A recent thematic series on cytochromes P450 in The Journal of Biological Chemistry consists of four minireviews covering new trends in P450 research and the many roles they play in disease. As important catalysts involved in hormone and drug biochemistry, these diverse enzymes are the center of attention in a number important fields.
In his introduction to the series, coordinating editor F. Peter Guengerich of Vanderbilt University illustrates how the P450 field has matured over the past 50 years. “With (more than) 18,000 known P450 sequences available and the number increasingly rapidly,” Guengerich writes, “it is humbling to realize that we understand the functions of only a fraction of these P450s.”
Most of the reactions that are catalyzed by P450s are called mixed-function oxidations and have the following stoichiometry: NAD(P)H + H+ + O2 + R → NADP+ + H2O + RO (where R is the substrate).
Understanding P450s has been instrumental in cancer biology, pharmacogenetics and insect control, and although we have a good understanding of the sheer breadth of applications, Guengerich emphasizes that “prediction of catalytic activities for individual P450s is still difficult.”
In the first minireview, Guengerich and Andrew W. Munro of the Manchester Institute of Biotechnology write about unusual P450 enzymes and reactions. Most P450 reactions can be rationalized with the complex FeO3+, an intermediate known as Compound I. Rearrangements of products or intermediates are often the explanation for unusual P450 reactions. “Although the vast majority of P450 reactions are oxidations, reductions are also known,” the authors write. Moreover, a minimum of three nonredox reactions have been reported.
In the second minireview, Courtney M. Krest of Pennsylvania State University and colleagues stress the importance enzyme purification played in the capture and characterization of P450 Compound I. The authors discuss techniques involved in the search for reactive intermediates and attempt to clarify controversial reports on the production of P450 Compound I using alternate approaches.
The third minireview, by Eric F. Johnson and C. David Stout at The Scripps Research Institute, highlights the notion that X-ray crystal structures, which are now available for 29 eukaryotic microsomal, mitochondrial and chloroplast P450s, offer a scaffold upon which mechanisms of function may be built. The authors add that “advances in the application of (nuclear magnetic resonance) spectroscopy for structural characterization of membrane P450s could increase our understanding of the conformational heterogenetiy of membrane-bound P450s.” The authors also point out that characterizing the structures of additional membrane P450s in insect and plant species would prove fortuitous in maneuvering around pesticide-resistance problems. Likewise, they acknowledge that understanding structures of P450s in microbes and eukaryotes might lead to new drug opportunities.
The final minireview, by Irina A. Pikuleva at Case Western Reserve University and Michael R. Waterman at Vanderbilt University, focuses on P450s in human diseases. The authors discuss 14 monogenic diseases related to altered enzymatic action on steroid hormones, cholesterol, vitamin D3 or eicosanoids. In their final remarks, the authors note that “development of new DNA-sequencing platforms and genome-wide association studies have revealed previously unanticipated associations and P450 contributions to a number of polygenic diseases.” They also conclude that within the next 10 years our understanding of P450 roles in various diseases undoubtedly will be broadened significantly.
Zachary R. Conley (firstname.lastname@example.org) is a freelance science writer based in the Kansas City area.