Fig. 1.

Retinoid cycle and bis-retinoid formation of lipofuscin in the eye

According to the proposed scheme that was published previously (Sparrow et al., 2010d), we here expand the schematic diagram regarding the formation of lipofuscin bis-retinoids; the leading feature is the formation of a novel bis-retinoid compound N-retinylidene-N-retinyl-glycerophosphoethanolamine (A2-GPE) (Yamamoto et al., 2011). Biogenesis of the latter starts with one molecule of all-trans-retinal incubated with GPE, followed by a [1,6]H-shift to give rise to N-retinylidene-glycerophosphoethanolamine (NR-GPE). Via a multi-step cascade, a proposed intermediate, dihydropyridinium A2-GPE is generated, and undergoes auto-oxidation to yield A2-GPE. Phosphate hydrolysis of the latter by phospholipase D (PLD) produces N-retinylidene-N-retinyl-ethanolamine (A2E), indicating that A2-GPE, like N-retinylidene-N-retinyl-phosphatidylethanolamine (A2PE), may also serve as the precursor of A2E