Lipofuscin Formation Catalyzed by the Milk Protein β‑Lactoglobulin: Lysine Residues in Cycloretinal Synthesis

Lipofuscins are toxic autofluorescent byproducts of the visual cycle. The accumulation of lipofuscins such as cycloretinal in the retina is thought to play a role in the progression of age-related macular degeneration (AMD). Intriguingly, the milk protein β-lactoglobulin (BLG) can promote the cyclodimerization of <i>all-trans</i>-retinal to cycloretinal both <i>in vitro</i> and <i>in vivo</i>. Here, site-directed mutagenesis of BLG and mass spectrometric analysis with substrate analogues demonstrate that lysine residues play a key role in catalysis. It is also shown that catalytic activity necessitates the presence of a physical binding site and cannot be mediated by a peptide chain. These studies provide insight into the mechanism of the cyclodimerization process and provide a model system for biocatalysis and biosynthesis of cycloretinal <i>in vivo</i>. In the long term, these studies may pave the way for drug development and inhibitor design as an early treatment regimen for AMD

Priming of Azabicycle Biosynthesis in the Azinomycin Class of Antitumor Agents

The biosynthesis of the azabicyclic ring system of the azinomycin family of antitumor agents represents the “crown jewel” of the pathway and is a complex process involving at least 14 enzymatic steps. This study reports on the first biosynthetic step, the inroads, in the construction of the novel aziridino [1,2-<i>a</i>]­pyrrolidine, azabicyclic core, allowing us to support a new mechanism for azabicycle formation