Altered CYP19A1 and CYP3A4 Activities Due to Mutations in the Flavin Mononucleotide Binding Domain of Human P450 Oxidoreductase

Pandey, Amit V.; Udhane, Sameer S.; Parween, Shaheena; Kagawa, Norio (April 2017). Altered CYP19A1 and CYP3A4 Activities Due to Mutations in the Flavin Mononucleotide Binding Domain of Human P450 Oxidoreductase. FASEB journal, 31(S1), 669.6-669.6. Federation of American Societies for Experimental Biology

Abstract Cytochromes P450 proteins are responsible for the metabolism of many steroid
hormones as well as drugs and xenobiotics. All cytochromes P450s in the endoplasmic
reticulum rely on P450 oxidoreductase (POR) for their catalytic activities. Previously we and
others have shown that mutations in POR cause metabolic disorders of steroid hormone
biosynthesis and also affect certain drug metabolizing P450 activities. Human POR has
distinct subdomains, which bind flavin molecules and interact with redox partners. We
studied the mutations identified in flavin mononucleotide (FMN) binding domain of POR that
interacts with partner proteins. We found that mutations A115V, T142A located close to the
FMN binding site had reduced flavin content compared to wild type POR and lost almost all
activity to metabolize androstenedione via CYP19A1 and also showed reduced CYP3A4 acitivies.

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