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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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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).
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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).

Mentions: The JmjC domain is a double-stranded β-helical (DSBH) fold also called the jelly-roll fold or double Greek motif. The DSBH fold is composed of eight β-strands that form a β-sandwich structure comprised of two four-stranded antiparallel β-sheets (Figure 2) [11]. Most 2-OG oxygenases also contain additional secondary structure elements that surround the DSBH and define the different subfamilies. This includes additional β-strands that extend the DSBH, at least one helix on the C-terminal side of the DSBH, and inserts between the fourth and fifth β-strand. This DSBH core fold provides a rigid scaffold for the cosubstrates 2-OG and Fe2+, which are located in the more open end of the barrel (Figure 2). The iron is coordinated by two histidinyl residues together with a glutamyl or aspartyl residue in a conserved HxE/DxH motif found among 2-OG oxygenases. The 2-OG binding is less well conserved, and the cofactor coordinates the iron in a bidentate manner via its 2-oxo group and one of its 1-carboxylate oxygens, whereas the 5-carboxylate is usually bound to the side-chain of a basic residue (Arg/Lys) and to a hydroxyl group from a Ser/Thr or Tyr residue. The substrate binding varies considerably among the different subfamilies of 2-OG oxygenases/demethylases and the specific interactions identified thus far are beyond the scope of this review. However, crystallographic studies have revealed that it often involves residues from the first and second β-strand, together with strands and loops that extend the DSBH. Other protein domain modules, such as a plant homeodomain (PHD), Tudor, AT-rich interaction domain (ARID) or CxxC zinc finger motifs that vary between the different subfamilies, are usually also required for interaction with DNA/RNA or chromatin protein substrates [11-13]. An overview of the different protein domains as well as annotation of substrate specificities found in Jmj enzymes with defined or hypothetical roles in chromatin biology is given in Table 1.


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)

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).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

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).
Mentions: The JmjC domain is a double-stranded β-helical (DSBH) fold also called the jelly-roll fold or double Greek motif. The DSBH fold is composed of eight β-strands that form a β-sandwich structure comprised of two four-stranded antiparallel β-sheets (Figure 2) [11]. Most 2-OG oxygenases also contain additional secondary structure elements that surround the DSBH and define the different subfamilies. This includes additional β-strands that extend the DSBH, at least one helix on the C-terminal side of the DSBH, and inserts between the fourth and fifth β-strand. This DSBH core fold provides a rigid scaffold for the cosubstrates 2-OG and Fe2+, which are located in the more open end of the barrel (Figure 2). The iron is coordinated by two histidinyl residues together with a glutamyl or aspartyl residue in a conserved HxE/DxH motif found among 2-OG oxygenases. The 2-OG binding is less well conserved, and the cofactor coordinates the iron in a bidentate manner via its 2-oxo group and one of its 1-carboxylate oxygens, whereas the 5-carboxylate is usually bound to the side-chain of a basic residue (Arg/Lys) and to a hydroxyl group from a Ser/Thr or Tyr residue. The substrate binding varies considerably among the different subfamilies of 2-OG oxygenases/demethylases and the specific interactions identified thus far are beyond the scope of this review. However, crystallographic studies have revealed that it often involves residues from the first and second β-strand, together with strands and loops that extend the DSBH. Other protein domain modules, such as a plant homeodomain (PHD), Tudor, AT-rich interaction domain (ARID) or CxxC zinc finger motifs that vary between the different subfamilies, are usually also required for interaction with DNA/RNA or chromatin protein substrates [11-13]. An overview of the different protein domains as well as annotation of substrate specificities found in Jmj enzymes with defined or hypothetical roles in chromatin biology is given in Table 1.

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