Pyrroloquinoline quinone (4,5-dihydro-4,5-dioxo-1H-pyrrolo-[2,3-f]quinoline-2,7,9-tricarboxylic acid: PQQ) is a water soluble, heat-stable, tricyclic ortho-quinone. It serves as redox cofactor for various bacterial dehydrogenases. It is synthesised from two residues (Glu and Tyr) encoded in the precursor peptide PqqA. Several genes (PqqA-G) are required to derive PQQ from these Glu and Tyr. A likely candidate for catalysing the first step in PQQ formation, the linkage between the C98 of Glu and C9a of Tyr, is PqqE. This is because it is the only enzyme in the pathway with significant sequence similarity to other radical SAM proteins capable of catalysing C-C bond formation. The reaction catalyzed by PqqE is a radical driven C-C bond formation required to link the glutamate and tyrosine moieties at atoms C9 and C9a of PQQ. The exact mechanism is unknown but the analogy to radical SAM proteins implies the following mechanism: The reduced 4Fe-4S cluster transfers an electron to the sulfur of SAM. The C5'-S+ bond of SAM is cleaved, producing methionine and a highly oxidizing 5'-deoxyadenosyl radical. The radical abstracts a hydrogen atom from the tyrosine in PqqA, creating a tyrosine radical at position C9a. The radical reacts with atom C9 of glutamate leading to cyclisation. The exact role of SAM is not yet known.

PqqE is a 380 residue protein with a molecular mass of 43 kDA and a theoretical pI of about 5.7. An FFAS search revealed significant homologies with proteins from the radical SAM protein family. The best homologue was Molybdenum cofactor biosynthesis protein A (PDB ID: 1tv7) which was, therefore, used as a template for homology modelling. Because the homologue has such a good score (6.7 times lower than the threshold of -9.5) we have a reliable model for amino acids 5 to 333 in PqqE. It is concluded that PqqE is a family member of radical S-adenosylmethionine (SAM) enzymes, because its sequence suggests that it contains a SAM domain with an iron-sulfur cluster. The four iron atoms of the cluster are coordinated by three cysteines (C26, C30, C33) from the conserved CxxxCxxC (C, Cys; x, any amino acid) motif of radical SAM enzymes and one atom is coordinated by the SAM (Figure ?(Figure9C)9C) PqqE-related enzymes often contain a Y at residue 27(Tyr) and have therefore a CxxxCxYC pattern.

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