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A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane

Dufe, Veronica; Ingner, Daniel; Heby, Olle; Khomutov, Alex R.; Persson, Lo LU and Al-Karadagi, Salam (2007) In Biochemical Journal 405(2). p.261-268
Abstract
The critical role of polyamines in key processes such as cell growth, differentiation and macromolecular synthesis makes the enzymes involved in their synthesis potential targets in the treatment of certain types of cancer and parasitic diseases. Here we present a study on the inhibition of human and Leishmania donovani ODC (ornithine decarboxylase), the first committed enzyme in the polyamine biosynthesis pathway, by APA (1-amino-oxy-3-aminopropane). The present study shows APA to be a potent inhibitor of both human and L. donovani ODC with a Ki value of around 1.0 nM. We also show that L. donovani ODC binds the substrate, the co-enzyme pyridoxal 5'-phosphate and the irreversible inhibitor alpha-difluoromethylornithine (a curative agent... (More)
The critical role of polyamines in key processes such as cell growth, differentiation and macromolecular synthesis makes the enzymes involved in their synthesis potential targets in the treatment of certain types of cancer and parasitic diseases. Here we present a study on the inhibition of human and Leishmania donovani ODC (ornithine decarboxylase), the first committed enzyme in the polyamine biosynthesis pathway, by APA (1-amino-oxy-3-aminopropane). The present study shows APA to be a potent inhibitor of both human and L. donovani ODC with a Ki value of around 1.0 nM. We also show that L. donovani ODC binds the substrate, the co-enzyme pyridoxal 5'-phosphate and the irreversible inhibitor alpha-difluoromethylornithine (a curative agent of West African sleeping sickness) with less affinity than human ODC. We have also determined the three-dimensional structure of human ODC in complex with APA, which revealed the mode of the inhibitor binding to the enzyme. In contrast with earlier reports, the structure showed no indication of oxime formation between APA and PLP (pyridoxal 5'-phosphate). Homology modelling suggests a similar mode of binding of APA to L. donovani ODC. A comparison of the ODC-APA-PLP structure with earlier ODC structures also shows that the protease-sensitive loop (residues 158-168) undergoes a large conformational change and covers the active site of the protein. The understanding of the structural mode of APA binding may constitute the basis for the development of more specific inhibitors of L. donovani ODC. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
polyamine synthesis, inhibitor complex, cancer, drug target, tropical, parasite
in
Biochemical Journal
volume
405
issue
2
pages
261 - 268
publisher
Portland Press Limited
external identifiers
  • wos:000248158600006
  • scopus:34447117522
ISSN
0264-6021
DOI
10.1042/BJ20070188
language
English
LU publication?
yes
id
ef22a7f1-0359-4030-b28a-9c9173ff130f (old id 692895)
date added to LUP
2007-12-11 19:46:37
date last changed
2017-07-23 04:49:19
@article{ef22a7f1-0359-4030-b28a-9c9173ff130f,
  abstract     = {The critical role of polyamines in key processes such as cell growth, differentiation and macromolecular synthesis makes the enzymes involved in their synthesis potential targets in the treatment of certain types of cancer and parasitic diseases. Here we present a study on the inhibition of human and Leishmania donovani ODC (ornithine decarboxylase), the first committed enzyme in the polyamine biosynthesis pathway, by APA (1-amino-oxy-3-aminopropane). The present study shows APA to be a potent inhibitor of both human and L. donovani ODC with a Ki value of around 1.0 nM. We also show that L. donovani ODC binds the substrate, the co-enzyme pyridoxal 5'-phosphate and the irreversible inhibitor alpha-difluoromethylornithine (a curative agent of West African sleeping sickness) with less affinity than human ODC. We have also determined the three-dimensional structure of human ODC in complex with APA, which revealed the mode of the inhibitor binding to the enzyme. In contrast with earlier reports, the structure showed no indication of oxime formation between APA and PLP (pyridoxal 5'-phosphate). Homology modelling suggests a similar mode of binding of APA to L. donovani ODC. A comparison of the ODC-APA-PLP structure with earlier ODC structures also shows that the protease-sensitive loop (residues 158-168) undergoes a large conformational change and covers the active site of the protein. The understanding of the structural mode of APA binding may constitute the basis for the development of more specific inhibitors of L. donovani ODC.},
  author       = {Dufe, Veronica and Ingner, Daniel and Heby, Olle and Khomutov, Alex R. and Persson, Lo and Al-Karadagi, Salam},
  issn         = {0264-6021},
  keyword      = {polyamine synthesis,inhibitor complex,cancer,drug target,tropical,parasite},
  language     = {eng},
  number       = {2},
  pages        = {261--268},
  publisher    = {Portland Press Limited},
  series       = {Biochemical Journal},
  title        = {A structural insight into the inhibition of human and Leishmania donovani ornithine decarboxylases by 1-amino-oxy-3-aminopropane},
  url          = {http://dx.doi.org/10.1042/BJ20070188},
  volume       = {405},
  year         = {2007},
}