Authors

Discussion

Homology models of  K13 Kelch propeller in Plasmodium falciparum and in 7 other species show in silico a disulphide bond between blades 3 and  4. (PlasmoDB:comment 100016203, 2015-02-24). Encouragingly, S-S linked (4ZGC A) and unlinked (4YY8 B) P. falciparum X-ray structures were released in RCSB last June and April by Jiang et al.  Using SDM (Single Direct Mutator) suite on 4YY8 B revealed that 10 field alleles, including Ile543Thr which is linked to artemisinin-resistance in Vietnam, facilitate an S-S link between cysteines 532 and 580.  (V534L/I; Y541H; C542Y; I543T; G544R; A578S; V581F; V589I; G592R). All these are in B-strand 3a or 4a containing 532 or 580 or in H-bonded antiparallel B-strand 3b or 4b, except 578S in a less stable loop. Like KEAP1 in man, K13 may use Cys residues to detect oxidative stress, caused here by heme released as digestion develops in the early ring, to regulate growth rate and switch on antioxidant response. While the S-S link will affect function of both cysteines, Cys580Tyr, highly prevalent in Cambodian artemisinin resistance, prevents the S-S link by removing Cys580.  These features suggest that regulation of propeller sensitivity to oxidative stress is important in drug activity and parasite-resistance, and the role of dicysteine formation, and local redox potential, should be examined.