Dap1/PGRMC1 Binds and Regulates Cytochrome P450 Enzymes

Adam L. Hughes, David W. Powell, Martin Bard, James Eckstein, Robert Barbuch, Andrew J. Link, Peter Espenshade

Research output: Contribution to journalArticle

Abstract

Cytochrome P450 enzymes are heme-dependent monoxygenases that play a central role in human physiology. Despite the numerous physiological processes that P450 enzymes impact, the electron donors P450 oxidoreductase and cytochrome b5 are the only proteins known to interact with and modulate the activity of ER microsomal P450s. Here, we report that Dap1/PGRMC1 is required for ER P450 function in yeast and humans. We show that S. pombe Dap1 is a hemoprotein that binds and positively regulates Cyp51A1 and Cyp61A1, two P450s required for sterol biosynthesis. Similarly, loss of human PGRMC1 reduces activity of Cyp51A1, blocking cholesterol synthesis and increasing production of toxic sterol intermediates. PGRMC1 stably binds Cyp51A1 and human P450s from three additional families including Cyp3A4, which metabolizes pharmaceutical compounds. These findings demonstrate that PGRMC1 is required for P450 activity and suggest that interindividual variation in PGRMC1 function may impact multiple biochemical pathways and drug metabolism.

Original languageEnglish (US)
Pages (from-to)143-149
Number of pages7
JournalCell Metabolism
Volume5
Issue number2
DOIs
StatePublished - Feb 7 2007

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Cytochrome P-450 Enzyme System
Sterols
Physiological Phenomena
Cytochromes b5
Schizosaccharomyces
Poisons
Heme
Pharmaceutical Preparations
Oxidoreductases
Yeasts
Cholesterol
Electrons
Proteins

Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

Cite this

Hughes, A. L., Powell, D. W., Bard, M., Eckstein, J., Barbuch, R., Link, A. J., & Espenshade, P. (2007). Dap1/PGRMC1 Binds and Regulates Cytochrome P450 Enzymes. Cell Metabolism, 5(2), 143-149. https://doi.org/10.1016/j.cmet.2006.12.009

Dap1/PGRMC1 Binds and Regulates Cytochrome P450 Enzymes. / Hughes, Adam L.; Powell, David W.; Bard, Martin; Eckstein, James; Barbuch, Robert; Link, Andrew J.; Espenshade, Peter.

In: Cell Metabolism, Vol. 5, No. 2, 07.02.2007, p. 143-149.

Research output: Contribution to journalArticle

Hughes, AL, Powell, DW, Bard, M, Eckstein, J, Barbuch, R, Link, AJ & Espenshade, P 2007, 'Dap1/PGRMC1 Binds and Regulates Cytochrome P450 Enzymes', Cell Metabolism, vol. 5, no. 2, pp. 143-149. https://doi.org/10.1016/j.cmet.2006.12.009
Hughes AL, Powell DW, Bard M, Eckstein J, Barbuch R, Link AJ et al. Dap1/PGRMC1 Binds and Regulates Cytochrome P450 Enzymes. Cell Metabolism. 2007 Feb 7;5(2):143-149. https://doi.org/10.1016/j.cmet.2006.12.009
Hughes, Adam L. ; Powell, David W. ; Bard, Martin ; Eckstein, James ; Barbuch, Robert ; Link, Andrew J. ; Espenshade, Peter. / Dap1/PGRMC1 Binds and Regulates Cytochrome P450 Enzymes. In: Cell Metabolism. 2007 ; Vol. 5, No. 2. pp. 143-149.
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