AGMO Expression, Regulation and Function in Macrophages

Tetrahydrobiopterin is a compound with structural similarities to the vitamins folic acid and riboflavin. All three compounds share a pteridine backbone. In contrast to the two vitamins, tetrahydrobiopterin is synthesised in the body of animals and humans. It acts as a cofactor for distinct enzymatic reactions: (i) The aromatic amino acid hydroxylases which are important for degradation of the essential amino acid phenylalanine and the biosynthesis of catecholamine and serotonin neurotransmitters; (ii) the nitric oxide synthases which are essential for neurotransmission, host defence to tumours and pathogens and regulation of the blood pressure by vascular relaxation; and (iii) the ether lipid cleaving enzyme alkylglycerol monooxygenase. While the other tetrahydrobiopterin-dependent enzymes have been well characterised and their sequences and physiological roles are known in detail, physiological functions of alkylglycerol monooxygenase have not been described until now. Investigation of alkylglycerol function has been hampered by the lack of sequence information on this exceptionally labile membrane enzyme. Research led by the applicant has recently succeeded in defining the gene coding for alkylglycerol monooxygenase by a combinatory approach using bioinformatics and candidate gene expression. The present project aims to describe a physiological role of alkylglycerol monooxygenase. A set of preparatory experiments shows that alkylglycerol monooxygenase activity, though widespread in many rat and murine organs and tissues, is almost exclusively expressed in cells of monocyte/macrophage origin and is dependent on endogenous tetrahydrobiopterin levels. By joining forces with the renowned group of Prof. Keith Channon from the University of Oxford, a leading scientist in the field of tetrahydrobiopterin research who also has a tight cooperation with the macrophage specialist Prof. Greaves from the University of Oxford, this project will shed light on a role of alkylglycerol monooxygenase in macrophages. The Channon group has created a conditional mouse model for tetrahydrobiopterin deficiency which is unique in the world. With this tool we now have the exceptional possibility to investigate cofactor dependence of alkylglycerol monooxygenase in vivo, test what role alkylglycerol monooxygenase has in macrophage differentiation and how tetrahydrobiopterin levels influence ether lipid profiles in vivo.