Density functional studies on thromboxane biosynthesis: mechanism and role of the heme-thiolate system.
Reaction mechanisms for the isomerization of prostaglandin H(2) to thromboxane A(2), and degradation to 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and malondialdehyde (MDA), catalyzed by thromboxane synthase, were investigated using the unrestricted Becke-three-parameter plus Lee-Yang-Parr (UB3LYP) density functional level theory. In addition to the reaction pathway through Fe(IV)-porphyrin intermediates, a new reaction pathway through Fe(III)-porphyrin pi-cation radical intermediates was found. Both reactions proceed with the homolytic cleavage of endoperoxide O-O to give an alkoxy radical. This intermediate converts into an allyl radical intermediate by a C-C homolytic cleavage, followed by the formation of thromboxane A(2) having a 6-membered ring through a one electron transfer, or the degradation into HHT and MDA. The proposed mechanism shows that an iron(III)-containing system having electron acceptor ability is essential for the 6-membered ring formation leading to thromboxane A(2). Our results suggest that the step of the endoperoxide O-O homolytic bond cleavage has the highest activation energy following the binding of prostaglandin H(2) to thromboxane synthase.
Yanai
Tetsuya K
TK
Faculty of Science, Ibaraki University, Bunkyo, Mito 310-8512, Japan.
Mori
Seiji
S
D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D006418:Heme / Q000737:chemistry* / Q000378:metabolism; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D011166:Porphyrins / Q000737:chemistry; D044262:Prostaglandin H2 / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013930:Thromboxane-A Synthase / Q000378:metabolism*; D013931:Thromboxanes / Q000096:biosynthesis* / Q000378:metabolism
D008024:Ligands; D011166:Porphyrins; D013931:Thromboxanes; C028565:porphyrin pi cation radical; D044262:Prostaglandin H2; D006418:Heme; D003577:Cytochrome P-450 Enzyme System; D007501:Iron; D013930:Thromboxane-A Synthase