Identification of two dihydrodipicolinate synthase isoforms from Pseudomonas aeruginosa that differ in allosteric regulation.

Autor: Impey RE; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia., Panjikar S; Australian Synchrotron, ANSTO, Clayton, Australia.; Department of Molecular Biology and Biochemistry, Monash University, Melbourne, Australia., Hall CJ; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia., Bock LJ; National Infection Service, Public Health England, Porton Down, Salisbury, UK., Sutton JM; National Infection Service, Public Health England, Porton Down, Salisbury, UK., Perugini MA; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia., Soares da Costa TP; Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Australia.
Jazyk: angličtina
Zdroj: The FEBS journal [FEBS J] 2020 Jan; Vol. 287 (2), pp. 386-400. Date of Electronic Publication: 2019 Aug 05.
DOI: 10.1111/febs.15014
Abstrakt: Pseudomonas aeruginosa is one of the leading causes of nosocomial infections, accounting for 10% of all hospital-acquired infections. Current antibiotics against P. aeruginosa are becoming increasingly ineffective due to the exponential rise in drug resistance. Thus, there is an urgent need to validate and characterize novel drug targets to guide the development of new classes of antibiotics against this pathogen. One such target is the diaminopimelate (DAP) pathway, which is responsible for the biosynthesis of bacterial cell wall and protein building blocks, namely meso-DAP and lysine. The rate-limiting step of this pathway is catalysed by the enzyme dihydrodipicolinate synthase (DHDPS), typically encoded for in bacteria by a single dapA gene. Here, we show that P. aeruginosa encodes two functional DHDPS enzymes, PaDHDPS1 and PaDHDPS2. Although these isoforms have similar catalytic activities (k cat  = 29 s -1 and 44 s -1 for PaDHDPS1 and PaDHDPS2, respectively), they are differentially allosterically regulated by lysine, with only PaDHDPS2 showing inhibition by the end product of the DAP pathway (IC 50  = 130 μm). The differences in allostery are attributed to a single amino acid difference in the allosteric binding pocket at position 56. This is the first example of a bacterium that contains multiple bona fide DHDPS enzymes, which differ in allosteric regulation. We speculate that the presence of the two isoforms allows an increase in the metabolic flux through the DAP pathway when required in this clinically important pathogen. DATABASES: PDB ID: 6P90.
(© 2019 Federation of European Biochemical Societies.)
Databáze: MEDLINE
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