Protein and nucleic acid modification processes play a central role in cellular viability. These range from the regulation of transcription via the modification of DNA,1 the splicing of RNA prior to translation2 and the control of cell signaling at a multitude of levels via covalent modifications of proteins, e.g. refs. 3 and 4. Peptides are also known to undergo extensive modifications, in particular, during the bacterial generation of cellular defense molecules that are increasingly being studied as possible mammalian antibiotics.5 This review is focused on a unique set of posttranslational modifications that convert canonical amino acid side chains within either a peptide or folded protein into quinone-containing redox cofactors.6,7 The peptide-derived quinocofactor, pyrroloquinoline quinone (PQQ), was the first to be detected in 1964, in association with the bacterial enzyme, glucose dehydrogenase.8 This was followed by X-ray characterizations of PQQ, either alone9 or in a non-covalent complex with several dehydrogenases.10-12 The property of PQQ as a reversibly-bound cofactor that can be shared among many redox proteins contrasts with the remaining quinocofactors presented in Scheme 1, each of which is found to be covalently associated with its cognate protein. There was a considerable lag between the characterization of PQQ and the remainder of the quinocofactors, with identification of trihydroxyphenylalanine quinone (TPQ)13 and tryptophan tryptophylquinone (TTQ)14 occurring in the early 1990s, followed by lysyl tyrosine quinone (LTQ)15 in 1996 and cysteine tryptophylquinone (CTQ)16 in 2001. These quinocofactors are found to function either in prokaryotes or eukaryotes, with TPQ being the exception that spans these two biological domains. The distinguishing features of each cofactor are highlighted in Table 1, with the underlying commonality being that each is constructed around an aromatic side chain (tryptophan or tyrosine). This review brings a primary focus to the variety of biosynthetic pathways for the production of quinocofactors [cf. refs. 7,17,18] and the reader is referred to a number of treatises that are centered primarily on the enzymatic mechanisms surrounding the mature cofactors.19-21 Open in a separate window Scheme 1 Structures of the established quinocofactors, TPQ, LTQ, TTQ, CTQ, and PQQ.