Sandbox Reserved 1098: Difference between revisions

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PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>.

There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.

There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.

Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.

The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.

=== The mechanism ===

~~As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors.~~ At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site.

At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site.

The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref> and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>.

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 PDD00013907 is, as already stated, an anthraquinone which is a polycyclic aromatic hydrocarbon usually used in biopesticides as a pest repellant. Here it is considered as a free <scene name='82/829351/7jb/1'>ligand</scene> (of identification number on PDB: 7JB) that can bind to the <scene name='82/829351/Parg/1'>PARG</scene> creating the<scene name='82/829351/Complex/1'> protein complex 6HMM</scene>.
-There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>. Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.
+There are several possible post-translational modifications to stabilize DNA. Most commonly there would be phosphorylation, acetylation or methylation <ref>PMID: 21037856</ref>.
+Another post-translational modification concerning the 6HMM protein is made on the poly(ADP-ribose) protein (PAR). PAR is composed of a repetition of ADP-ribose units linked through glycosidic ribose-ribose bonds <ref>doi: 10.1038/nature10404</ref>. This allows the repair of single-strand breaks on DNA <ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792.">DOI: 10.1021/acs.jmedchem.8b01407</ref>. <scene name='82/829351/Parg/1'>PARG</scene>, a constituent of the <scene name='82/829351/6hmm/1'>6HMM protein</scene> will degrade PAR to allow the <scene name='82/829351/Parp1_on_dna/1'>poly (ADP-ribose) polymerase (PARP)</scene> to free itself from the damaged site, that is now repaired, and completes as such reparation <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12.">PMID: 27689388</ref>.
 The anthraquinone PDD00013907 is a weakly active and cytotoxic anthraquinone 8a acting as a free ligand binding in the ADP-ribose binding site of the <scene name='82/829351/Parg/1'>PARG</scene>. This PDD00013907 should lead to the inhibition of <scene name='82/829351/Parg/1'>PARG</scene>, which is of interest in the search of novel cancer therapies <ref name="James DI, Smith KM, Jordan AM, Fairweather EE, Griffiths LA, Hamilton NS, Hitchin JR, Hutton CP, Jones S, Kelly P, McGonagle AE, Small H, Stowell AI, Tucker J, Waddell ID, Waszkowycz B, Ogilvie DJ. First-in-Class Chemical Probes against Poly(ADP-ribose) Glycohydrolase (PARG) Inhibit DNA Repair with Differential Pharmacology to Olaparib. ACS Chem Biol. 2016 Oct 12."/>.
 === The mechanism ===
-As said previously, poly(ADP-ribosylation) is an important post-translational modification for DNA repair. The mechanism behind this repair relies on several factors. At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site.
+At first, the Poly (ADP-ribose) polymerase (PARP), more specifically the subtype [http://www.uniprot.org/uniprot/P09874 PARP1], will recognize and will bind to the single-stranded break on the DNA. It will then autophosphorylate due to NAD+ and form PAR chains. These will recruit other repair proteins to the site.
 The role of PARG is the hydrolyzation of the specific ribose-ribose bonds present in PAR which leads to its degradation and as such the reparation cycle will be finished<ref name="Waszkowycz B, Smith KM, McGonagle AE, Jordan AM, Acton B, Fairweather EE, Griffiths LA, Hamilton NM, Hamilton NS, Hitchin JR, Hutton CP, James DI, Jones CD, Jones S, Mould DP, Small HF, Stowell AIJ, Tucker JA, Waddell ID, Ogilvie DJ. Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. J Med Chem. 2018 Dec 13;61(23):10767-10792."/>. This degradation is important because without PARG the repair cycle cannot be completed <ref>PMID: 17548475</ref>  and may lead to cell death. This is partially due to the still present PARP on the previously damaged site maintained by the non-degraded PAR <ref>PMID: 16140981</ref>.