How many ways to craft a cofactor?

Standard textbooks define enzymatic cofactors as low molecular weight structures that are separate from and can bind reversibly to their cognate protein. As with all established paradigms, change is almost guaranteed, and work over the last decade has forced us to expand our definition of cofactor to include structures that are derived from the protein itself. Early studies of ribonucleotide reductase had indicated the presence of a protein-derived tyrosyl radical as the storage site for the free radical that initiates the conversion of ribonucleotides to deoxyribonucleotides (1). This was followed by the equally unorthodox finding of a protein-bound glycyl radical in select anaerobic proteins (2). More complex posttranslationally derived redox cofactors appeared on the scene in l990, with the discovery of the tyrosine-derived cofactor TPQ in a eukaryotic copper amine oxidase (3) (Fig. 1). The field of quino-cofactors has turned out to be structurally rich, with variants being reported that are formed from tryptophan as well as tyrosine. In a recent issue of PNAS, Datta et al. (4) amaze us further with a new quino-cofactor derived from the cross-linking of oxidized tryptophan and cysteine and designated CTQ (Fig. 1). Quino-cofactors derived from protein-bound tyrosine (TPQ, LTQ) and tryptophan (TTQ, CTQ). This exciting discovery follows an earlier report of a cofactor in which a tryptophyl quinone is cross-linked to a second tryptophan to form TTQ (5) (Fig. 1) and is related to the finding that tyrosine-based quinone cofactors also have been observed to be cross-linked to a second amino acid, i.e., the lysine tyrosyl quinone in lysyl oxidase, LTQ (6) (Fig. 1). What is remarkable is the lack of both sequence and structural homology among the tyrosyl-containing and tryptophyl quinone-containing proteins. It appears that nature has found multiple pathways to generate cofactors that are chemically and mechanistically similar. The extensive …