Residues stabilizing the heme moiety of the nitric oxide sensor soluble guanylate cyclase.
Soluble guanylate cyclase, a heterodimer consisting of an alpha- and a heme-containing beta-subunit, is the major receptor for the biological messenger nitric oxide (NO) and is involved in various signal transduction pathways. The heme moiety of the enzyme is bound between the axial heme ligand histidine(105) and the recently identified counterparts of the heme propionic acids, tyrosine(135) and arginine(139). The latter residues together with an invariant serine(137) form the unique heme binding motif Y-x-S-x-R. In this work, we show that replacement of the serine(137) with alanine destabilizes the binding of the heme moiety and impairs NO-mediated soluble guanylate cyclase activation.
Schmidt
Peter M
PM
Institute of Cardiovascular Research, Bayer Healthcare, Wuppertal, Germany. Peter.Schmidt@medizin-uni-magdeburg.de
Rothkegel
Christiane
C
Wunder
Frank
F
Schröder
Henning
H
Stasch
Johannes-Peter
JP
D000409:Alanine / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006152:Cyclic GMP / Q000378:metabolism; D004048:Diethylamines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005838:Genotype; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017942:Nitric Acid / Q000378:metabolism / Q000494:pharmacology; D009589:Nitrogen Oxides; D010069:Oxadiazoles / Q000494:pharmacology; D011524:Protoporphyrins / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000235:genetics*; D012995:Solubility; D014162:Transfection
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D001565:Benzoates; D004048:Diethylamines; D004791:Enzyme Inhibitors; D009589:Nitrogen Oxides; D010069:Oxadiazoles; D011524:Protoporphyrins; D011720:Pyrazoles; D011725:Pyridines; D011810:Quinoxalines; C480588:BAY 58-2667; D017942:Nitric Acid; D006418:Heme; D012694:Serine; C087229:diethylamine dinitric oxide adduct; C028025:protoporphyrin IX; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D000409:Alanine