Dihydrofolate reductase and cell growth activity inhibition by the beta-carboline-benzoquinolizidine plant alkaloid deoxytubulosine from Alangium lamarckii: its potential as an antimicrobial and anticancer agent.
Beta-carboline-benzoquinolizidine plant alkaloid deoxytubulosine (DTB) was evaluated and assessed for the first time for its biochemical and biological activity employing the biomarker dihydrofolate reductase (DHFR) (5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) as the probe enzyme, a key target in cancer chemotherapy. DHFR, employed in the present investigations was purified from Lactobacillus leichmannii. DTB, isolated from the Indian medicinal plant Alangium lamarckii was demonstrated to exhibit potent cytotoxicity. The alkaloid potently inhibited the cell growth of L. leichmannii and the cellular enzyme activity of DHFR (IC50=40 and 30 microM for the cell growth and enzyme inhibitions, respectively). DTB concentrations >75 microM resulted in a total loss of the DHFR activity, thus suggesting that the beta-carboline-benzoquinolizidine plant alkaloid is a promising potential antitumor agent. Our results are also suggestive of its potential antimicrobial activity. DTB binding to DHFR appears to be slow and reversible. Inhibition kinetics revealed that DHFR has a Ki value of 5x10(-6) M for DTB and that the enzyme inhibition is a simple linear 'non-competitive' type.
Rao
K N
KN
Radiation Biology & Biochemistry Division, Bhabha Atomic Research Centre, Bombay, India. rbbd@magnum.barctl.ernet.in
Venkatachalam
S R
SR
D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001667:Binding, Competitive; D005493:Folic Acid Antagonists / Q000302:isolation & purification / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007194:India; D007778:Lactobacillus / Q000187:drug effects; D019684:Magnoliopsida / Q000737:chemistry; D010946:Plants, Medicinal / Q000737:chemistry*; D011807:Quinolizines / Q000302:isolation & purification / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000378:metabolism*; D014372:Tubercidin / Q000302:isolation & purification / Q000494:pharmacology*
D000470:Alkaloids; D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D005493:Folic Acid Antagonists; D006131:Growth Inhibitors; D011807:Quinolizines; C111890:carboline-benzoquinolizidine alkolid deoxytubulosine; D013762:Tetrahydrofolate Dehydrogenase; D014372:Tubercidin