NMR studies uncover alternate substrates for dihydrodipicolinate synthase and suggest that dihydrodipicolinate reductase is also a dehydratase.
Despite extensive effort, the drug target dihydrodipicolinate synthase (DHDPS) continues to evade effective inhibition. We used NMR spectroscopy to examine the substrate specificity of this enzyme and found that two pyruvate analogues previously classified as weak competitive inhibitors were turned over productively by DHDPS. Four other analogues were confirmed not to be substrates. Finally, our examination of the natural product of DHDPS and its degradation revealed that dihydrodipicolinate reductase (DHDPR) possesses previously unrecognized dehydratase activity.
Devenish
Sean R A
SR
Biomolecular Interaction Centre and School of Biological Sciences, University of Canterbury, Christchurch 8140, New Zealand. srad2@cam.ac.u
Blunt
John W
JW
Gerrard
Juliet A
JA
D050746:Dihydrodipicolinate Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010848:Picolinic Acids / Q000737:chemistry; D011773:Pyruvates / Q000737:chemistry; D013379:Substrate Specificity
C550634:4-hydroxy-2,3,4,5-tetrahydro-2-dipicolinic acid; D010848:Picolinic Acids; D011773:Pyruvates; D050746:Dihydrodipicolinate Reductase; D006836:Hydro-Lyases; C020040:4-hydroxy-tetrahydrodipicolinate synthase