title: Biliverdin IX is an endogenous inhibitor of soluble guanylyl cyclase.
abstract: Heme oxygenase (HO) converts heme to carbon monoxide (CO) and biliverdin IX. CO is a weak activator of soluble guanylyl cyclase (SGC), the enzyme that catalyzes the conversion of GTP to the second messenger cGMP. HO overexpression has recently been shown to inhibit production of cGMP by SGC in vivo. The aim of the present study was to investigate a possible influence of biliverdin IX on SGC activity. Using recombinant alpha(1)/beta(1) isoform of SGC, we show an inhibitory effect of biliverdin IX in the micromolar range both on basal and NO stimulated guanylyl cyclase activity. Bilirubin IX which differs from biliverdin IX in two hydrogen atoms had no effect. Biliverdin IX reduced maximal guanylyl cyclase activity (V(max) values) while it had no effect on the K(M) values indicating unchanged affinity towards the substrate GTP. Concentration response experiments using the NO donor, 2,2-diethyl-1-nitroso-oxyhydrazine (DEA/NO), showed that enzyme activities at maximal DEA/NO concentration were reduced by biliverdin IX. The affinity of the NO-donor, DEA/NO, towards SGC was significantly reduced in the presence of biliverdin IX. Biliverdin IX lowered enzyme activity at maximal activator concentrations of YC-1 and protoporphyrin IX (PPIX) while it had no significant effect on the EC(50) values of these two NO independent activators. The inhibitory effect of biliverdin IX on PPIX activated enzyme activity is not shared by ODQ, which indicates that the inhibitory mechanism of biliverdin IX is different from ODQ.
authors.affiliation: Institut für Experimentelle und Klinische Pharmakologie, Universität Hamburg, Martinistrasse 52, Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Koglin
authors.forename: Sönke
authors.initials: S
authors.lastname: Behrends
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001664:Biliverdine / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007313:Insecta / Q000166:cytology; D012995:Solubility
chemical_list: D004791:Enzyme Inhibitors; D006162:Guanylate Cyclase; D001664:Biliverdine