tRNA N6-adenosine threonylcarbamoyltransferase (OSGEP) (OSGEP)

Kae1, known in humans as O-sialoglycoprotein endopeptidase (OSGEP), is the highly conserved catalytic subunit of the KEOPS (Kinase, Endopeptidase and Other Proteins of Small size) complex (UniProt P55788). Its primary biological role is the synthesis of N6-threonylcarbamoyladenosine (t6A), a universal tRNA modification essential for accurate translation and reading frame maintenance (Thiaville et al., 2014, PMID: 25246651). This modification occurs at position 37 of tRNAs that decode ANN codons, ensuring the stability of the codon-anticodon interaction. In humans, mutations in the OSGEP gene are a primary cause of Galloway-Mowat syndrome, a rare autosomal recessive disorder characterized by podocyte dysfunction and microcephaly (Braun et al., 2017, PMID: 28805828). Beyond its role in genetic disease, Kae1 has emerged as a promising therapeutic target in infectious diseases, particularly malaria. Inhibition of the Plasmodium falciparum Kae1 ortholog leads to the accumulation of misfolded proteins and subsequent parasite death (Gligorijevic et al., 2017, PMID: 28714418). Small molecule inhibitors, such as those identified in the Malaria Box, have demonstrated potent antimalarial activity by targeting this enzyme. However, achieving selectivity over the human ortholog remains a significant therapeutic challenge due to the high structural conservation of the active site.

Other names

Kae1O-sialoglycoprotein endopeptidaseKinase-associated endopeptidase 1t6A-modifying enzymeKEOPS complex subunit Kae1GC-rich sequence DNA-binding factor 1-likeGCFC1L

Inhibition of the KEOPS complex catalytic activity, specifically preventing the N6-threonylcarbamoylation of tRNA, which leads to translational errors, proteotoxic stress, and cell death.