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.
MeSH terms
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Alanine / genetics*
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Amino Acid Sequence
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Amino Acid Substitution
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Animals
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Benzoates / pharmacology
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Binding Sites / genetics
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CHO Cells
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Cricetinae
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Cricetulus
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Cyclic GMP / metabolism
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Diethylamines / pharmacology
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Genotype
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Guanylate Cyclase / antagonists & inhibitors
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Guanylate Cyclase / genetics*
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Guanylate Cyclase / metabolism
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Heme / metabolism*
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Molecular Sequence Data
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Mutation, Missense
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Nitric Acid / metabolism
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Nitric Acid / pharmacology
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Nitrogen Oxides
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Oxadiazoles / pharmacology
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Protoporphyrins / pharmacology
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Pyrazoles / pharmacology
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Pyridines / pharmacology
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Quinoxalines / pharmacology
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Sequence Homology, Amino Acid
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Serine / genetics*
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Solubility
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Transfection
Substances
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1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
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3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
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Benzoates
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Diethylamines
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Enzyme Inhibitors
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Nitrogen Oxides
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Oxadiazoles
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Protoporphyrins
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Pyrazoles
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Pyridines
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Quinoxalines
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BAY 58-2667
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Nitric Acid
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Heme
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Serine
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diethylamine dinitric oxide adduct
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protoporphyrin IX
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Guanylate Cyclase
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Cyclic GMP
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Alanine