In conclusion we identify in this report the molecular natur

In conclusion, we identify in this report the molecular nature of the 12- and 15-lipoxygenases in M. mulatta and P. pygmaeus and also that the expression of the rhesus enzyme in lung epithelial cells is regulated by interleukin-4. The switch from a mainly 12-LO enzyme to a mainly 15-LO enzyme during evolution indicates that the 15-lipoxygenating activity of the enzyme in higher primates is of importance for the function of this enzyme. Also, our results show that 12/15-LO from primates can have distinct differences in using endocannabinoids as substrate.
Acknowledgement
Introduction Twenty carbon fatty acids serve a variety of important physiological functions in humans, from providing cellular membrane structure to serving as substrates from which a number of important cell signaling molecules and secondary messengers are derived [1]. In particular, arachidonic CAY10603 serves as one major precursor for a number of molecules termed eicosanoids that have significant roles in human diseases, including types 1 and 2 diabetes and atherosclerosis, as well as the neurological diseases Parkinson’s disease (PD) and Alzheimer’s disease (AD) [2], [3], [4]. The following review will focus on the 12- and 15-lipoxygenase enzymes (12-LOX, 15-LOX), their products, and the varied effects of those products in human metabolic, vascular, and neurological diseases. Arachidonic acid (AA) is released from the cell membrane by phospholipases, such as phospholipase A1, in response to various cytokines, peptides, and growth factors that become active under inflammatory conditions [5], [6]. There are three families of enzymes involved in the oxidative metabolism of AA. These include the lipoxygenases, which produce leukotrienes (LT), hydroperoxyeicosatetraenoic acids (HPETEs), hydroxyeicosatetraenoic acids (HETEs), and hydroxyoctadecadienoic acids (HODEs); the cyclooxygenases (COX-1 and COX-2) which produce prostaglandins including G2 and H2 as well as thromboxanes; and cytochrome P-450 monooxygenases which produce epoxides and HETEs [6], [7]. Of note, prostaglandin H2 is further metabolized to prostaglandins D2, F2α, and I2 (prostacyclin), as well as to thromboxane (TxA2) [8]. Lipoxygenases (LOXs) are found in both plants and in animals. The mouse has seven different ALOX genes (note that the LOX genes are termed by convention “ALOX”, for arachidonic acid lipoxygenase), while humans have five known genes [7]. The different LOX enzymes are named for the numbered carbon where they oxygenate their polyunsaturated fatty acid (PUFA) substrates, with the use of stereoisomer nomenclature (S and R) as appropriate (e.g., 12S-LOX and 12R-LOX) [7]. As shown in Table 1, the human LOX enzymes include 5-LOX (which produces LTs), 12-LOX (with platelet-type and leukocyte-type forms), and 15-LOX (which is further separated into the reticulocyte or leukocyte-type, 15-LOX-1, and the epidermis-type, 15-LOX-2) [9], [10]. The human leukocyte-type 12-LOX and the human reticulocyte-type 15-LOX-1 can form similar products from common substrates and are often referred to in the literature as 12/15-LOXs [6], [10]. Furthermore, there is significant species-specific variation in the products formed by the different 12- and 15-LOX isoforms. Mice do not express 15-LOX and only express the leukocyte-derived 12-LOX [11]. Rabbits express both reticulocyte-derived 15-LOX and leukocyte-derived 12-LOX [12]. These differences often make it difficult to translate data obtained in different animal models of disease to their human counterparts. This may, for instance, explain conflicting data on the effects of different 12- and 15-LOX isoforms on vascular function and on atherosclerosis [13]. In humans, 12/15-LOXs act upon AA to create a number of important lipid mediators (Fig. 1). These include 12- and 15HPETEs and 12- and 15HETEs [7]. The 15-LOX-1 enzyme also produces 13-S-hydroxyoctadecadienoic acid (HODE) from linoleic acid [14]. These lipid products have a variety of functions in human tissues. For example, 12(S)-HETE and 15(S)-HPETE are involved in monocyte binding in the vasculature, by stimulating protein kinase C (PKC) and various cellular adhesion molecules (CAMs) [6], [15]. Some products, including 13HPODE, are pro-inflammatory and act via various transcription factors including NF-κB [16]. HETEs are also involved in cell growth, acting through various mitogen-activated protein kinases (MAPKs) [17].