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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 J.·2007·Cell Metabolism
DOI 10.1016/j.cmet.2006.12.009
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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.

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  • TMEM97 levels can be regulated by changes in cholesterol levels; when cholesterol levels are reduced, TMEM97 expression can be induced by sterol regulatory element-binding protein-2.

    “Although TMEM97, unlike emopamil binding protein, is not thought to have isomerase activity, TMEM97 levels can be regulated by changes in cholesterol levels. More specifically, when cholesterol levels are reduced, TMEM97 expression can be induced by sterol regulatory element-binding protein-2 [75,76,77,78].”

    From Sigma-2 Receptors—From Basic Biology to Therapeutic Target: A Focus on Age-Related Degenerative Diseases (2023) · cites this paper as [78]

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Metadata

Authors
Hughes, A. L., Powell, D. W., Bard, M., Eckstein, J., Barbuch, R., Link, A. J., & Espenshade, P. J.
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2007-02
Volume
5
Issue
2
Pages
143-149
ISSN
1550-4131
DOI
10.1016/j.cmet.2006.12.009
Cited by
204
References
1
Language
en
Licence

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