New transition state–based inhibitor for human ornithine decarboxylase inhibits growth of tumor cells

Abstract

Pyridoxal 5 ¶-phosphate (PLP) -dependent ornithine decarboxylase (ODC) is the key enzyme in polyamine synthesis. ODC is overexpressed in many tumor cells and thus a potential drug target. Here we show the design and synthesis of a coenzyme-substrate analogue as a novel precursor inhibitor of ODC. Structural analysis of the crystal structure of human ODC disclosed an additional hydrophobic pocket surrounding the E-amino group of its substrate ornithine. Molecular modeling methods showed favorable interactions of the BOC-protected pyridoxylornithine conjugate, termed POB, in the active site of human ODC. The synthesized and purified POB completely inhibited the activity of newly induced ODC activity at 100 Mmol/L in glioma LN229 and COS7 cells. In correlation with the inhibition of ODC activity, a timedependent inhibition of cell growth was observed in myeloma, glioma LN18 and LN229, Jurkat, COS7, and SW2 small-cell lung cancer cells if DNA synthesis and cell number were measured, but not in the nontumorigenic human aortic smooth muscle cells. POB strongly inhibited cell proliferation not only of low-grade glioma LN229 cells in a dose-dependent manner (IC 50 f50 Mmol/L) but also of high-grade glioblastoma multiforme cells. POB is much more efficient in inhibiting proliferation of several types of tumor cells than A-DL-difluoromethylornithine, the best known irreversible inhibitor of ODC. [Mol Cancer Ther 2007;6(6):1831 -9]

Volatile Composition and Biological Activities of the Leaf Essential Oil from Zanthoxylum limoncello Grown in Oaxaca, México

“…Similarly, the interaction of the carbonyl group of 2-undecenal can be produced with Asn319 at the subunit A, but the first hydration layer could be participating in the non-direct interaction with Ala39 ( Figure 4B). [20] However, in both cases, there were aromatic rings and reactive functional groups which may produce unnatural rearrangements of the ODC. Interestingly, due to the differences in the algorithms of SwissDock and MTiAutodock, the influence of the first hydration layer on the indirect interaction with Ala39 was not predicted as initially suggested by PatchDock software.…”

Poisoning Pyridoxal 5-Phosphate-Dependent Enzymes: A New Strategy to Target the Malaria Parasite Plasmodium falciparum

“…Among these, N-(5-phosphopyridoxyl)-ornithine inhibited rat liver ODC by binding to the holoenzyme in a non-competitive manner with respect to substrate and cofactor. Recently, a new analog, the BOC-protected pyridoxyl-ornithine conjugate (POB), was shown to inhibit human ODC in cells as well as the growth of various tumor and transformed cells effectively, whereas non-tumorigenic cells were less affected [13]. Another analog, pyridoxyl-histidine methyl ester (PHME), was able to inhibit human histidine decarboxylase in human mastocytoma cells without affecting proliferation [14].…”

Effect of L-Cycloserine on Cellular Responses Mediated by Macrophages and T Cells

“…ornithine decarboxylase) are known to be highly expressed in various cancer cell lines and inhibition of the enzymes consequently reduced cancer cell proliferation. 55) Due to this, such enzyme is at present regarded as a target of anti-cancer drugs. 55) In contrast, L-CS did not strongly block the proliferation of cancer cell lines even at 100 mM (Fig.…”

“…55) Due to this, such enzyme is at present regarded as a target of anti-cancer drugs. 55) In contrast, L-CS did not strongly block the proliferation of cancer cell lines even at 100 mM (Fig. 2C).…”