Cytochrome P450 metabolizing fatty acids in living organisms

Abstract

Cytochrome P450s (P450s) are ubiquitous enzymes found in most classes of organisms including animals, plants, bacteria and fungi. P450s are heme–thiolate metalloenzymes that are usually membrane-bound on the cytosolic face of the endoplasmic reticulum (except the bacterial ones which are often soluble). The vast majority of P450s catalyse, in the presence of NADPH or NADH, the insertion of an atom of oxygen from O2 into a molecule of substrate according to the overall reaction RH + NAD(P)H + O2 + H + fi ROH + NAD(P) + H2O. They are thus monooxygenases catalysing mostly hydroxylation reactions. The number of genes encoding P450s ranges from a few dozen in animal genomes to several hundreds in bacterial genomes or in plant genomes, in which they represent up to 1% of total genes. Cytochrome P450s are classified in the same family when they share > 40% identity in amino acid sequence and in the same subfamily when they share > 55% identity. They are major actors in the metabolism of xenobiotics, as well as endogenous compounds like plant hormones, many secondary metabolites and oxygenated derivatives of fatty acids. Since the pioneering work of Preiss and Block (1964), Lebeault et al. (1971) and Soliday and Kolattukudy (1977), shed light on the presence of cytochrome P450s metabolizing fatty acids (FA) in animals, micro-organisms and plants, respectively, interest in the study of these enzymes in all organisms has greatly increased because the products of the reactions possess fundamental biological activities. Bioactivation of arachidonic acid (C20:4) in the so-called ‘arachidonic cascade’ in mammals illustrates the diversity and biological activities of oxygenated FAs, as well as the role of cytochrome P450s in their production. A large amount of data was recently acquired on P450 functions in animals and also in microbes and plants. The goal of this minireview series is to draw attention to this new knowledge. Mammalian P450s cover many aspects of biology. In this series of minireviews, we have chosen to focus on involvement of FA x-hydroxylases in human genetic diseases. In plants, studies of Arabidopsis mutants have confirmed key roles for cytochrome P450s in the synthesis of FA-based hydrophobic barriers. Recent biochemical studies have also revealed the existence of FA-metabolizing P450s with different specificities. The possible biological roles of these newly characterized P450s is discussed. In bacteria and fungi, P450s metabolizing FA are mainly studied as actors in FA and alkane degradation, but as shown here, they are also involved in the production of molecules like sphingolipids, polyketides and oxylipins. Recent progress in the functional characterization of P450 families, combined with the wealth of phylogenetic information coming from sequencing projects for a wide array of organisms, has started to give insights into the evolution of P450-dependent functions. Concerning FA metabolism, it is clear that many P450 families have evolved in connection with a specific common biological function. A typical example concerns plant FA x-hydroxylases from the CYP86 family, which is dedicated to the synthesis of protective envelopes (i.e. cutin and suberin). Another important observation is that identical P450-dependent catalytic activities have evolved separately several times during evolution. This point is again illustrated by FA x-hydroxylation, which is carried out by different families in animals, plants and fungi (CYP4A, CYP86A and CYP52 respectively). Despite the great progress made in recent years in the characterization of the biological roles of P450s in all kingdoms, the functions of many P450 families and family members revealed by genome sequencing projects remain unknown. Elucidation of their function, which is some cases might be species specific, will undoubtedly be a major challenge in P450 research in the years to come.