Oxidative opening of the aromatic ring: Tracing the natural history of a large superfamily of dioxygenase domains and their relatives.
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abstract
A diverse collection of enzymes comprising the protocatechuate dioxygenases (PCADs) has been characterized in several extradiol aromatic compound degradation pathways. Structural studies have shown a relationship between PCADs and the more broadly-distributed, functionally enigmatic Memo domain linked to several human diseases. To better understand the evolution of this PCAD-Memo protein superfamily, we explored their structural and functional determinants to establish a unified evolutionary framework, identifying 15 clearly-delineable families, including a previously-underappreciated diversity in five Memo clade families. We place the superfamily's origin within the greater radiation of the nucleoside phosphorylase/hydrolase-peptide/amidohydrolase fold prior to the last universal common ancestor of all extant organisms. In addition to identifying active-site residues across the superfamily, we describe three distinct, structurally-variable regions emanating from the core scaffold often housing conserved residues specific to individual families. These were predicted to contribute to the active-site pocket, potentially in substrate specificity and allosteric regulation. We also identified several previously-undescribed conserved genome contexts, providing insight into potentially novel substrates in PCAD clade families. We extend known conserved contextual associations for the Memo clade beyond previously-described associations with the AMMECR1 domain and a radical S-adenosylmethionine family domain. These observations point to two distinct yet potentially overlapping contexts wherein the elusive molecular function of the Memo domain could be finally resolved, thereby linking it to nucleotide base and aliphatic isoprenoid modification. In total, this report throws light on the functions of large swaths of the experimentally-uncharacterized PCAD-Memo families.
