Small-molecule inhibitor: epoxomicin
Name
- Common name
- epoxomicin
Inhibition
- History
- Hanada et al. (1992) first described epoxomicin, a natural product of actinomycete strain No. Q996-17 that exhibited in vivo antitumor activity against B16 melanoma.
- Peptidases inhibited
- Epoxomicin is a very selective inhibitor of the chymotrypsin-like activity of the proteasome that is due to catalytic subunit 3. The value of ka was 35,400 M-1s-1 (Meng et al., 1999). Inhibition of the activities of the other catalytic subunits of the proteasome was two- to three-orders of magnitude slower, and there was no detectable inhibition of papain, cathepsin B, calpain, chymotrypsin or trypsin by 50 micromolar epoxomicin. Serine carboxypeptidase A is not inhibited, although it is by some other proteasome inhibitors (Kozlowski et al., 2001).
- Mechanism
- Inhibition is irreversible. Meng et al. (1999) propose that epoxomicin acts as a suicide substrate, and that there is activation of the epoxide within the active site via hydrogen-bonding between the epoxide oxygen and a nearby, proton-donating amino acid side-chain. The crystal structure of an epoxomicin:20S proteasome complex determined by Groll et al. (2000) further explained the selectivity of the inhibitor.
- Pharmaceutical relevance
- Epoxomicin was discovered in a screen for anti-cancer agents, and also has anti-inflammatory activity, so it can be regarded as a possible lead to new drugs (Meng et al., 1999). Epoxomicin has trypanocidal (Glenn et al., 2004) and anti-plasmodial activity (Mordmuller et al., 2006).
![[epoxomicin (T01.012 inhibitor) structure ]](/merops/smi/structures/triple.gif)
