Evidence that feedback inhibition of NAD kinase controls responses to oxidative stress

Julianne H. Grose, Lisa Joss, Sidney F. Velick, John R. Roth

Research output: Contribution to journalArticle

85 Scopus citations

Abstract

Formation of NADP+ from NAD+ is catalyzed by MAD kinase (NadK; EC 2.7.1.23). Evidence is presented that K is the only NAD kinase of Salmonella enterica and is essential for growth. NadK is inhibited allosterically by NADPH and NADH. Without effectors, NadK exists as an equilibrium mixture of dimers and tetramers (KD = 1.0 ± 0.8 mM) but is converted entirely to tetramers in the presence of the inhibitor NADPH. Comparison of NadK kinetic parameters with pool sizes of NADH and NADPH suggests that NadK is substantially inhibited during normal growth and, thus, can increase its activity greatly in response to temporary drops in the pools of inhibitory NADH and NADPH. The primary inhibitor is NADPH during aerobic growth and NADH during anaerobic growth. A model is proposed in which variation of NadK activity is central to the adjustment of pyridine nucleotide pools in response to changes in aeration, oxidative stress, and UV irradiation. It is suggested that each of these environmental factors causes a decrease in the level of reduced pyridine nucleotides, activates NadK, and increases production of NADP(H) at the expense of NAD(H). Activation of NadK may constitute a defensive response that resists loss of protective NADPH.

Original languageEnglish (US)
Pages (from-to)7601-7606
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number20
DOIs
StatePublished - May 16 2006

Keywords

  • Metabolic control
  • NAD metabolism
  • NADP synthesis
  • Pyridine nucleotides
  • Sedimentation equilibrium

ASJC Scopus subject areas

  • Genetics
  • General

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