Molecular Regulation of Heme Biosynthesis in Higher Vertebrates

https://doi.org/10.1016/S0079-6603(08)60875-2Get rights and content

Publisher Summary

The regulation of heme biosynthesis in animals has been a topic of interest for many years. It is generally agreed that the first enzyme of the heme pathway, 5-aminolevulinate synthase, determines the rate of heme biosynthesis and the regulation of this enzyme is, therefore, a major focus of this chapter. The heme biosynthetic pathway is present in all cell types except mature erythrocytes. The final step of heme biosynthesis occurs in mitochondria and the heme is then utilized for the formation of different hemoproteins located in mitochondria, microsomes, peroxisomes, the cytosol, and probably the nucleus. Heme can control the biosynthesis of some proteins. In erythroid cells, heme controls the translation of proteins, notably α- and β-globin chains, by modulating the activity of a specific kinase. All nucleated animal cells must synthesize heme for incorporation into respiratory cytochromes, but erythroid and liver cells have the highest rates of heme synthesis. Erythroid cells synthesize about 90% of the total heme in the body for assembly into hemoglobin. Although the bulk of heme in the liver is made in situ, the liver may also obtain some heme from serum haptoglobin–hemoglobin and heme–hemopexin complexes, following intravascular hemolysis. All enzymes of the heme biosynthetic pathway, except for protoporphyrinogen oxidase, have been cloned from higher vertebrates. The genes encoding these enzymes are located on different chromosomes.

References (158)

  • B.K. May et al.

    Curr. Top. Cell. Regul.

    (1986)
  • T. Helfman et al.

    Am. J. Med. Sci.

    (1993)
  • S. Taketani et al.

    JBC

    (1994)
  • I.A. Borthwick et al.

    Methods Enzymol.

    (1986)
  • M. Rohde et al.

    ABB

    (1990)
  • G. Srivastava et al.

    JBC

    (1988)
  • G.C. Ferreira et al.

    JBC

    (1993)
  • M. Marceau et al.

    JBC

    (1990)
  • J.G. Conboy et al.

    JBC

    (1992)
  • D.F. Bishop et al.

    Genomics

    (1990)
  • J.G. Conboy et al.

    Blood

    (1991)
  • B. Lewin

    Cell

    (1990)
  • G. Braidotti et al.

    JBC

    (1993)
  • M.J. Evans et al.

    JBC

    (1989)
  • A.H. Kaya et al.

    Genomics

    (1994)
  • S. Granick

    JBC

    (1966)
  • D. Darr et al.

    Biol. Invest. Dermatol.

    (1994)
  • A.B. Sachs

    Cell

    (1993)
  • J.W. Hamilton et al.

    ABB

    (1991)
  • P.D. Drew et al.

    BBRC

    (1989)
  • N. Hayashi et al.

    ABB

    (1972)
  • G. Srivastava et al.

    BBRC

    (1983)
  • K. Pfeifer et al.

    Cell

    (1989)
  • M. Kiebler et al.

    Cell

    (1993)
  • S.C. Dogra et al.

    ABB

    (1993)
  • J.W. Hamilton et al.

    ABB

    (1992)
  • L.A. Mattschoss et al.

    JBC

    (1986)
  • C.N. Hahn et al.

    JBC

    (1991)
  • J.S. He et al.

    JBC

    (1991)
  • R. Ramsden et al.

    JBC

    (1993)
  • M.D. Maines et al.

    JBC

    (1986)
  • G.M. Trakshel et al.

    JBC

    (1986)
  • I. Cruse et al.

    JBC

    (1988)
  • W.K. McCoubrey et al.

    Gene

    (1994)
  • Y. Sun et al.

    JBC

    (1990)
  • M.D. Maines

    Mol. Cell. Neurosci.

    (1993)
  • J. Alam et al.

    JBC

    (1994)
  • K. Takeda et al.

    JBC

    (1994)
  • J. Alam et al.

    JBC

    (1992)
  • D. Metcalf

    Blood

    (1993)
  • S.B. Krantz

    Blood

    (1991)
  • V.C. Broudy et al.

    Blood

    (1991)
  • S.H. Orkin

    Cell

    (1990)
  • B.A. Witthuhn et al.

    Cell

    (1993)
  • H. Fujita et al.

    BBA

    (1991)
  • B. Grandchamp et al.

    JBC

    (1985)
  • H. Kohno et al.

    JBC

    (1993)
  • G. Balla et al.

    Lab. Invest.

    (1991)
  • U. Müller-Eberhard et al.

    Am. J. Hematol.

    (1993)
  • S.S. Bottomley et al.

    Semin. Hematol.

    (1988)
  • Cited by (128)

    • Mitochondrial biogenesis in organismal senescence and neurodegeneration

      2020, Mechanisms of Ageing and Development
      Citation Excerpt :

      NRF1 was first identified as a positive regulator of cytochrome c transcription and since then its role in the transcription of nuclear-encoded mitochondrial transcripts has expanded (Evans and Scarpulla, 1989). Particularly, NRF1 forms homodimers and positively regulates the expression of several components of the oxidative phosphorylation pathway, the mitochondrial protein import machinery, ion channel components and heme biosynthesis enzymes (Biswas and Chan, 2010; Blesa et al., 2008b, 2007; Kiyama et al., 2018; May et al., 1995; Satoh et al., 2013; Virbasius et al., 1993). In addition, it indirectly controls mitochondrial genome expression, through binding on the promoter regions of the principal mtDNA regulators, mitochondrial transcription factor A (TFAM) and the assistant factors mitochondrial transcription factor B1 (TFB1M) and mitochondrial transcription factor B2 (TFB2M), yet results about TFAM are inconsistent (Baar et al., 2003; Gleyzer et al., 2005; Virbasius and Scarpulla, 1994).

    • Inherited Porphyrias

      2020, Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Metabolic Disorders
    • Pregnane X receptor in drug-induced liver injury: Friend or foe?

      2018, Liver Research
      Citation Excerpt :

      Heme is required for various cellular functions such as oxygen transport in hemoglobin and electron transport in hemoproteins like the CYPs.72,73 Heme is synthesized in the liver and bone marrow by a series of well-controlled enzymatic processes that starts with the condensation of succinyl coA and glycine by the first and rate limiting enzyme alanine synthase 1 (ALAS1); and ends with the insertion of ferrous iron into the protoporphyrin Ⅸ (PPⅨ) ring to form heme by ferrochelatase (FECH).72 Both mPXR and hPXR have been reported to upregulate the expression of ALAS1 by binding to the ALAS1 drug-responsive enhancer sequences in the 5′ flanking region of ALAS1.74,75

    • No changes in heme synthesis in human Friedreich´s ataxia erythroid progenitor cells

      2017, Gene
      Citation Excerpt :

      In general, heme plays a fundamental role in many crucial biochemical reactions, and its biosynthesis is finely tuned to these requirements which vary significantly among various cells and tissues. There is a dramatic difference in synthetic rates because 85% of organismal heme is synthesized in erythroid cells (May et al., 1995). The heme synthesis rate in erythroid cells depends on the availability of iron for ferrochelatase (Ponka, 1997).

    View all citing articles on Scopus
    View full text