PLP and PMP Radicals: A New Paradigm in Coenzyme B6 Chemistry

Enzymes frequently rely on a broad repertoire of cofactors to perform chemically challenging transformations. The B6 coenzymes, composed of pyridoxal 5′-phosphate (PLP) and pyridoxamine 5′-phosphate (PMP), are used by many transaminases, racemases, decarboxylases, and enzymes catalyzing α,β and β,γ-eliminations. Despite the variety of reactions catalyzed by B6-dependent enzymes, the mechanism of almost all such enzymes is based on their ability to stabilize high-energy anionic intermediates in their reaction pathways by the pyridinium moiety of PLP/PMP. However, there are two notable exceptions to this model, which are discussed in this article. The first enzyme, lysine 2,3-aminomutase, is a PLP-dependent enzyme that catalyzes the interconversion of l-lysine to l-β-lysine using a one-electron-based mechanism utilizing a [4Fe-4S] cluster and S-adenosylmethionine. The second enzyme, CDP-6-deoxy-l-threo-d-glycero-4-hexulose-3-dehydrase, is a PMP-dependent enzyme involved in the formation of 3,6-dideoxysugars in bacteria. This enzyme also contains an iron-sulfur cluster and uses a one-electron based mechanism to catalyze removal of a C-3 hydroxy group from a 4-hexulose. In both cases, the participation of free radicals in the reaction pathway has been established, placing these two B6-dependent enzymes in an exclusive class by themselves.