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

Tamu Dufe, Veronica LU ; Ingner, Daniel; Heby, Olle; Khomutov, A R; Persson, Lo LU and Al-Karadaghi, Salam LU (2007) In Biochemical Journal 405(Pt 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 α-difluoromethylornithine (a curative agent of... (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 α-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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type
Contribution to journal
publication status
published
subject
keywords
inhibitor complex, polyamine synthesis, cancer, drug target, tropical parasite
in
Biochemical Journal
volume
405
issue
Pt 2
pages
261 - 268
publisher
Portland Press Limited
ISSN
0264-6021
DOI
10.1042/BJ20070188.
language
English
LU publication?
yes
id
d3fb8f02-3276-4d79-aa74-0cb51268a2b2 (old id 948882)
date added to LUP
2008-01-28 12:59:28
date last changed
2016-04-16 03:20:28
@article{d3fb8f02-3276-4d79-aa74-0cb51268a2b2,
  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 α-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       = {Tamu Dufe, Veronica and Ingner, Daniel and Heby, Olle and Khomutov, A R and Persson, Lo and Al-Karadaghi, Salam},
  issn         = {0264-6021},
  keyword      = {inhibitor complex,polyamine synthesis,cancer,drug target,tropical parasite},
  language     = {eng},
  number       = {Pt 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 3-aminooxy-1-aminopropane},
  url          = {http://dx.doi.org/10.1042/BJ20070188.},
  volume       = {405},
  year         = {2007},
}