Mycosporine-like amino acids (MAAs) are a group of UV absorbing, photostable small molecule secondary metabolites biosynthesized mainly by marine algae to provide protection from exposure to high solar radiation. MAAs have absorption maxima around 310-360 nm and high extinction coefficients that makes them industrially attractive as natural photoprotective compounds. The chemical structure of MAAs consist of a functionalized cyclohexenone or cyclohexenimine core. The marine cyanobacterium Nostoc linckia, harbors a ~6-kb gene cluster responsible for the biosynthesis of MAAs where two ATP-grasp ligases MysC and MysD in the pathway catalyze the condensation of two amino acid residues to the core. To gain insights into the enzyme mechanism, we solved the X-ray crystal structure of MysD to a final resolution of 2.8 Å. The overall protein structure shows a homodimer with an ATP-grasp fold in each monomer. Additionally, the ATP-grasp fold of MysD shows multiple unique features involved in ligand binding as compared to other structural homologs, suggesting a distinct catalytic role. We observed extra electron density in the putative substrate binding pocket which was modelled as L-threonine. Indeed, our in vitro biochemical assays showed that MysD has the highest preference to L-Thr while having the least preference to aromatic amino acids. Modelling substrate mycosporine glycine into the MysD active site and the co-substrate ATP reveals crucial residues for substrate binding. We performed site-directed mutagenesis in the active site to probe residues critical to the catalytic activity and obtained kinetic parameters. This work aims to establish the structure–function relationship of novel enzymes involved in mycosporine-like amino acids biosynthesis toward the design and development of a range of structurally diverse small molecules.

Expanding the chemical diversity of mycosporine-like amino acids

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