Unique structural features in a deep-sea CYP51 relate to high pressure adaptation

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• Cytochromes P450 (CYP) are a vast enzyme superfamily with diverse functions, from synthesizing essential compounds to metabolizing xenobiotics.
• Sterol 14α-demethylases (CYP51s) are crucial enzymes in sterol biosynthesis.
• Understanding CYP51 structure-function relationships is vital for drug development and metabolic studies.

Purpose of the Study:

• To determine the crystal structures of deep-sea fish (Coryphaenoides armatus) and human sterol 14α-demethylases (CYP51s).
• To elucidate the molecular basis for observed differences in catalytic rates, substrate selectivity, and inhibitor resistance.
• To investigate the structural adaptations of deep-sea P450 enzymes in relation to their environment.

Main Methods:

• X-ray crystallography was employed to determine the high-resolution structures of C. armatus CYP51 and human CYP51.
• Comparative structural analysis was performed to identify key differences and similarities between the two enzymes.
• Bioinformatic tools and artificial intelligence molecular modeling were used for comparison with experimental structures.

Main Results:

• Both C. armatus and human CYP51 structures exhibit conformational flexibility, explaining faster catalysis, lower selectivity, and inhibitor resistance.
• Unique structural features, including the FG arm/β4 hairpin positioning, were observed in the fish CYP51, differing from AI predictions.
• The structure of C. armatus CYP51, the first deep-sea P450 characterized, highlights potential regulation by the membrane environment.

Conclusions:

• The determined structures provide a molecular understanding of CYP51 function and regulation.
• Structural distinctions in C. armatus CYP51 suggest co-adaptation with deep-sea membrane lipid composition.
• These findings offer insights into enzyme evolution and adaptation to extreme environments.