Characterization of Orphan Human Cytochromes P450

Abstract

Of the 57 human cytochromes P450 (P450) and 58 pseudogenes discovered to date, (http://drnelson.utmem.edu/CytochromeP450.html ), 1/4 still remain "orphans" in the sense that their function, expression sites, and regulation are still largely not elucidated. The post-human genome-sequencing project era has presented the research community with novel challenges. Despite many insights gathered about gene location and genetic variations in our human genome, we still lack important knowledge about these novel P450 enzymes and their functions in endogenous and exogenous metabolism, as well as their possible roles in the metabolism of toxicants and carcinogens. Our own list of such orphans currently consists of 13 members: P450 2A7, 2S1, 2U1, 2W1, 3A43, 4A22, 4F11, 4F22, 4V2, 4X1, 4Z1, 20A1, and 27C1. Some of the orphans, e.g. P450s 2W1 and 2U1, already have putative assigned functions in arachidonic acid metabolism and may activate carcinogens. However, at this point, for the majority of them more knowledge is available about their genes and single nucleotide polymorphisms than of their biological functions. It is noteworthy that most P450 orphans express high interspecies sequence conservation and have orthologs in rodents (e.g. CYP4X1/Cyp4x1, CYP4V2/Cyp4v3). This review summarizes recent knowledge about the P450 orphans and questions remaining about their specific roles in human metabolism.

Self-Sufficient Catalytic System of Human Cytochrome P450 4A11 and NADPH-P450 Reductase

“…Therefore, the development of this system presents the prospect of its use in the mutagenesis study for structure-function relationships. Human has 57 human P450s and many of them still remain "orphans" in the sense that their function, expression sites, and regulation are still largely not elucidated (Stark and Guengerich, 2007). Characterization of these orphan P450s can provide the unraveled roles of human P450 enzyme so far.…”

Oxidation of the Endogenous Cannabinoid Arachidonoyl Ethanolamide by the Cytochrome P450 Monooxygenases: Physiological and Pharmacological Implications

“…However, P450s are also found across all living organisms and are involved in the biotransformation of a diverse range of xenobiotics as well as endogenous substrates (Nebert and Russell, 2002). Although the catalytic function for the majority of the human P450 enzymes is known, there are a significant number of "orphan" P450s, belonging to families 2, 3, 4, 20, and 27, for which the catalytic activity is still unknown (Stark and Guengerich, 2007). Of those with known function, approximately 15 of the human isoforms that are primarily in families 1, 2, and 3 are involved in the metabolism of xenobiotics (Wienkers and Heath, 2005).…”

“…The functional significance of 25% of human P450s is still unknown, and they are referred to collectively as "orphan" P450s (Stark and Guengerich, 2007). Detection of mRNA for the orphan human CYP4X1 in several tissues was recently reported by Stark et al (2008).…”

Differential Regulation by Heat Stress of Novel Cytochrome P450 Genes from the Dinoflagellate Symbionts of Reef-Building Corals

“…Conversely, the Symbiodinium CYP-3 gene product showed a high level of sequence similarity with the known cytochrome P450 CYP20A1. Because its biological function is not known, this CYP20A1 protein is the so-called "orphan" P450 (28,60,61), and its possible role during heat stress in the coral-alga symbiosis has not been elucidated yet. The high level of similarity of the CYP-1 and CYP-3 sequences to the sequences of metazoan P450 genes suggests that there might have been host contamination, while our results for aposymbiotic A. millepora coral egg-sperm specimens indicated that CYP genes discovered did not originate from coral.…”