*3.1. Serine and Sphingolipids*

One of the many fates of biosynthesized L-serine is to combine with palmitoyl-Co-A to form sphingolipids (Figure 2) catalyzed by the enzyme serine palmitoyl-Co-A transferase (SPT) [20]. Even though there are multiple interconnected pathways, which can control the formation of various sphingolipids, the most common pathway is serine incorporation [21]. Neural retinal sphingolipids have been well characterized addressing their beneficial and toxic capacities [3,22–25]. It is very well known that the most vital role of sphingolipids is aiding in sphingomyelin formation, which enables efficient synaptic transmission [3]. Perhaps, that is one reason why the sphingolipid content in the inner retina is quite high [3]. Moreover, sphingolipids in the form of sphingosine-1-phosphate are thought to have anti-apoptotic role, further rationalizing the abundance of sphingolipids in the outer retina [3]. It is important to note that the role of sphingolipid levels and their derivatives have not ye<sup>t</sup> been assessed in the RPE. Given that the RPE may be a vital source of serine for the neural retina, it is imperative to determine how its transport might be facilitated.

**Figure 2.** Pathway depicting sphingolipid biosynthesis from L-serine. Metabolic intermediates involved in the enzymatic synthesis of sphingolipids from L-serine are shown here. The enzymes involved in respective steps are shown in bold italics below the arrow for the individual reaction.

### *3.2. Serine and RPE Phagocytosis*

The e fficient phagocytosis of photoreceptor outer segments by the RPE is elemental to retinal health. From extensive examination of the process, it has been determined that any delay or ine fficiency in the phagocytosis can lead to gross abnormalities for both the neural retina and the RPE [26]. The metabolism of the RPE is largely dependent on recycling the outer segmen<sup>t</sup> phospholipids, as they provide an important source of fuel [27–29]. The neural retina eliminates older disks in order to maintain optimal function. So how is serine vital for maintaining such an important step? In order for the RPE to recognize and phagocytose the correct portion of the outer segments, phosphatidylserine will localize to the extracellular surfaces of those digestible regions [30]. Since almost 10% of the entire outer segmen<sup>t</sup> is daily phagocytosed from each photoreceptor, it helps us appreciate the enormous amount of serine that needs to be available. Furthermore, it has been suggested that sphingolipids may also play a regulatory role in order to ensure efficient phagocytosis, since disruption of sphingolipid metabolism via SPT and ceramide synthase inhibition impaired phagocytosis [31,32]. In addition, glycosphingolipids like lactosylceramides and gangliosides are major lipid raft components and assist in cell adhesion, membrane polarity and phagocytosis initiation [33–36]. This raises the possibility that the sphingolipid pool in RPE may assist in facilitating outer segmen<sup>t</sup> phagocytosis as well as maintaining the tight junction barrier and cellular polarity. Since serine is an integral component of sphingolipids, it goes without saying that this presents another facet of serine availability contributing to efficient neural retina:RPE interdependence.
