Disease relevance of dehydrobilirubin

• RESULTS: Biliverdin significantly improved survival of recipients following SITx after prolonged intestinal ischemia (6 hours) [1].
• Phytobilins (light harvesting and photoreceptor pigments in higher plants, algae, and cyanobacteria) are synthesized from biliverdin IXalpha (BV) by ferredoxin-dependent bilin reductases (FDBRs) [2].
• The enzyme is expressed at high levels as a soluble catalytically active protein that results in the accumulation of biliverdin within the E. coli cells [3].
• Biliverdin binds covalently to agrobacterium phytochrome Agp1 via its ring A vinyl side chain [4].
• Hmu O, a heme degradation enzyme in the pathogen Corynebacterium diphtheriae, catalyzes the oxygen-dependent conversion of hemin to biliverdin, carbon monoxide, and free iron [5].

High impact information on dehydrobilirubin

• Both their presence in many diverse bacteria and their simplified assembly with biliverdin suggest that BphPs are the progenitors of phytochrome-type photoreceptors [6].
• In some cases, a unique haem oxygenase responsible for the synthesis of biliverdin is part of the BphP operon [6].
• Little is known about the structures of the ring-cleaving enzymes responsible, although microsomal haem oxygenase, which catalyses the breakdown of haem to biliverdin in mammals, has very similar spectroscopic properties to myoglobin [7].
• Both, however, catalyze oxidation of heme to biologically active molecules: iron, a gene regulator; biliverdin, an antioxidant; and carbon monoxide, a heme ligand [8].
• In contrast, 10 microM biliverdin, another HO-dependent metabolite of heme, had no effect [9].

Chemical compound and disease context of dehydrobilirubin

• In phytochrome Agp1 of Agrobacterium tumefaciens, biliverdin is covalently attached to a cysteine residue close to the N terminus (position 20) [4].
• The metabolites of the heme oxygenase pathway, biliverdin, carbon monoxide, and iron may modulate acetaminophen toxicity [10].
• This study shows an antiapoptotic effect of heme oxygenase-1 in colon cancer cells which could be mediated by the formation of bilirubin and biliverdin [11].
• Phycocyanobilin:ferredoxin oxidoreductase (PcyA) catalyzes the sequential reduction of the vinyl group of the D-ring and the A-ring of biliverdin IXalpha (BV) using ferredoxin to produce phycocyanobilin, a pigment used for light-harvesting and light-sensing in red algae and cyanobacteria [12].
• In summary, biliverdin administration in jaundiced Gunn rat pups produces BAEP abnormalities consistent with those observed in the sulfadimethoxine model and human newborn hyperbilirubinemia and resulted in increased plasma bilirubin levels that correlate with the degree of neurological dysfunction [13].

Biological context of dehydrobilirubin

• A comparison of the mechanisms by which biliverdin exerted these salutary effects compared with inhalation of CO, which we previously showed had salutary effects, suggests that the 2 compounds (biliverdin and CO) exert their effects in part by different mechanisms [1].
• The results define an approach to produce dorsal axis-deficient embryos by photo-transforming its biliverdin by irradiation with 366-nm UV light and identify an unsuspected role for biliverdin IXalpha in X. laevis embryogenesis [14].
• These results showed that hydrolysis is not an obligatory step in the conversion of verdohemochrome to biliverdin and, moreover, indicated how heme can be converted, with verdohemochrome as an intermediate, into biliverdin in which the two terminal oxygen atoms are derived from different O2 molecules [15].
• Here, we generated mice lacking functional heme oxygenase 1 (Hmox1; EC 1.14.99.3), which catabolizes heme to biliverdin, carbon monoxide, and free iron, to assess its participation in iron homeostasis [16].
• Heme oxygenase (HO-1) provides a cellular defense mechanism during oxidative stress and catalyzes the rate-limiting step in heme metabolism that produces biliverdin (BV) [17].

Anatomical context of dehydrobilirubin

• Biliverdin treatment (1) led to a significant decrease in mRNA expression of iNOS, Cox-2, and ICAM-1 as well as the inflammatory cytokines IL-6 and IL-1beta; (2) decreased neutrophil infiltration into the jejunal muscularis; and (3) prevented SITx-induced suppression of intestinal circular muscle contractility [1].
• Biliverdin reductase in a stable form was purified to homogeneity from rat liver cytosol [18].
• The heme oxygenase system in the microsomes from pig spleen, rat spleen, and rat kidney also failed to oxidize Co-heme to biliverdin [19].
• Our results indicate that lipid peroxidation is a significant cause of NO-induced necrosis in human lung epithelial cells, and that the increased NO survival of L1 cells is due at least in part to decreased lipid peroxidation mediated by HO-1-generated biliverdin or bilirubin [20].
• Utilizing an in vitro coupled assay system, we show that isolated plastids from cucumber cotyledons convert the linear tetrapyrrole biliverdin IX alpha to the free phytochrome chromophore, phytochromobilin, which assembles with oat apophytochrome to yield photoactive holoprotein [21].

Associations of dehydrobilirubin with other chemical compounds

• Tracer doses of purified radiolabeled biliverdin, bilirubin, bilirubin monoglucuronide (BMG) or diglucuronide (BDG) were administered intravenously to intact normal or jaundiced homozygous Gunn rats [22].
• Crystal structure of phycocyanobilin:ferredoxin oxidoreductase in complex with biliverdin IXalpha, a key enzyme in the biosynthesis of phycocyanobilin [2].
• Heme oxygenase (HO) catalyzes the conversion of heme to carbon monoxide, iron, and biliverdin, which is immediately reduced to bilirubin (BR) [23].
• However, inhibition by bilirubin, biliverdin and chenodeoxycholic acid was found to be pH-dependent, with markedly less inhibition at the high values of pH [24].
• Exogenous CO administration or treatment with the CO-releasing agent methylene chloride mimicked the protective effect of HO-1, whereas treatment with exogenous biliverdin or overexpression of ferritin by recombinant adenoviral gene transfer did not [25].

Gene context of dehydrobilirubin

• Heme oxygenase-1 (HO-1) is a cytoprotective protein that catalyzes the degradation of heme to biliverdin, iron, and carbon monoxide (CO) [26].
• BVR reduces biliverdin, the HO-1 and HO-2 product, to bilirubin [27].
• Biliverdin reductase, a novel regulator for induction of activating transcription factor-2 and heme oxygenase-1 [28].
• The heme oxygenase (HO) enzymes catalyze the rate-limiting step in the breakdown of heme to iron, carbon monoxide, and biliverdin [29].
• In contrast, hemin and biliverdin seem to induce Cyp1a1 indirectly by serving as precursors to the endogenous formation of bilirubin via normal heme metabolism pathways [30].

Analytical, diagnostic and therapeutic context of dehydrobilirubin

• Western blots were performed for biliverdin reductase and HO-1 expression [1].
• Purified mature recombinant HY2 protein exhibits P Phi B synthase activity (i.e., ferredoxin-dependent reduction of biliverdin IX alpha to P Phi B), as confirmed by HPLC and by the ability of the bilin reaction products to combine with apophytochrome to yield photoactive holophytochrome [31].
• Biliverdin therapy protects rat livers from ischemia and reperfusion injury [17].
• Using a high performance liquid chromatography (HPLC)-based assay, we have demonstrated that isolated oat etioplasts convert the linear tetrapyrrole biliverdin IX alpha to (3E)-phytochromobilin, the proposed precursor of the chromophore of the plant photoreceptor phytochrome [32].
• We have investigated the binding of P450 reductase and biliverdin reductase to truncated, soluble hHO-1 by fluorescence resonance energy transfer and site-specific mutagenesis [33].

References