Oxalone and Lactone Moieties of Podophyllotoxin Exhibit Properties of Both the B and C Rings of Colchicine in Its Binding with Tubulin
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- 作者：Suvroma Gupta ; Lalita Das ; Ajit B. Datta ; Asim Poddar ; Mark E. Janik ; and Bhabatarak Bhattacharyya
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：May 23, 2006
- 年：2006
- 卷：45
- 期：20
- 页码：6467 - 6475
- 全文大小：211K
- 年卷期：v.45,no.20(May 23, 2006)
- ISSN：1520-4995
文摘
Thermodynamics of podophyllotoxin binding to tubulin and its multiple points of attachmentwith tubulin has been studied in detail using isothermal titration calorimetry. The calorimetric enthalpyof the association of podophyllotoxin with tubulin is negative and occurs with a negative heat capacitychange (
es/gifchars/Delta.gif" BORDER=0 >Cp = -2.47 kJ mol-1 K-1). The binding is unique with a simultaneous participation of bothhydrophobic and hydrogen-bonding forces with unfavorable negative entropic contribution at highertemperature, favored with an enthalpy-entropy compensation. Interestingly, the binding of 2-methoxy-5-(2',3',4'-trimethoxyphenyl)tropone (AC, a colchicine analogue without the B ring) with tubulin is enthalpy-favored. However, the podophyllotoxin-tubulin association depending upon the temperature of the reactionhas a favorable entropic and enthalpic component, which resembles both B- and C-ring properties ofcolchicine. On the basis of the crystal structure of the podophyllotoxin-tubulin complex, distancecalculations have indicated a possible interaction between threonine 179 of es/gifchars/alpha.gif" BORDER=0>-tubulin and the hydroxygroup on the D ring of podophyllotoxin. To confirm the involvement of the oxalone moiety as well as thelactone ring of podophyllotoxin in tubulin binding, analogues of podophyllotoxin are synthesized withmethoxy substitution at the 4' position of ring D along with its isomer and another analogue epimerizedat ring E. From these results, involvement of oxalone as well as the lactone ring of the drug in a specificorientation inclusive of ring A is indicated for podophyllotoxin-tubulin binding. Therefore, podophyllotoxin, like colchicine, behaves as a bifunctional ligand having properties of both the B and C rings ofcolchicine by making more than one point of attachment with the protein tubulin.