A novel approach to inhibit intracellular vitamin B-6-dependent enzymes: proof of principle with human and plasmodium ornithine decarboxylase and human histidine decarboxylase

作者：Wu, Fang; Christen, Philipp; Gehring, Heinz^*

来源：The FASEB Journal, 2011, 25(7): 2109-2122.

DOI：10.1096/fj.10-174383

• coenzyme-substrate-conjugate inhibitors
• drug development
• multisubstrate inhibitors
• polyamines
• pyridoxal-5 '-phosphate-dependent enzymes

Pyridoxal-5'-phosphate (vitamin B-6)-dependent enzymes play central roles in the metabolism of amino acids. Moreover, the synthesis of polyamines, which are essential for cell growth, and of biogenic amines, such as histamine and other signal transmitters, relies on these enzymes. Certain B-6 enzymes thus are prime targets for pharmacotherapeutic intervention. We have devised a novel, in principle generally applicable strategy for obtaining small-molecule cell-permeant inhibitors of specific B-6 enzymes. The imine adduct of pyridoxal-5'-phosphate and the specific amino acid substrate, the first intermediate in all pyridoxal-5'-phosphate-dependent reactions of amino acids, was reduced to a stable secondary amine. This coenzyme-substrate-conjugate was modified further to make it membrane-permeant and, guided by structure-based modeling, to boost its affinity to the apoform of the target enzyme. Inhibitors of this type effectively decreased the respective intracellular enzymatic activity (IC50 in low micromolar range), providing lead compounds for inhibitors of human ornithine decarboxylase (hODC), plasmodium ornithine decarboxylase, and human histidine decarboxylase. The inhibitors of hODC interfere with the metabolism of polyamines and efficiently prevent the proliferation of tumor cell lines (IC50 similar to 25 mu M). This approach to specific inhibition of intracellular B-6 enzymes might be applied in a straightforward manner to other B-6 enzymes of emerging medicinal interest.-Wu, F., Christen, P., Gehring, H. A novel approach to inhibit intracellular vitamin B-6-dependent enzymes: proof of principle with human and plasmodium ornithine decarboxylase and human histidine decarboxylase. FASEB J. 25, 2109-2122 (2011). www.fasebj.org

• 出版日期2011-7
• 单位上海交通大学