonic acid. Supported by the NIH (HL46403 and HL07423), Pfizer Inc., Philip Morris USA Inc. and Philip Morris International.