Molecular and catalytic properties of three rat leukotriene C(4) synthase homologs.
The committed step in the biosynthesis of cysteinyl-leukotrienes is catalyzed by leukotriene C(4) synthase as well as microsomal glutathione S-transferase (MGST) type 2 and type 3, which belong to a family of membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG). We cloned and characterized these three enzymes from the rat to allow a side-by-side comparison of structural and catalytic properties. The proteins are 79.6-86.7% identical to the human orthologs. Rat MGST3 fails to convert leukotriene A(4) into leukotriene C(4), which in turn challenges the proposed catalytic role of a conserved Arg and Tyr residue for the leukotriene C(4) synthase reaction. Comparative inhibitor studies of all three enzymes, using MK-886 and cysteinyl-leukotrienes, indicate that their catalytic centers originate from structurally related and overlapping active sites. Hence, it seems feasible to design enzyme inhibitors, which simultaneously target several members of this protein family to yield compounds with increased anti-inflammatory action.
Schröder
Oliver
O
Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-17177 Stockholm, Sweden.
Sjöström
Mattias
M
Qiu
Hong
H
Stein
Jürgen
J
Jakobsson
Per Johan
PJ
Haeggström
Jesper Z
JZ
D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D002478:Cells, Cultured; D003001:Cloning, Molecular; D003545:Cysteine / Q000737:chemistry; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000737:chemistry; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism; D015289:Leukotrienes / Q000737:chemistry; D008969:Molecular Sequence Data; D008970:Molecular Weight; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D018411:Spodoptera / Q000737:chemistry / Q000201:enzymology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D002722:Chlorobenzenes
D003545:Cysteine; D004791:Enzyme Inhibitors; D005982:Glutathione Transferase; D007211:Indoles; D007527:Isoenzymes; D015289:Leukotrienes; D011994:Recombinant Proteins; C112381:cysteinyl-leukotriene; C060893:MK-886; D002722:Chlorobenzenes; C041116:leukotriene-C4 synthase