How evolution shaped the structure of steroidogenic cytochrome P450 11A

Area of Science:

• Biochemistry
• Evolutionary Biology
• Structural Biology

Background:

• Cytochrome P450 enzyme 11A1 (CYP11A1) is crucial for steroid hormone biosynthesis, catalyzing cholesterol side-chain cleavage.
• This enzyme initiates the production of pregnenolone, a precursor for all major steroid hormones.

Purpose of the Study:

• To investigate the structural and functional evolution of CYP11A1.
• To understand how structural modifications in ancestral CYP11A1 (CYP11A_N1) influenced its catalytic properties compared to extant forms.

Main Methods:

• Resurrection of an ancestral CYP11A1 isoform (CYP11A_N1).
• X-ray crystallography to determine the structure of the ancestral CYP11A_N1.
• Comparative analysis of structural features between ancestral and extant CYP11A1.

Main Results:

• The first structure of an ancestral mitochondrial cytochrome P450 was determined.
• Identified significant structural differences between CYP11A_N1 and extant CYP11A1.
• These structural changes correlate with altered substrate specificities and catalytic properties for cholesterol metabolism.

Conclusions:

• Structural evolution of CYP11A1 has significantly impacted steroid hormone biosynthesis.
• Understanding ancestral enzyme structures provides insights into the functional diversification of P450 enzymes.
• This study highlights the role of structural changes in shaping the evolutionary trajectory of essential metabolic pathways.