Cellular and molecular biology of prostacyclin synthase.
Prostacyclin synthase (PGIS) cDNA comprises 1500 nucleotides coding for a 500 amino acid protein. It is a heme protein with spectral characteristics of cytochrome p450 (CYP). It does not possess the typical CYP mono-oxygenase activity but catalyzes the rearrangement of prostaglandin H2 to form PGI2. Analysis of its structure-function by molecular modeling and site-directed mutagenesis reveals a long substrate channel lined by hydrophobic residues. Cys-441 has been identified as the proximal axial ligand of heme. Tyr-430 is nitrated by peroxynitrite which results in reduced PGIS catalytic activity, suggesting that Tyr-430 is located close to the heme pocket. PGIS is constitutively expressed and may be upregulated by cytokines, reproductive hormones, and growth factors. It is physically colocalized with cyclooxygenases and phospholipases, and functionally coupled with these enzymes. PGIS coupling with COX-2 has been shown to play an important role in vascular protection, embryo development and implantation, and cancer growth.
Wu
Kenneth K
KK
Vascular Biology Research Center, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. kenneth.k.wu@uth.tmc.edu
Liou
Jun-Yang
JY
D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase