Enzymic degradation of heme. Oxygenative cleavage requiring cytochrome P-450

Tenhunen, Raimo; Marver, Harvey S.; Pinstone, N. R.; Trager, William; Cooper, David Y.; Schmid, Rudi

doi:10.1021/bi00759a029

Cited by 146 publications

(83 citation statements)

References 19 publications

(34 reference statements)

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“…The enzymatic nature of the heme catabolic process and the essential features of its biochemistry were initially described by the Schmid group (Tenhunen et al, 1968(Tenhunen et al, , 1970. Similarities of this process to the cytochrome P450-dependent mixed function oxidase system, which had been earlier described by Estabrook and colleagues (Estabrook et al, 1963;Cooper et al, 1965), subsequently led to the proposed role of cytochrome P450 as the terminal oxidase in the heme catabolic system (Tenhunen et al, 1972). However, the disparity in organ distribution and tissue concentrations of cytochrome P450 and the HO system, among other considerations, 1 Abbreviations: HO, heme oxygenase; CO, carbon monoxide; HO-1, heme oxygenase isozyme 1 (inducible form); HO-2, heme oxygenase isozyme 2 (constitutive form); ALA, ␦-aminolevulinic acid; O 2 Ϫ ; AP-1, activator protein-1; PKC, protein kinase C; SnCl 2 , stannous chloride; HETE, hydroxyeicosatetraenoic acid; COX, cyclooxygenase; SnMP, tin mesoporphyrin IX dichloride; CoPP, cobalt protoporphyrin IX dichloride; NOD, nonobese diabetic; CoCl 2 , cobaltous chloride; eNOS, endothelial nitric-oxide synthase; AKT, protein kinase (activator); p, phosphorylated; NO, nitric oxide; NOS, nitricoxide synthase; ZnPP, zinc protoporphyrin IX dichloride; YC-1, 3-(5Ј-hydroxymethyl-2Ј-furyl)-1-benzyl indazole; SHR, spontaneously hypertensive rats; ZnDP, zinc 2,4-bis glycol deuteroporphyrin; NTS, nucleus of the tractus solitarius; BK Ca channel, large-conductance calcium-activated potassium channel; CORM, carbon monoxide releasing molecule; sGC, soluble guanylate cyclase; GSH, glutathione; si, small interfering; ROS, reactive oxygen species; ONOO Ϫ , peroxynitrite; NF-B, nuclear factor-B; CNS, central nervous system; LPS, lipopolysaccharide; LDL, low-density lipoprotein; HSP, heat shock protein; PGA, prostaglandin A; STAT, signal transducer and activator of transcription; IL, interleukin; SnPP, tin protoporphyrin IX dichloride; EC-SOD, extracellular superoxide dismutase; TNF, tumor necrosis factor; PPAR, peroxisome proliferator-activated receptor; VSMC, vascular smooth muscle cell; L or D-4F, amino acid apolipoprotein A1-4F; iNOS, inducible nitric-oxide synthase; MAPK, mitogen-activated protein kinase; VEGF, vascular endothelial growth factor; cdk2, cyclin-dependent kinase 2; ERK, extracellular left the putative role of cytochrome P450 in heme catabolism an unsettled matter.…”

Section: Introductionsupporting

confidence: 60%

Pharmacological and Clinical Aspects of Heme Oxygenase

Abraham

Kappas²

2008

Pharmacol Rev

980

977

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Section: Introductionsupporting

confidence: 60%

Pharmacological and Clinical Aspects of Heme Oxygenase

Abraham

Kappas²

2008

Pharmacol Rev

980

977

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“…Verdohemochrome is hydrolyzed in vitro to biliverdin, and biliverdin is reduced to bilirubin. Hydrolysis of an oxygen-bridged intermediate was, however, excluded as a step in the enzymatic degradation of heme to physiological bile pigments by the finding that both terminal lactam oxygen atoms ofbilirubin are incorporated from 02 without any incorporation of oxygen from water (2). This result contrasted with an earlier report that biliverdin from the coupled oxidation of hemoglobin and ascorbate contains only one atom of oxygen from 02(3).…”

mentioning

confidence: 72%

“…More recently, the two terminal oxygen atoms were found to be derived from different molecules of 02 in the coupled oxidation of octaethylheme and in the physiological formation ofbile pigments (4-7). These findings, together with the assumption that the conversion of verdohemochrome or verdohemin to biliverdin requires hydrolysis, have resulted in the rejection of these oxygen-bridged compounds as possible intermediates in heme degradation (2,(4)(5)(6)(7).…”

mentioning

confidence: 99%

Verdohemochrome IX alpha: preparation and oxidoreductive cleavage to biliverdin IX alpha.

Saito¹,

Itano²

1982

Proc. Natl. Acad. Sci. U.S.A.

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Several studies have shown that both terminal oxygen atoms of biliverdin are derived from molecular oxygen. Since the conversion of verdohemochrome to biliverdin has been assumed to be hydrolytic, these findings seemed to exclude verdohemochrome as an intermediate in the degradation of heme to biliverdin. Coupled oxidation of myoglobin and ascorbate yielded a pure preparation of verdohemochrome IX alpha. The structure and ferrous state of this product were determined from its composition, ligand reactions, 1H NMR spectrum, and conversion to biliverdin IX alpha dimethyl ester. Reaction with ascorbate and 18O2 converted this compound to biliverdin that contained an atom of 18O. Successive treatment of verdohemochrome, first oxidation with H2O2 and then reduction with phenylhydrazine, yielded the iron complex of biliverdin. 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.

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“…1). The involvement of ␣-meso-hydroxyheme rationalizes both the chemistry of the process and the finding that an atom of molecular oxygen is incorporated into the CO (18). Finally, in a reaction also catalyzed by HO-1, verdoheme is cleaved in an NADPH-and O 2 -dependent manner to give biliverdin (19,20).…”

mentioning

confidence: 81%

Oxidation of the meso-Methylmesoheme Regioisomers by Heme Oxygenase

Torpey

Montellano

1996

Journal of Biological Chemistry

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The oxidation of heme by heme oxygenase (HO-1) results in highly regiospecific extrusion of the ␣-mesocarbon as CO and the formation of biliverdin IX␣. The first step in the accepted mechanism for this process is ␣-meso-hydroxylation of the heme. To define further the reaction mechanism, the oxidations of the four isomers of meso-methylmesoheme by human truncated HO-1 supported by NADPH-cytochrome P450 reductase, H 2 O 2 , or ascorbate have been examined. Surprisingly, the results establish that (a) HO-1 can oxidize an ␣-meso-methyl-substituted heme to biliverdin IX␣ without proceeding via the ␣-meso-hydroxy intermediate; (b) the normal HO-1 ␣-regiospecificity is inverted in favor of the substituted ␥-position by introduction of a ␥-meso methyl group; and (c) the ␤-and ␦-meso-methylmesohemes are oxidized less regiospecifically to mixtures of methylsubstituted and -unsubstituted mesobiliverdins. The results indicate that electronic rather than steric effects primarily control the regiospecificity of heme cleavage by HO-1.Heme oxygenase, which oxidizes heme 1 to biliverdin IX␣ and CO ( Fig. 1), is of particular interest because of the physiological activities of its reaction products. Biliverdin, which functions as an endogenous antioxidant (1), is reduced to bilirubin and is excreted after conjugation with glucuronic acid (2). However, the excretion of bilirubin is often impaired in newborn children and in other individuals with a glucuronyltransferase deficiency (3). The neurotoxic properties of unconjugated bilirubin make its accumulation undesirable, and inhibition of heme oxygenase is one possible approach to the treatment of this problem. More recently, a potentially important but controversial role as a second messenger akin to nitric oxide has been proposed for the CO produced by heme oxygenase (4 -6).Two forms of heme oxygenase are known: HO-1, which is induced by a variety of agents and stress conditions and is found in highest concentration in the spleen and liver, and HO-2, which is not induced by xenobiotics and is found in highest concentration in the brain and testes (7,8). Human HO-1 is a 32-kDa protein with a C-terminal lipophilic domain that anchors it to the endoplastic reticulum (9). We have demonstrated that a fully active truncated version of human HO-1 (hHO-1) lacking the 23 C-terminal amino acids that constitute the membrane anchor can be expressed in Escherichia coli in high yields (10). A protein lacking the 26 N-terminal amino acids in which the last two amino acids have been mutated (S262R, S263L) has been independently expressed and shown to retain partial activity (11).The heme oxygenase reaction proceeds via a multistep mechanism that depends on reduction equivalents provided by NADPH and P450 reductase. The first step of the reaction is thought to be the O 2 -dependent oxidation of heme to ␣-mesohydroxyheme (Fig. 1). The principal experimental evidence for this intermediate is the finding that synthetic ␣-meso-hydroxyheme is converted to biliverdin IX␣ both by HO-1 (12, 13) and by a...

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Enzymic degradation of heme. Oxygenative cleavage requiring cytochrome P-450

Cited by 146 publications

References 19 publications

Pharmacological and Clinical Aspects of Heme Oxygenase

Pharmacological and Clinical Aspects of Heme Oxygenase

Verdohemochrome IX alpha: preparation and oxidoreductive cleavage to biliverdin IX alpha.

Oxidation of the meso-Methylmesoheme Regioisomers by Heme Oxygenase

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