African sleeping sickness
Eflornithine is used to treat second stage cases of African sleeping sickness. It acts by irreversibly inhibiting the enzyme ornithine decarboxylase (ODC), an enzyme which converts ornithine to putrescine.
While polyamines are present in the host environment, T. brucei is inefficient at importing them. Therefore, this pathogen is highly dependent on polyamine biosynthesis . Overall, these properties make polyamine synthesis an excellent therapeutic target. Nevertheless, it is worth remembering that human cells also require and manufacture polyamines through a similar pathway. This raises concern over possible toxicity, but fortunately human cells prove much less susceptible to eflornithine. This is, in part, due to a faster turnover rate of ODC in humans .
Excessive hair growth
Eflornithine - an irreversible, mechanism-based inhibitor
Another more colourful name given to this inhibitor class is “Trojan horse substrates.” Like in the classic Greek tale, the enzyme is deceived by the inhibitor, mistaking it for substrate. It permits the inhibitor entry into its active site and activates it, bringing about the enzyme's demise. Note the structural similarity between eflornithine and ornithine (ODC’s substrate).
Eflornithine requires activation by ornithine decarboxylase, mechanistically analogous to substrate turnover, so we'll first review this enzyme’s catalytic mechanism.