Oxygenases are a family of enzymes that catalyse the breaking of molecular oxygen with incorporation of, at least, one oxygen atom into an organic substrate. Since molecular oxygen is a diradical and most organic molecules have no unpaired-electrons, reactions catalysed by oxygenases involve changes in the spin state of the system that are forbidden in non-relativistic quantum theory. To overcome this limitation, oxygenases usually require metal or redox cofactors for catalysis. Intriguingly, some oxygenases can catalyse oxygen incorporation reactions even in the absence of any cofactor, but the detailed mechanism followed by these enzymes to overcome this limitation is still unknown. In the present work we give insight onto the mechanism for the enzymatic cofactor-independent oxidation of 3,5-dihydroxyphenylacetyl-CoA (DPA-CoA) by the combination of multi-reference calculations on a model system, with QM/MM calculations for the enzymatic reaction. Our results reveal that intersystem crossing takes place without requiring concerted protonation of molecular oxygen. We characterized and identifed the nine concurrent electronic states, showing that a first electron transfer is concomitant with the triplet-singlet transition (intersystem crossing). The enzyme apparently plays a passive role in promoting the intersystem crossing, although spontaneous reorganization of the water-wire connecting the active site with the bulk presets the substrate for subsequent chemical transformations. We believe that our results are fairly general showing that stabilization of the singlet radical-pair state between molecular oxygen and enolates is enough to promote spin-forbidden reaction without the need of neither metal cofactors nor basic residues in the active site.