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A more recent version of this article appeared on December 1, 2004

Papers In Press, published online ahead of print September 1, 2004
J. Lipid Res., doi:10.1194/jlr.M400300-JLR200
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Submitted on August 5, 2004
Revised on August 27, 2004
Accepted on August 30, 2004

Phospholipids modify substrate binding and enzyme activity of human cytochrome P450 27A1 (CYP27A1)

Dilyara A. Murtazina, Ulla Andersson, In-Su Hahn, Ingemar Bjorkhem, G. A. S. Ansari, and Irina A. Pikuleva

Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555-1031

Corresponding Author: irpikule{at}utmb.edu

Cytochrome P450 27A1 (P450 27A1) is an important metabolic enzyme involved in bile acid biosynthesis and activation of vitamin D3 in mammals. Recombinant P450 27A1 heterologously expressed in Escherichia coli was found to be co-purified with phospholipids (PLs). The phospholipid (PL) content varied in different preparations and was dependent on the purification protocol. A link between the increased amounts of PLs and deterioration of the enzyme substrate binding properties was also observed. Tandem negative ionization mass spectrometry identified phosphatidyl glycerol (PG) as the major PL co-purified with P450 27A1. Subsequent reconstitution of P450 into exogenous PG vesicles assessed the effect of this contamination on substrate binding and enzyme activity. Two other PLs, phosphatidyl ethanolamine (PE) and phosphatidyl serine (PS), were also tested. PG and PE increased the Kd for 5b-cholestane-3a,7a,12a-triol and cholesterol binding, whereas PS had no effect on either of the substrate binding. PG and PE did not significantly alter 5b-cholestane-3a,7a,12a-triol hydroxylase activity and even stimulated cholesterol hydroxylase activity. PS inhibited 5b-cholestane-3a,7a,12a-triol hydroxyse activity and had no effect on cholesterol hydroxylase activity. Our study shows the potential for PLs to regulate the activity of P450 27A1 in vivo and alter the amount of cholesterol degraded through the “classical” and the “alternative” bile acid biosynthetic pathways.


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