title: Residues stabilizing the heme moiety of the nitric oxide sensor soluble guanylate cyclase.
abstract: 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.
authors.affiliation: Institute of Cardiovascular Research, Bayer Healthcare, Wuppertal, Germany. Peter.Schmidt@medizin-uni-magdeburg.de
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schmidt
authors.forename: Christiane
authors.initials: C
authors.lastname: Rothkegel
authors.forename: Frank
authors.initials: F
authors.lastname: Wunder
authors.forename: Henning
authors.initials: H
authors.lastname: Schröder
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
mesh_terms: 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
chemical_list: 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