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http://purl.uniprot.org/citations/25264482http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25264482http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/25264482http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Citation
http://purl.uniprot.org/citations/25264482http://www.w3.org/2000/01/rdf-schema#comment"

Background

Dihydroneopterin aldolase (DHNA) catalyzes the conversion of 7,8-dihydroneopterin to 6-hydroxymethyl-7,8-dihydropterin and also the epimerization of DHNP to 7,8-dihydromonapterin. Previously, we determined the crystal structure of Staphylococcus aureus DHNA (SaDHNA) in complex with the substrate analogue neopterin (NP). We also showed that Escherichia coli DHNA (EcDHNA) and SaDHNA have significantly different binding and catalytic properties by biochemical analysis. On the basis of these structural and functional data, we proposed a catalytic mechanism involving two proton wires.

Results

To understand the structural basis for the biochemical differences and further investigate the catalytic mechanism of DHNA, we have determined the structure of EcDHNA complexed with NP at 1.07-Å resolution [PDB:2O90], built an atomic model of EcDHNA complexed with the substrate DHNP, and performed molecular dynamics (MD) simulation analysis of the substrate complex. EcDHNA has the same fold as SaDHNA and also forms an octamer that consists of two tetramers, but the packing of one tetramer with the other is significantly different between the two enzymes. Furthermore, the structures reveal significant differences in the vicinity of the active site, particularly in the loop that connects strands β3 and β4, mainly due to the substitution of nearby residues. The building of an atomic model of the complex of EcDHNA and the substrate DHNP and the MD simulation of the complex show that some of the hydrogen bonds between the substrate and the enzyme are persistent, whereas others are transient. The substrate binding model and MD simulation provide the molecular basis for the biochemical behaviors of the enzyme, including noncooperative substrate binding, indiscrimination of a pair of epimers as the substrates, proton wire switching during catalysis, and formation of epimerization product.

Conclusions

The EcDHNA and SaDHNA structures, each in complex with NP, reveal the basis for the biochemical differences between EcDHNA and SaDHNA. The atomic substrate binding model and MD simulation offer insights into substrate binding and catalysis by DHNA. The EcDHNA structure also affords an opportunity to develop antimicrobials specific for Gram-negative bacteria, as DHNAs from Gram-negative bacteria are highly homologous and E. coli is a representative of this class of bacteria."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.org/dc/terms/identifier"doi:10.1186/2045-3701-4-52"xsd:string
http://purl.uniprot.org/citations/25264482http://purl.org/dc/terms/identifier"doi:10.1186/2045-3701-4-52"xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Li Y."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Li Y."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Lu Z."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Lu Z."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Yan H."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Yan H."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Blaszczyk J."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Blaszczyk J."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Ji X."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/author"Ji X."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/date"2014"xsd:gYear
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/date"2014"xsd:gYear
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/name"Cell Biosci."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/name"Cell Biosci."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/pages"52"xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/pages"52"xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/title"Crystallographic and molecular dynamics simulation analysis of Escherichia coli dihydroneopterin aldolase."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/title"Crystallographic and molecular dynamics simulation analysis of Escherichia coli dihydroneopterin aldolase."xsd:string
http://purl.uniprot.org/citations/25264482http://purl.uniprot.org/core/volume"4"xsd:string
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