Cytochrome P450: The Metabolizer

Abstract

Why can't Grandpa drink grapefruit juice with his Lipitor? Why is John hypersensitive to aspirin? The answers lie in a study of cytochrome P450s (CYP101), a family of enzymes that are responsible for the transformation of vitamins, pharmaceuticals and other foreign chemicals into soluble and readily excreted molecules. This goal is achieved primarily by hydroxylation reactions, which occur in these molecules through a series of extremely fast sequential reactions, called an enzymatic cycle. In order to better understand certain intermediates in the cycle, the reaction must be stopped at given points. In a particular variant of cytochrome P450s, the presence of an aspartic acid near the active site causes immediate protonation of the peroxo group, making it impossible to stop the hydroxylation reaction. However, in the mutant form, CYP101 D251N, the aspartic acid is replaced with an asparagine, which blocks protonation on an atomic level. Scientists need to study these molecules and characterize the molecular structures of the reaction intermediates in order to understand what factors affect the process, such as mutation of particular protein sites and blockage by interfering chemicals. The Marquette University High School SMART Team (Students Modeling A Research Topic) modeled both the wild‐type and the D251N mutant of P450cam using MSOE's 3D printing technology. Supported by grants from NIH‐SEPA and NIH‐CTSA.