Search

Jumonji‐C (JmjC) domain‐containing protein 7 (JMJD7) is a human Fe(II) and 2‐oxoglutarate dependent oxygenase that catalyzes stereospecific C3‐hydroxylation of lysyl‐residues in developmentally regulated GTP binding proteins 1 and 2 (DRG1/2). We report studies exploring a diverse set of lysine derivatives incorporated into the DRG1 peptides as potential human JMJD7 substrates and inhibitors. The results indicate that human JMJD7 has a relatively narrow substrate scope beyond lysine compared to some other JmjC hydroxylases and lysine‐modifying enzymes. The geometrically constrained (E)‐dehydrolysine is an efficient alternative to lysine for JMJD7‐catalyzed C3‐hydroxylation. γ‐Thialysine and γ‐azalysine undergo C3‐hydroxylation, followed by degradation to formylglycine. JMJD7 also catalyzes the S‐oxidation of DRG1‐derived peptides possessing methionine and homomethionine residues in place of lysine. Inhibition assays show that DRG1 variants possessing cysteine/selenocysteine instead of the lysine residue efficiently inhibit JMJD7 via cross‐linking. The overall results inform on the substrate selectivity and inhibition of human JMJD7, which will help enable the rational design of selective small‐molecule and peptidomimetic inhibitors of JMJD7. [ABSTRACT FROM AUTHOR]

Jumonji-C (JmjC) domain-containing protein 7 (JMJD7) is a human Fe(II) and 2-oxoglutarate dependent oxygenase that catalyzes stereospecific C3-hydroxylation of lysyl-residues in developmentally regulated GTP binding proteins 1 and 2 (DRG1/2). We report studies exploring a diverse set of lysine derivatives incorporated into the DRG1 peptides as potential human JMJD7 substrates and inhibitors. The results indicate that human JMJD7 has a relatively narrow substrate scope beyond lysine compared to some other JmjC hydroxylases and lysine-modifying enzymes. The geometrically constrained (E)-dehydrolysine is an efficient alternative to lysine for JMJD7-catalyzed C3-hydroxylation. γ-Thialysine and γ-azalysine undergo C3-hydroxylation, followed by degradation to formylglycine. JMJD7 also catalyzes the S-oxidation of DRG1-derived peptides possessing methionine and homomethionine residues in place of lysine. Inhibition assays show that DRG1 variants possessing cysteine/selenocysteine instead of the lysine residue efficiently inhibit JMJD7 via cross-linking. The overall results inform on the substrate selectivity and inhibition of human JMJD7, which will help enable the rational design of selective small-molecule and peptidomimetic inhibitors of JMJD7., (© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)