Enzyme-assisted suicide: molecular basis for the antifungal activity of 5-hydroxy-4-oxonorvaline by potent inhibition of homoserine dehydrogenase

Chem Biol. 2003 Oct;10(10):989-95. doi: 10.1016/j.chembiol.2003.09.015.


The structure of the antifungal drug 5-hydroxy-4-oxonorvaline (HON) in complex with its target homoserine dehydrogenase (HSD) has been determined by X-ray diffraction to 2.6 A resolution. HON shows potent in vitro and in vivo activity against various fungal pathogens despite its weak (2 mM) affinity for HSD in the steady state. The structure together with structure-activity relationship studies, mass spectrometry experiments, and spectroscopic data reveals that the molecular mechanism of antifungal action conferred by HON involves enzyme-dependent formation of a covalent adduct between C4 of the nicotinamide ring of NAD(+) and C5 of HON. Furthermore, novel interactions are involved in stabilizing the (HON*NAD)-adduct, which are not observed in the enzyme's ternary complex structure. These findings clarify the apparent paradox of the potent antifungal actions of HON given its weak steady-state inhibition characteristics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminolevulinic Acid / analogs & derivatives
  • Aminolevulinic Acid / chemistry
  • Aminolevulinic Acid / pharmacology*
  • Antifungal Agents / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Inhibitors / pharmacology
  • Homoserine Dehydrogenase / antagonists & inhibitors*
  • Homoserine Dehydrogenase / chemistry
  • Homoserine Dehydrogenase / metabolism
  • Kinetics
  • NAD / chemistry
  • NAD / metabolism
  • Structure-Activity Relationship


  • Antifungal Agents
  • Enzyme Inhibitors
  • NAD
  • 2-amino-5-hydroxy-4-oxopentanoic acid
  • Aminolevulinic Acid
  • Homoserine Dehydrogenase

Associated data

  • PDB/1Q7G