Limits...
Protein Hydroxylation Catalyzed by 2-Oxoglutarate-dependent Oxygenases.

Markolovic S, Wilkins SE, Schofield CJ - J. Biol. Chem. (2015)

Bottom Line: Subsequently, they have been shown to catalyze N-demethylation (via hydroxylation) of N(ϵ)-methylated histone lysyl residues, as well as hydroxylation of multiple other residues.Recent work has identified roles for 2OG oxygenases in the modification of translation-associated proteins, which in some cases appears to be conserved from microorganisms through to humans.Here we give an overview of protein hydroxylation catalyzed by 2OG oxygenases, focusing on recent discoveries.

View Article: PubMed Central - PubMed

Affiliation: From the Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom.

Show MeSH

Related in: MedlinePlus

Outline mechanism and characteristic fold of 2OG oxygenases.A, within the active site, Fe(II) (orange) is bound in an octahedral manner by an HX(D/E) … H facial triad. The remaining coordination sites are initially occupied by water molecules, two of which are displaced upon binding of 2OG. Binding of the substrate (purple) displaces the final water molecule, creating an open coordination site for oxygen (red) to bind. Oxidative decarboxylation of 2OG generates succinate and CO2 and yields a ferryl intermediate (FeIV=O) that reacts with the substrate to form the hydroxylated product. Note that N-methyl demethylation (shown in gray) occurs via hydroxylation of the methyl group to form a hemiaminal intermediate that subsequently collapses to yield formaldehyde and the demethylated product. B, view from a crystal structure of a PHD in complex with a HIF-1α fragment peptide substrate (Protein Data Bank ID: 3HQR). The core double-stranded β-helix fold (salmon) is conserved in 2OG oxygenases and consists of eight β-strands that form two anti-parallel β-sheets. The HIF-1α peptide (purple) binds such that the side chain of Pro 564 is oriented toward the metal within the active site. A magnified view of the active site (right) highlights residues involved in binding Fe(II) (yellow) and 2OG (light blue). Note that in this structure, N-oxalylglycine (NOG) and Mn(II) replace 2OG and Fe(II), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4543633&req=5

Figure 1: Outline mechanism and characteristic fold of 2OG oxygenases.A, within the active site, Fe(II) (orange) is bound in an octahedral manner by an HX(D/E) … H facial triad. The remaining coordination sites are initially occupied by water molecules, two of which are displaced upon binding of 2OG. Binding of the substrate (purple) displaces the final water molecule, creating an open coordination site for oxygen (red) to bind. Oxidative decarboxylation of 2OG generates succinate and CO2 and yields a ferryl intermediate (FeIV=O) that reacts with the substrate to form the hydroxylated product. Note that N-methyl demethylation (shown in gray) occurs via hydroxylation of the methyl group to form a hemiaminal intermediate that subsequently collapses to yield formaldehyde and the demethylated product. B, view from a crystal structure of a PHD in complex with a HIF-1α fragment peptide substrate (Protein Data Bank ID: 3HQR). The core double-stranded β-helix fold (salmon) is conserved in 2OG oxygenases and consists of eight β-strands that form two anti-parallel β-sheets. The HIF-1α peptide (purple) binds such that the side chain of Pro 564 is oriented toward the metal within the active site. A magnified view of the active site (right) highlights residues involved in binding Fe(II) (yellow) and 2OG (light blue). Note that in this structure, N-oxalylglycine (NOG) and Mn(II) replace 2OG and Fe(II), respectively.

Mentions: In addition to the roles associated with protein modification, 2OG oxygenases function in fatty acid metabolism, carnitine biosynthesis, and phytanic acid catabolism, as well as in DNA and mRNA repair, regulation, and modification (6). 2OG oxygenases employ a conserved mechanism in which sequential binding of 2OG to the active site is followed by that of substrate and then oxygen (4, 7). Oxidative decarboxylation of 2OG yields a ferryl intermediate (FeIV=O), which reacts with the substrate to effect 2-electron oxidation, normally hydroxylation (Fig. 1A). N-Methyl demethylation proceeds via initial hydroxylation of the methyl group to form a hemiaminal intermediate, which fragments to give formaldehyde and the demethylated product.


Protein Hydroxylation Catalyzed by 2-Oxoglutarate-dependent Oxygenases.

Markolovic S, Wilkins SE, Schofield CJ - J. Biol. Chem. (2015)

Outline mechanism and characteristic fold of 2OG oxygenases.A, within the active site, Fe(II) (orange) is bound in an octahedral manner by an HX(D/E) … H facial triad. The remaining coordination sites are initially occupied by water molecules, two of which are displaced upon binding of 2OG. Binding of the substrate (purple) displaces the final water molecule, creating an open coordination site for oxygen (red) to bind. Oxidative decarboxylation of 2OG generates succinate and CO2 and yields a ferryl intermediate (FeIV=O) that reacts with the substrate to form the hydroxylated product. Note that N-methyl demethylation (shown in gray) occurs via hydroxylation of the methyl group to form a hemiaminal intermediate that subsequently collapses to yield formaldehyde and the demethylated product. B, view from a crystal structure of a PHD in complex with a HIF-1α fragment peptide substrate (Protein Data Bank ID: 3HQR). The core double-stranded β-helix fold (salmon) is conserved in 2OG oxygenases and consists of eight β-strands that form two anti-parallel β-sheets. The HIF-1α peptide (purple) binds such that the side chain of Pro 564 is oriented toward the metal within the active site. A magnified view of the active site (right) highlights residues involved in binding Fe(II) (yellow) and 2OG (light blue). Note that in this structure, N-oxalylglycine (NOG) and Mn(II) replace 2OG and Fe(II), respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4543633&req=5

Figure 1: Outline mechanism and characteristic fold of 2OG oxygenases.A, within the active site, Fe(II) (orange) is bound in an octahedral manner by an HX(D/E) … H facial triad. The remaining coordination sites are initially occupied by water molecules, two of which are displaced upon binding of 2OG. Binding of the substrate (purple) displaces the final water molecule, creating an open coordination site for oxygen (red) to bind. Oxidative decarboxylation of 2OG generates succinate and CO2 and yields a ferryl intermediate (FeIV=O) that reacts with the substrate to form the hydroxylated product. Note that N-methyl demethylation (shown in gray) occurs via hydroxylation of the methyl group to form a hemiaminal intermediate that subsequently collapses to yield formaldehyde and the demethylated product. B, view from a crystal structure of a PHD in complex with a HIF-1α fragment peptide substrate (Protein Data Bank ID: 3HQR). The core double-stranded β-helix fold (salmon) is conserved in 2OG oxygenases and consists of eight β-strands that form two anti-parallel β-sheets. The HIF-1α peptide (purple) binds such that the side chain of Pro 564 is oriented toward the metal within the active site. A magnified view of the active site (right) highlights residues involved in binding Fe(II) (yellow) and 2OG (light blue). Note that in this structure, N-oxalylglycine (NOG) and Mn(II) replace 2OG and Fe(II), respectively.
Mentions: In addition to the roles associated with protein modification, 2OG oxygenases function in fatty acid metabolism, carnitine biosynthesis, and phytanic acid catabolism, as well as in DNA and mRNA repair, regulation, and modification (6). 2OG oxygenases employ a conserved mechanism in which sequential binding of 2OG to the active site is followed by that of substrate and then oxygen (4, 7). Oxidative decarboxylation of 2OG yields a ferryl intermediate (FeIV=O), which reacts with the substrate to effect 2-electron oxidation, normally hydroxylation (Fig. 1A). N-Methyl demethylation proceeds via initial hydroxylation of the methyl group to form a hemiaminal intermediate, which fragments to give formaldehyde and the demethylated product.

Bottom Line: Subsequently, they have been shown to catalyze N-demethylation (via hydroxylation) of N(ϵ)-methylated histone lysyl residues, as well as hydroxylation of multiple other residues.Recent work has identified roles for 2OG oxygenases in the modification of translation-associated proteins, which in some cases appears to be conserved from microorganisms through to humans.Here we give an overview of protein hydroxylation catalyzed by 2OG oxygenases, focusing on recent discoveries.

View Article: PubMed Central - PubMed

Affiliation: From the Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, United Kingdom.

Show MeSH
Related in: MedlinePlus