The roles of Jumonji-type oxygenases in human disease

Abstract

The iron- and 2-oxoglutarate-dependent oxygenases constitute a phylogenetically conserved class of enzymes that catalyze hydroxylation reactions in humans by acting on various types of substrates, including metabolic intermediates, amino acid residues in different proteins and various types of nucleic acids. The discovery of jumonji (Jmj), the founding member of a class of Jmj-type chromatin modifying enzymes and transcriptional regulators, has culminated in the discovery of several branches of histone lysine demethylases, with essential functions in regulating the epigenetic landscape of the chromatin environment. This work has now been considerably expanded into other aspects of epigenetic biology and includes the discovery of enzymatic steps required for methyl-cytosine demethylation as well as modification of RNA and ribosomal proteins. This overview aims to summarize the current knowledge on the human Jmj-type enzymes and their involvement in human pathological processes, including development, cancer, inflammation and metabolic diseases.

Figure 1. Phylogenetic tree of the human 2-oxoglutarate-dependent oxygenases

Different subfamilies discussed in the text are highlighted in various colors. Red asterisks indicate members for which no enzymatic activity has been determined yet.

Figure 2. The overall fold of the catalytic JmjC domain in iron- and 2-oxoglutarate-dependent histone demethylases and nucleotide hydroxylases

(A) Jmj prototype member JmjD2A (PDB ID: 2OQ7) in complex with Ni²⁺ (which replaces the endogenous Fe²⁺) and the 2-oxoglutarate competitive inhibitor N-oxalyl glycine (NOG). The double-stranded β-helical core elements are labeled I–VIII and colored cyan, the additional β-strands in blue and the helices in red. Ni²⁺ is shown as a green sphere and NOG as yellow sticks. (B) Overlay of the catalytic core (displayed are the active site metal, the Glu-His triad of active site residues and NOG) of human JmjD2A (green) compared to human ALKBH2 (PDB ID: 3BTX; light blue), indicating similar folding patterns of the catalytic domain. (C) Catalytic core of human methyladenosine demethylase FTO (PDB ID: 3LFM [14]) demonstrating the double-stranded β-helical fold and including the active site metal (blue sphere).