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The roles of Jumonji-type oxygenases in human disease.

Johansson C, Tumber A, Che K, Cain P, Nowak R, Gileadi C, Oppermann U - Epigenomics (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, UK.

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.

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Phylogenetic tree of the human 2-oxoglutarate-dependent oxygenasesDifferent subfamilies discussed in the text are highlighted in various colors. Red asterisks indicate members for which no enzymatic activity has been determined yet.
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Figure 1: Phylogenetic tree of the human 2-oxoglutarate-dependent oxygenasesDifferent subfamilies discussed in the text are highlighted in various colors. Red asterisks indicate members for which no enzymatic activity has been determined yet.

Mentions: Cupins are ancient protein domains, found in archaea, bacteria and eukarya, and are often metalloenzymes with metal ion-containing active sites based around a histidine cluster – hence the jumonji C (JmjC) enzymes belong to a large family of metalloproteins that, despite low sequence similarities, share a common Fe2+- and 2-OG-dependent catalytic core. The human 2-OG oxygenase family consists of over 60 members, to which the different Jmj-type lysine demethylases contribute significantly (Figure 1). All members of this family share few conserved sequence motifs necessary for iron and cofactor binding (with exceptions discussed below), and are mechanistically defined by their ability to hydroxylate their specific substrates using an activated oxo-ferryl intermediate [6]. In brief, the catalytic sequence proceeds through distinct steps of 2-OG cofactor and molecular oxygen binding and activation, resulting in a highly reactive oxo-ferryl intermediate that reacts with the specific substrate atom, usually resulting in a hydroxylated substrate and concomitant CO2 and succinate formation. In terms of lysine demethylase reactions, the hydroxylated substrate is an unstable hemiaminal intermediate derived from the lysine methyl hydroxylation of the Nε -side-chain [6]. This intermediate then fragments into formaldehyde and a lysine side-chain decreased by a methyl group. Importantly, this mechanism allows to demethylate all possible Nε-methyl states (mono-, di- and tri-) found in methylated histone lysine residues and thus differs significantly from the mechanism of monoamine oxidases such as LSD1 and LSD2 (KDM 1A and B) [7] which are important mediators of chromatin function, and which can only demethylate mono- or di-methyl lysine states. Other important functions found in the human 2-OG family comprise hydroxylation of metabolic intermediates (e.g., phytanoic acid degradation [PHYH] [8], or involvement in carnitine synthesis [BBOX, TMLH] [9]), amino acids found, for example, in collagen (e.g., PLOD enzymes (Figure 1)) [10], or transcription factors (e.g., HIFα by 2-OG oxygenases such as FIH and PHD enzymes).


The roles of Jumonji-type oxygenases in human disease.

Johansson C, Tumber A, Che K, Cain P, Nowak R, Gileadi C, Oppermann U - Epigenomics (2014)

Phylogenetic tree of the human 2-oxoglutarate-dependent oxygenasesDifferent subfamilies discussed in the text are highlighted in various colors. Red asterisks indicate members for which no enzymatic activity has been determined yet.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4233403&req=5

Figure 1: Phylogenetic tree of the human 2-oxoglutarate-dependent oxygenasesDifferent subfamilies discussed in the text are highlighted in various colors. Red asterisks indicate members for which no enzymatic activity has been determined yet.
Mentions: Cupins are ancient protein domains, found in archaea, bacteria and eukarya, and are often metalloenzymes with metal ion-containing active sites based around a histidine cluster – hence the jumonji C (JmjC) enzymes belong to a large family of metalloproteins that, despite low sequence similarities, share a common Fe2+- and 2-OG-dependent catalytic core. The human 2-OG oxygenase family consists of over 60 members, to which the different Jmj-type lysine demethylases contribute significantly (Figure 1). All members of this family share few conserved sequence motifs necessary for iron and cofactor binding (with exceptions discussed below), and are mechanistically defined by their ability to hydroxylate their specific substrates using an activated oxo-ferryl intermediate [6]. In brief, the catalytic sequence proceeds through distinct steps of 2-OG cofactor and molecular oxygen binding and activation, resulting in a highly reactive oxo-ferryl intermediate that reacts with the specific substrate atom, usually resulting in a hydroxylated substrate and concomitant CO2 and succinate formation. In terms of lysine demethylase reactions, the hydroxylated substrate is an unstable hemiaminal intermediate derived from the lysine methyl hydroxylation of the Nε -side-chain [6]. This intermediate then fragments into formaldehyde and a lysine side-chain decreased by a methyl group. Importantly, this mechanism allows to demethylate all possible Nε-methyl states (mono-, di- and tri-) found in methylated histone lysine residues and thus differs significantly from the mechanism of monoamine oxidases such as LSD1 and LSD2 (KDM 1A and B) [7] which are important mediators of chromatin function, and which can only demethylate mono- or di-methyl lysine states. Other important functions found in the human 2-OG family comprise hydroxylation of metabolic intermediates (e.g., phytanoic acid degradation [PHYH] [8], or involvement in carnitine synthesis [BBOX, TMLH] [9]), amino acids found, for example, in collagen (e.g., PLOD enzymes (Figure 1)) [10], or transcription factors (e.g., HIFα by 2-OG oxygenases such as FIH and PHD enzymes).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Headington, OX3 7DQ, UK.

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.

Show MeSH
Related in: MedlinePlus