Visual cycle-derived bisretinoids as endogenous natural products: enzyme-free formation, photochemical reactivity, and retinal degeneration.

Covering: up to 2026Bisretinoids are a chemically distinct class of endogenous natural products formed by the non-enzymatic condensation of visual-cycle retinoids. Derived from dietary provitamin A carotenoids via retinaldehyde intermediates, these pigments form spontaneously within the photoreceptor disc membranes through Schiff base chemistry with phosphatidylethanolamine, generating structurally diverse pyridinium, dihydropyridine and retinal dimer species. In contrast to enzyme-directed biosynthesis, bisretinoid biogenesis is governed by the intrinsic electrophilicity of the conjugated retinaldehydes within a lipid-dense environment. Their extended polyene systems endow them with distinctive excited-state properties, enabling efficient intersystem crossing and photosensitized generation of singlet oxygen under visible light. Subsequent oxidative fragmentation produces reactive electrophilic carbonyl species, including methylglyoxal and glyoxal, which covalently modify biomolecules and contribute to retinal pigment epithelium dysfunction and drusen formation. Despite their well-documented pathological roles, bisretinoids have not been systematically examined within a natural product framework. Here, we integrate the current knowledge of their biogenesis, electronic structure, and photochemical reactivity and consider how factors such as retinaldehyde flux, membrane composition, and iron homeostasis modulate their accumulation and reactivity. By framing bisretinoids as autochthonous natural products governed by intrinsic chemical principles, this review highlights new opportunities for mechanistically informed therapeutic intervention in retinal degeneration.