kelch13

Kelch13 is a gene in the malaria parasite Plasmodium falciparum that encodes a Kelch-domain containing protein, often referred to as K13. The predicted protein typically features an N-terminal region compatible with a BTB/POZ scaffold and a six-bladed beta-propeller Kelch domain at the C-terminus, and it is thought to participate in a Cullin-3-based E3 ubiquitin ligase complex involved in protein turnover and endocytosis. The exact biological function of K13 in malaria parasites remains not fully understood.

In the mid-2010s, specific point mutations in the Kelch propeller domain of K13 were found to correlate with delayed parasite clearance after artemisinin-based combination therapy (ACT) in parts of Southeast Asia. The most prominent allele is C580Y; other well-described variants include R539T, I543T, and Y493H. These mutations have been widely used as molecular markers of artemisinin resistance and are monitored by surveillance programs. Their prevalence varies by region, being relatively common in parts of Southeast Asia and generally rare but emerging in Africa. Detection relies on sequencing the propeller domain of K13 from field isolates.

Mechanistic understanding of K13's role in resistance remains incomplete. While K13 alterations are linked to the parasite’s response to artemisinin-induced stress, the precise molecular function and how specific mutations translate into reduced drug susceptibility are active areas of research. The prevailing view is that K13 mutations contribute to, but do not solely determine, artemisinin resistance and are one factor among several influencing ACT efficacy.