The Plasmodium
falciparum artemisinin-resistance marker PfKelch13 showing functional equivalence
to the human Keap1 protein in regulating stress response and Nrf2 binding
Parveen Nikhat
Res. J. Biotech.; Vol. 20(9); 34-49;
doi: https://doi.org/10.25303/209rjbt034049; (2025)
Abstract
Malaria is caused by P. falciparum and the WHO recommends artemisinin derivatives
as the frontline treatment as artemisinin-based combination therapy (ACT). However,
the global emergence and spread of artemisinin resistance during the past two decades
has caused a serious setback in the long-term efficacy of ACT. Mutations in the
P. falciparum Kelch13 (PfKelch13) protein confer artemisinin-resistance phenotype
in clinical isolates and under laboratory conditions. PfKelch13 belongs to the kelch
protein family and has a broad-complex, tramtrack and bric-à-brac/poxvirus and zinc-finger
(BTB/POZ) domain and a C-terminal Kelch repeat propeller (KREP) domain with six
kelch repeats.
Most artemisinin resistance-causing mutations occur within the KREP domain, implying
its functional importance. PfKelch13 KREP shows maximum sequence homology to the
KREP domain of KLHL19 (also known as Keap1; Kelch-like ECH-associated protein 1)
and is speculated as a structural homolog. This study investigates the sequence-structure
homology between human Keap1 and PfKelch13 to identify comparative functional aspects
in mammalian cells. We hereby report that PfKelch13 in mammalian cells interacts
with mammalian Nrf2 similarly to that of Keap1. Thus, our results signify the role
of PfKelch13 in artemisinin-induced oxidative stress.
