NAD+-protein-glutamate ADP-ribosyltransferase activity
Definition
Target type: molecularfunction
Catalysis of the reaction: L-glutamyl-[protein] + NAD+ = 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + nicotinamide. [PMID:19764761, PMID:25043379, RHEA:58224]
NAD+-protein-glutamate ADP-ribosyltransferase activity, also known as poly(ADP-ribose) polymerase (PARP) activity, is a critical molecular function involved in a wide range of cellular processes. This enzymatic activity catalyzes the transfer of ADP-ribose units from NAD+ to specific glutamate residues on target proteins. This post-translational modification, known as ADP-ribosylation, plays a crucial role in regulating cellular signaling, DNA repair, and apoptosis.
The catalytic mechanism of NAD+-protein-glutamate ADP-ribosyltransferase activity involves the following steps:
1. **NAD+ binding:** The enzyme binds to NAD+ in its active site.
2. **Glutamate recognition:** The enzyme recognizes a specific glutamate residue on the target protein.
3. **ADP-ribose transfer:** The enzyme cleaves NAD+ and transfers an ADP-ribose moiety to the glutamate residue, forming a poly(ADP-ribose) chain.
4. **Poly(ADP-ribose) chain elongation:** The enzyme can catalyze the addition of multiple ADP-ribose units to the growing chain, creating a branched structure.
The specific target proteins and the length and structure of the poly(ADP-ribose) chain vary depending on the PARP enzyme and the cellular context.
PARP enzymes are classified into three main families: PARP1/PARP2, PARP3/PARP4/PARP5a/PARP5b, and PARP6/PARP7/PARP8/PARP9/PARP10/PARP11/PARP12. Each family has distinct functions and target proteins:
* **PARP1/PARP2:** Play a key role in DNA damage response. They are recruited to sites of DNA damage, where they catalyze the formation of long and branched poly(ADP-ribose) chains. These chains serve as a scaffold for the recruitment of DNA repair proteins and regulate the activity of other enzymes involved in DNA repair.
* **PARP3/PARP4/PARP5a/PARP5b:** These PARPs are involved in various cellular processes, including chromatin regulation, transcription, and apoptosis.
* **PARP6/PARP7/PARP8/PARP9/PARP10/PARP11/PARP12:** These PARPs have more specialized roles, often involved in specific signaling pathways or cellular processes.
Dysregulation of PARP activity has been implicated in various diseases, including cancer, neurodegenerative disorders, and inflammatory diseases. Therefore, PARP inhibitors have emerged as promising therapeutic agents in these areas.
In summary, NAD+-protein-glutamate ADP-ribosyltransferase activity (PARP activity) is a crucial enzymatic function that regulates a wide range of cellular processes by post-translational modification of proteins through ADP-ribosylation. The activity and specificity of PARP enzymes are tightly regulated, and their dysregulation is associated with a range of diseases. Understanding the molecular function of NAD+-protein-glutamate ADP-ribosyltransferase activity is essential for developing novel therapeutic strategies for treating diseases related to PARP activity.'
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Proteins (5)
| Protein | Definition | Taxonomy |
|---|---|---|
| Poly [ADP-ribose] polymerase 1 | A poly [ADP-ribose] polymerase 1 that is encoded in the genome of cow. [OMA:P18493, PRO:DNx] | Bos taurus (cattle) |
| Protein mono-ADP-ribosyltransferase PARP3 | A protein mono-ADP-ribosyltransferase PARP3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q9Y6F1] | Homo sapiens (human) |
| Poly [ADP-ribose] polymerase 2 | A poly [ADP-ribose] polymerase 2 that is encoded in the genome of human. [PRO:DNx] | Homo sapiens (human) |
| Protein mono-ADP-ribosyltransferase PARP16 | A protein mono-ADP-ribosyltransferase PARP16 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q8N5Y8] | Homo sapiens (human) |
| Poly [ADP-ribose] polymerase 1 | A poly [ADP-ribose] polymerase 1 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P09874] | Homo sapiens (human) |
Compounds (55)
| Compound | Definition | Classes | Roles |
|---|---|---|---|
| niacinamide | nicotinamide : A pyridinecarboxamide that is pyridine in which the hydrogen at position 3 is replaced by a carboxamide group. | pyridine alkaloid; pyridinecarboxamide; vitamin B3 | anti-inflammatory agent; antioxidant; cofactor; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; EC 3.5.1.98 (histone deacetylase) inhibitor; Escherichia coli metabolite; geroprotector; human urinary metabolite; metabolite; mouse metabolite; neuroprotective agent; Saccharomyces cerevisiae metabolite; Sir2 inhibitor |
| 1,5-dihydroxyisoquinoline | 1,5-dihydroxyisoquinoline: structure in first source isoquinoline-1,5-diol : An isoquinolinol that is isoquinoline in which the hydrogens at positions 1 and 5 are replaced by hydroxy groups. | isoquinolinol | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| 3-aminobenzamide | benzamides; substituted aniline | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor | |
| 4-amino-1,8-naphthalimide | 4-amino-1,8-naphthalimide: inhibits ADP-ribosylation; sometimes abreviated as 4-AN; | benzoisoquinoline; dicarboximide | |
| phenanthridone | phenanthridone : A member of the class of phenanthridines that is phenanthridine with an oxo substituent at position 6. A poly(ADP-ribose) polymerase (PARP) inhibitor, it has been shown to exhibit immunosuppressive activity. phenanthridone: coal tar derivative; structure given in first source | lactam; phenanthridines | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; immunosuppressive agent; mutagen |
| 5-aminoisoquinolinone | 5-aminoisoquinolinone: structure in first source | isoquinolines | |
| benzamide | benzamide : An aromatic amide that consists of benzene bearing a single carboxamido substituent. The parent of the class of benzamides. | benzamides | |
| pj-34 | PJ34 : A member of the class of phenanthridines that is 5,6-dihydrophenanthridine substituted at positions 2 and 6 by (N,N-dimethylglycyl)amino and oxo groups, respectively. It is a potent inhibitor of poly(ADP-ribose) polymerases PARP1 and PARP2 (IC50 of 110 nM and 86 nM, respectively) and exhibits anti-cancer, cardioprotective and neuroprotective properties. | phenanthridines; secondary carboxamide; tertiary amino compound | angiogenesis inhibitor; anti-inflammatory agent; antiatherosclerotic agent; antineoplastic agent; apoptosis inducer; cardioprotective agent; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; neuroprotective agent |
| 3-aminobenzoic acid | 3-aminobenzoic acid : An aminobenzoic acid carrying an amino group at position 3. 3-aminobenzoic acid: RN given refers to parent cpd | aminobenzoic acid | |
| 1-hydroxyphthalazine | 1-hydroxyphthalazine: RN given refers to cpd with unspecified locants; do not confuse with cpd phthalazinol RN: 56611-65-5 | phthalazines | |
| chlorthenoxazin | chlorthenoxazin: RN given refers to parent cpd; structure | benzoxazine | |
| isocarbostyril | isoquinolinone : An isoquinoline containing one or more oxo groups. | isoquinolines | |
| flavone | flavone : The simplest member of the class of flavones that consists of 4H-chromen-4-one bearing a phenyl substituent at position 2. flavone: RN given refers to unlabeled cpd; structure given in first source | flavones | metabolite; nematicide |
| 2,4(1h,3h)-quinazolinedione | 2,4(1H,3H)-quinazolinedione: structure given in first source | ||
| 4-hydroxybenzamide | |||
| naphthalimides | Naphthalimides: Compounds with three fused rings that appear like a naphthalene fused to piperidone or like a benz(de)isoquinoline-1,3-dione (not to be confused with BENZYLISOQUINOLINES which have a methyl separating the naphthyl from the benzyl rings). Members are CYTOTOXINS. | ||
| 4-fluorobenzamide | 4-fluorobenzamide: structure in first source | ||
| 5-iodo-6-amino-1,2-benzopyrone | |||
| alantolactone | alantolactone : A sesquiterpene lactone that is 3a,5,6,7,8,8a,9,9a-octahydronaphtho[2,3-b]furan-2-one bearing two methyl substituents at positions 5 and 8a as well as a methylidene substituent at position 3. alantolactone: allergenic sesquiterpene lactone; crystalline mixture of alantolactones from group of sesquiterpenes; structure | naphthofuran; olefinic compound; sesquiterpene lactone | antineoplastic agent; apoptosis inducer; plant metabolite |
| 4-aminobenzamide | benzamides | ||
| 4-Methoxybenzamide | benzamides | ||
| 3-methoxybenzamide | |||
| 3',4'-dihydroxyflavone | 3',4'-dihydroxyflavone: inhibitors of arachidonic acid peroxidation | ||
| 3,4-dihydro-5-methyl-1(2h)-isoquinolinone | 3,4-dihydro-5-methyl-1(2H)-isoquinolinone: structure given in first source | isoquinolines | |
| 1-oxo-1,2,3,4-tetrahydroisoquinoline | 1-oxo-1,2,3,4-tetrahydroisoquinoline: structure given in first source | ||
| cyclo(alanylalanyl) | |||
| N-[4-[[[4-(4-methoxyphenyl)-4-oxanyl]methylamino]-oxomethyl]phenyl]-2-furancarboxamide | aromatic amide; furans | ||
| ha 1100 | HA 1100: intracellular calcium antagonist | ||
| apigenin | Chamomile: Common name for several daisy-like plants (MATRICARIA; TRIPLEUROSPERMUM; ANTHEMIS; CHAMAEMELUM) native to Europe and Western Asia, now naturalized in the United States and Australia. | trihydroxyflavone | antineoplastic agent; metabolite |
| luteolin | 3'-hydroxyflavonoid; tetrahydroxyflavone | angiogenesis inhibitor; anti-inflammatory agent; antineoplastic agent; apoptosis inducer; c-Jun N-terminal kinase inhibitor; EC 2.3.1.85 (fatty acid synthase) inhibitor; immunomodulator; nephroprotective agent; plant metabolite; radical scavenger; vascular endothelial growth factor receptor antagonist | |
| amentoflavone | biflavonoid; hydroxyflavone; ring assembly | angiogenesis inhibitor; antiviral agent; cathepsin B inhibitor; P450 inhibitor; plant metabolite | |
| 3',4',7-trihydroxyflavone | 3',4',7-trihydroxyflavone: from the Sudanese medicinal plant Albizia zygia; structure in first source | flavones | |
| adenosine diphosphate (hydroxymethyl)pyrrolidinediol | dihydroxypyrrolidine; purine ribonucleoside 5'-diphosphate | ||
| ag 14361 | benzimidazoles | ||
| gpi 6150 | |||
| rucaparib | AG14447: Poly(ADP-ribose) polymerase inhibitor; structure in first source | azepinoindole; caprolactams; organofluorine compound; secondary amino compound | antineoplastic agent; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| 3,4-dihydro-5-(4-(1-piperidinyl)butoxy)-1(2h)-isoquinolinone | |||
| latonduine a | latonduine A: structure in first source | ||
| veliparib | benzimidazoles | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor | |
| olaparib | cyclopropanes; monofluorobenzenes; N-acylpiperazine; phthalazines | antineoplastic agent; apoptosis inducer; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor | |
| niraparib | 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide : A member of the class of indazoles that is 2H-indazole substituted by 4-(piperidin-3-yl)phenyl and aminocarbonyl groups at positions 2 and 7, respectively. It is a potent PARP1 inhibitor with IC50 of 3.2 nM. | benzenes; indazoles; piperidines; primary carboxamide | antineoplastic agent; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| niraparib | niraparib : A 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide that has S-configuration. It is a potent inhibitor of PARP1 and PARP2 (IC50 of 3.8 and 2.1 nM, respectively) and approved as a first-line maintenance treatment for women with advanced ovarian cancer after responding to platinum-based chemotherapy. niraparib: structure in first source | 2-[4-(piperidin-3-yl)phenyl]-2H-indazole-7-carboxamide | antineoplastic agent; apoptosis inducer; EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor; radiosensitizing agent |
| cep 26401 | pyridazines; ring assembly | ||
| iwr-1 endo | IWR-1-endo : A dicarboximide having an endo bridged phthalimide structure, substituted at nitrogen by a 4-(quinolin-8-ylcarbamoyl)benzoyl group. | benzamides; bridged compound; dicarboximide; quinolines | axin stabilizer; Wnt signalling inhibitor |
| nms-p118 | NMS-P118: a PARP-1 inhibitor; structure in first source | ||
| g007-lk | G007-LK: potent and specific small-molecule tankyrase inhibitor; structure in first source | ||
| nu 1025 | NU 1064: structure in first source | phenols; quinazolines | EC 2.4.2.30 (NAD(+) ADP-ribosyltransferase) inhibitor |
| 2-methyl-4(3h)-quinazolinone | 2-methyl-4(3H)-quinazolinone: from Bacillus cereus; structure given in first source | ||
| 4-hydroxyquinazoline | 4-oxo-3,4-dihydroquinazoline: structure in first source | quinazolines | |
| 1,4-Dihydrothieno[3,2-d]pyrimidin-4-one | organic heterobicyclic compound; organonitrogen heterocyclic compound; organosulfur heterocyclic compound | ||
| xav939 | XAV939 : A thiopyranopyrimidine in which a 7,8-dihydro-5H-thiopyrano[4,3-d]pyrimidine skeleton is substituted at C-4 by a hydroxy group and at C-2 by a para-(trifluoromethyl)phenyl group. XAV939: selectively inhibits beta-catenin-mediated transcription; structure in first source | (trifluoromethyl)benzenes; thiopyranopyrimidine | tankyrase inhibitor |
| 2-(4-methoxyphenyl)-1H-quinazolin-4-one | quinazolines | ||
| bmn 673 | talazoparib: inhibits both PARP1 and PARP2; structure in first source | ||
| me0328 | ME0328: inhibits ARTD3; structure in first source | ||
| nvp-tnks656 |