Unique Structural Features Relate to Evolutionary Adaptation of Cytochrome P450 in the Abyssal Zone

Area of Science:

• Biochemistry
• Structural Biology
• Evolutionary Biology

Background:

• Cytochromes P450 (CYPs) are a vast enzyme superfamily with diverse functions.
• Sterol 14α-demethylases (CYP51) are crucial for sterol biosynthesis in metazoans and may be an ancestral P450 form.

Purpose of the Study:

• Determine the crystal structures of CYP51 from the deep-sea fish *Coryphaenoides armatus* and human.
• Conduct comparative sequence-structure-function analysis to understand CYP51 properties.

Main Methods:

• X-ray crystallography to obtain ligand-free CYP51 structures.
• Comparative sequence and structural analysis.

Main Results:

• Identified specific structural elements in *C. armatus* CYP51 associated with increased conformational flexibility.
• Observed significant repositioning of membrane-associated segments (FG arm, β4 hairpin) in *C. armatus* CYP51.
• The deep-sea CYP51 exhibits faster catalytic rates, lower substrate selectivity, and resistance to inhibition.

Conclusions:

• The unique structure of *C. armatus* CYP51 suggests enhanced flexibility and altered catalytic properties.
• The deep-sea P450 structure implies a greater role for the membrane environment in enzyme regulation.
• This represents a co-adaptation of membrane protein structure with lipid composition for deep-sea life.