Journal article
Catalytic mechanism and cofactor preference of dihydrodipicolinate reductase from methicillin-resistant Staphylococcus aureus
SR Dommaraju, C Dogovski, PE Czabotar, L Hor, BJ Smith, MA Perugini
Archives of Biochemistry and Biophysics | ELSEVIER SCIENCE INC | Published : 2011
Abstract
Given the rapid rise in antibiotic resistance, including methicillin resistance in Staphylococcus aureus (MRSA), there is an urgent need to characterize novel drug targets. Enzymes of the lysine biosynthesis pathway in bacteria are examples of such targets, including dihydrodipicolinate reductase (DHDPR, E.C. 1.3.1.26), which is the product of an essential bacterial gene. DHDPR catalyzes the NAD(P)H-dependent reduction of dihydrodipicolinate (DHDP) to tetrahydrodipicolinate (THDP) in the lysine biosynthesis pathway. We show that MRSA-DHDPR exhibits a unique nucleotide specificity utilizing NADPH (K m = 12 μM) as a cofactor more effectively than NADH (Km = 26 μM). However, the enzyme is inhib..
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Awarded by Australian Research Council
Funding Acknowledgements
We would firstly like to thank all members of the Perugini laboratory for helpful discussions during the preparation of this manuscript, in particular Renwick C.J. Dobson, Michael W.D. Griffin, Natalia E. Ketaren, and Voula Mitsakos. We would also like to acknowledge the Defense Threat Reduction Agency (DTRA) (DTRA Project I.D. AB07CBT004) for project support, and the Australian Research Council for providing a Future Fellowship for M.A.P. (FT0991245) and P.E.C. (FT0992105). B.J.S. and P.E.C. acknowledge infrastructure support from the NHMRC (Grant No. 361646) and a Victorian State Government OIS Grant.