Overview of Heme Degradation Pathway

Mahin D. Maines1

1 University of Rochester School of Medicine, Rochester, New York
Publication Name:  Current Protocols in Toxicology
Unit Number:  Unit 9.1
DOI:  10.1002/0471140856.tx0901s00
Online Posting Date:  May, 2001
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Abstract

Heme oxygenase 1 and 2 activities are responsible for initiating most of the degradation of heme, although other enzyme pathways play a role as well. The degradation pathway also includes biliverdin reductase, the activity of which is coupled to oxidation of NADH and NADPH. This overview discusses the pathways and enzymes involved in heme degradation.

     
 
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Table of Contents

  • Literature Cited
  • Figures
     
 
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Materials

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Literature Cited

Literature Cited
   Alam, J., Cai, J., and Smith, A. 1994. Isolation and characterization of the mouse heme oxygenase‐1 gene. Distal 5′ sequences are required for induction by heme or heavy metals. J. Biol. Chem. 269:1001‐1009.
   Drummond, G.S., Valaes, T., and Kappas, A. 1996. Control of bilirubin production by synthetic heme analogs: Pharmacologic and toxicologic considerations. J. Perinatol. 16:S72‐S79.
   Ewing, J.F. and Maines, M.D. 1992. In situ hybridization and immunohistochemical localization of heme oxygenase‐2 mRNA and protein in normal rat brain: Differential distribution of isozyme 1 and 2. Mol. Cell. Neurosci. 3:559‐570.
   Ewing, J.F., Raju, V.S., and Maines, M.D. 1994. Induction of heart heme oxygenase‐1 (hsp32) by hyperthermia: Possible role in stress‐mediated elevation of cyclic 3′:5′‐guanosine monophosphate. J. Pharmacol. Exp. Ther. 271:408‐414.
   Fakhrai, H. and Maines, M.D. 1992. Expression and characterization of a cDNA for rat kidney biliverdin reductase: Evidence suggesting the liver and kidney enzymes are the same transcript product. J. Biol. Chem. 267:4023‐4029.
   Huang, T.J., Trakshel, G.M., and Maines, M.D. 1989. Detection of ten variants of biliverdin reductase in rat liver by two‐dimensional gel electrophoresis. J. Biol. Chem. 264:7844‐7849.
   Iyer, S., Woo, J., Cornejo, M.‐C., Gao, L., McCoubrey, W.K., Maines, M.D., and Buelow, R. 1998. Characterization and biological significance of immunosuppressive peptide D2702.75‐84 (E>V) binding protein: Isolation of heme oxygenase‐1. J. Biol. Chem. 273:2692‐2697.
   Liu, Y., Moenne‐Locccoz, P., Loehr, T.M., and Ortiz de Montellano, P.R. 1997. Heme oxygenase‐1 intermediates in verdoheme formation and the requirement for reduction equivalents. J. Biol. Chem. 272:6909‐6917.
   Kutty, R.K. and Maines, M.D. 1981. Purification and characterization of biliverdin reductase from the rat liver. J. Biol. Chem. 256:3956‐3962.
   Kutty, R.K. and Maines, M.D. 1987. Characterization of an NADPH‐dependent haem‐degrading system in ox heart mitochondria. Biochem. J. 246:467‐474.
   Maines, M.D. 1981. Zinc‐protoporphyrin is a selective inhibitor of heme oxygenase activity in the neonatal rat. Biochim. Biophys. Acta 673:339‐350.
   Maines, M.D. 1984. New developments in the regulation of heme metabolism and their implications. Crit. Rev. Toxicol. 12:241‐314.
   Maines, M.D. 1988. Heme oxygenase: Function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 2:2557‐2568.
   Maines, M.D. 1992. Heme Oxygenase: Clinical Applications and Functions. CRC Press, Boca Raton, Fla.
   Maines, M.D. 1997. The heme oxygenase system: A regulator of second messenger gases. Annu. Rev. Pharmacol. Toxicol. 37:517‐554.
   Maines, M.D. and Kappas, A. 1974. Cobalt induction of hepatic heme oxygenase; with evidence that cytochrome P450 is not essential for this enzyme activity. Proc. Natl. Acad. Sci. U.S.A. 71:4293‐4297.
   Maines, M.D., Polevoda, B.V., Huang, T.J., and McCoubrey, W.K. 1996. Human biliverdin IXα reductase is a zinc‐metalloprotein; Characterization of purified and Escherichia coli expressed enzymes. Eur. J. Biochem. 235:372‐381.
   Maines, M.D., Trakshel, G.M., and Kutty, R.K. 1986. Characterization of two constitutive forms of rat liver microsomal heme oxygenase: Only one molecular species of the enzyme is inducible. J. Biol.Chem. 261:411‐419.
   McCoubrey, W.K., Jr. and Maines, M.D. 1994. The structure, organization, and differential expression of the gene encoding rat heme oxygenase‐2. Gene 139:155‐161.
   McCoubrey, W.K., Ewing, J.F., and Maines, M.D. 1992. Human heme oxygenase: Characterization and expression of a full length cDNA and evidence suggesting the two HO‐2 transcripts differ by choice of polyadenylation signal. Arch. Biochem. Biophys. 295:13‐20.
   McCoubrey, W.K., Eke, B., and Maines, M.D. 1995. Multiple transcripts encoding HO‐2 in rat testis: Developmental and cell specific regulation of transcripts and protein. Biol. Reprod. 53:1330‐1338.
   McCoubrey, W.K., Huang, T.J., and Maines, M.D. 1997a. Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase‐3. Eur. J. Biochem. 247:725‐732.
   McCoubrey, W.K., Huang, T.J., and Maines, M.D. 1997b. Heme oxygenase‐2 is a hemoprotein and binds heme through heme regulatory motifs that are not involved in heme catalysis. J. Biol. Chem. 272:12568‐12574.
   Müller, R.M., Taguchi, H., and Shibahara, S. 1987. Nucleotide sequence and organization of the rat heme oxygenase gene. J. Biol. Chem. 262:6795‐6802.
   Raju, V.S., McCoubrey, W.K., Jr., and Maines, M.D. 1997. Regulation of heme oxygenase‐2 mRNA and protein by glucocorticoids: Characterization of a functional GRE. Biochim. Biophys. Acta 1351:89‐104.
   Rotenberg, M.O. and Maines, M.D. 1990. Isolation, characterization, and expression in Escherichia coli of a cDNA encoding rat heme oxygenase‐2. J. Biol. Chem. 265:7501‐7506.
   Rotenberg, M.O. and Maines, M.D. 1991. Characterization of a cDNA encoding rabbit brain heme oxygenase‐2 and identification of a conserved domain among mammalian heme oxygenase isozymes: Possible heme binding site Arch. Biochem. Biophys. 290:336‐344.
   Rublevskaya, I.N. and Maines, M.D. 1994. Interaction of Fe‐protoporphyrin IX and heme analogues with purified recombinant heme oxygenase‐2, the constitutive isozyme of the brain and testes. J. Biol. Chem. 269:26390‐26395.
   Sano, S., Sano, T., Morishima, I., Shiro, Y., and Maeda, Y. 1986. On the mechanism of the chemical and enzymatic oxygenation of α oxyprotohemin IX to Fe‐biliverdin IXα. Proc. Natl. Acad. Sci. U.S.A. 83:531‐535.
   Shibahara, S., Müller, R., Taguchi, H., and Yoshida, T. 1985. Cloning and expression of cDNA for rat heme oxygenase. Proc. Natl. Acad. Sci. U.S.A. 82:7865‐7869.
   Stocker, P., Yamamoto, Y., McDonach, A.F., Glazer, A.N., and Ames, B.N. 1987. Bilirubin is an antioxidant of possible physiological importance. Science 235:1043‐1047.
   Sun, Y., Rotenberg, M.O., and Maines, M.D. 1990. Developmental expression of heme oxygenase isozymes in rat brain: Two HO‐2 mRNAs are detected. J. Biol. Chem. 265:8212‐8217.
   Trakshel, G.M., Kutty, R.K., and Maines, M.D. 1986a. Purification and characterization of the major constitutive form of testicular heme oxygenase: The non‐inducible isoform. J. Biol. Chem. 261:11131‐11137.
   Trakshel, G.M., Kutty, R.K., and Maines, M.D. 1986b. Cadmium‐mediated inhibition of testicular heme oxygenase activity: The role of NADPH‐cytochrome c (P450) reductase. Arch. Biochem. Biophys. 251:175‐187.
   Vreman, H.J., Ekstrand, B.C., and Stevenson, D.K. 1993. Selection of metalloporphyrin heme oxygenase inhibitors based on potency and photoreactivity. Pediatr. Res. 33:195‐200.
   Weber, C.M., Eke, B.C., and Maines, M.D. 1994. Corticosterone regulates heme oxygenase‐2 and NO synthase transcription and protein expression in rat brain. J. Neurochem. 63:953‐962.
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