January, 2015 Molecule of the month: Cytochrome P450(s)

It's a new year and I thought I would bring out the molecule I had intended to write about in November, I thought I would focus on another topic that links to the theme of malaria (at the UTC) , but which is of wider importance in understanding the way animals, in particular, deal with chemical challenges. The cytochrome P450 family of proteins (often abbreviated to CYPs; an example is shown on the LHS), is an important target for insecticides (take a look at the links at Nicole Joussen's web site in Germany) in dealing with the spread of malaria via mosquitoes, but it is also an important class of enzymes in the process of drug validation (I like the way Emily Scott has organised her research into CYPs and drug discovery here [and then follow her research links]). The first thing to say is that it isn't a single enzyme. The CYPs are a group of enzymes which facilitate the "metabolism" of foreign compounds (xenobiotics). From an evolutionary perspective, they provide a selective advantage in mitigating the impact of potentially toxic molecules. From an enzymological point of view, they are of interest since they handle a wide range of substrates, making the relationship between the chemistry of catalysis and the specificity of substrate recognition an intriguing challenge. Let's look at the general structure function relationships in the CYP superfamily and then consider their importance both fundamentally and translationally with respect to toxicology: drugs and insecticides.


The CYPs are modular molecules (top figure, LHS) comprising two domains: the substrate binding domain and the redox domain: the structure of the first mammalian CYP was published in 2000. The reaction catalysed by these enzymes can be generalised in the schematic figure shown Left. The structures of the substrates can be substantially different (see below, RHS for a comparison of two substrates handled by a single P450). The CYPs represent a class of enzymes where there is a common redox centre that is used to diffuse the dangerous aspects of the toxic molecule. Enzymes exist with specificities that are unique, but there are also situations where evolution has led to the retention of a useful engine (the redox centre) which is then attached through historic (genetic) events including gene fusions and recombination, to generate a range of primary structures that recognise different small molecules. 

This structure-function concept is a theme found a number of times in Biology. For example all Immunoglobulins (antibodies: see my January 2013 Blog on these molecules) have a common stem (called the Fc region) which binds to cell receptors, associated with many different antigen combining elements, enabling us to eliminate many thousands of potentially harmful molecules. In the case of CYPs, a catalytic engine is harnessed to a range of small molecule scavenging units, which then prepare the offensive molecules for downstream elimination (in humans) in the liver. 

The interest in CYPs lies not only in their role in toxicological investigations of new drugs, but also in the application of insecticides in the battle against malaria. The role played by CYPs (as well as other enzymes including glutathione-S-transferases and haem metabolising enzymes) has formed a major part of the research programme at the Liverpool School of Tropical Medicine. You can read more about this here by following the links from Professor Hilary Ranson, Head of the Department of Vector Biology at the School. Understanding the relationship between mutation and the genetics of insecticide resistance, in particular in respect of the CYPs, is one of the major areas of research in the field of Tropical Medicine. So the molecule for January, 2015 represents a major challenge for fundamental Biochemistry, but also occupies a pivotal position in the delivery of new drugs to the market and in the management of malaria.