The regulatory potential of cytochrome P450-adrenodoxin interactions: Insights toward understanding redox partner regulation in drug metabolizing enzymes

Mitochondrial cytochrome P450 enzymes perform critical functions in steroidogenic, vitamin D, and vitamin A pathways. Their function relies on the formation of a redox complex with the soluble ferredoxin protein adrenodoxin (Adx). Mounting evidence indicates that cytochromes P450 (P450)-Adx interactions are highly context-dependent and are shaped by proximal P450 surface architecture and substrate occupancy within the active site. Although the core electron-transfer geometry is conserved across mitochondrial P450s, subtle differences at the interface and conformational adjustments allow the system to fine-tune electron delivery to support the distinct structural, mechanistic, and catalytic requirements of each enzyme. This role establishes Adx as an effector molecule in addition to an electron donor. This minireview surveys recent developments in our understanding of P450-Adx complexes, with particular attention drawn to differences in the P450 proximal surfaces. We also discuss these insights as a new framework for understanding analogous complexes in the microsomal P450s, which are important in drug metabolism. Significance Statement: Recent advancements in the study of P450-adrenodoxin complexes highlight the role of adrenodoxin as an effector molecule. This review seeks to contextualize these developments from the perspective of both potential therapeutics and lessons learned regarding drug metabolizing P450-redox partner protein complexes.