Amino Acids

, Volume 42, Issue 6, pp 2283–2291 | Cite as

δ1-Pyrroline-5-carboxylate reductase as a new target for therapeutics: inhibition of the enzyme from Streptococcus pyogenes and effects in vivo

  • Giuseppe Forlani
  • Davide Petrollino
  • Massimo Fusetti
  • Letizia Romanini
  • Bogusław Nocek
  • Andrzej Joachimiak
  • Łukasz Berlicki
  • Paweł Kafarski
Original Article

Abstract

Compounds able to interfere with amino acid biosynthesis have the potential to inhibit cell growth. In both prokaryotic and eukaryotic microorganisms, unless an ornithine cyclodeaminase is present, the activity of δ1-pyrroline-5-carboxylate (P5C) reductase is mandatory to proline production, and the enzyme inhibition should result in amino acid starvation, blocking in turn protein synthesis. The ability of some substituted derivatives of aminomethylenebisphosphonic acid and its analogues to interfere with the activity of the enzyme from the human pathogen Streptococcus pyogenes was investigated. Several compounds were able to suppress activity in the micromolar range of concentrations, with a mechanism of uncompetitive type with respect to the substrate P5C and non-competitive with respect to the electron donor NAD(P)H. The actual occurrence of enzyme inhibition in vivo was supported by the effects of the most active derivatives upon bacterial growth and free amino acid content.

Keywords

Amino acid metabolism Antibiotics P5C reductase Proline Streptococcus sp 

Abbreviations

IC50

Concentration causing 50% inhibition of enzyme activity

LC50

Concentration causing 50% inhibition of growth rate

OCD

Ornithine cyclodeaminase

P5C

δ1-Pyrroline-5-carboxylic acid

Supplementary material

726_2011_970_MOESM1_ESM.pdf (232 kb)
Supplementary material 1 (PDF 231 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Giuseppe Forlani
    • 1
  • Davide Petrollino
    • 1
  • Massimo Fusetti
    • 1
  • Letizia Romanini
    • 1
  • Bogusław Nocek
    • 2
  • Andrzej Joachimiak
    • 2
  • Łukasz Berlicki
    • 3
  • Paweł Kafarski
    • 3
  1. 1.Department of Biology and EvolutionUniversity of FerraraFerraraItaly
  2. 2.Biosciences Division, Argonne National LaboratoryMidwest Center for Structural GenomicsArgonneUSA
  3. 3.Department of Bioorganic ChemistryFaculty of Chemistry, Wrocław University of TechnologyWrocławPoland

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