Target-PARP+(Homo+sapiens)

Several forms of cancer are more dependent on PARP than regular cells, making PARP an attractive target for VDS based drug discovery. In addition to their use in cancer therapy, PARP inhibitors are considered a potential treatment for acute life-threatening diseases, such as stroke and myocardial infarction, as well as for long-term neurodegenerative diseases.
 * Organism:** Homo Sapiens
 * Target:** PARP1 (Poly ADP ribose polymerase)
 * NCBI Gene # or RefSeq#:** NM_001618.3
 * EC#:**[|2.4.2.30]
 * PDB # or closest PDB entry is using homology model:**
 * Background/Disease:**

Poly (ADP-ribose) polymerase 1(PRAP1), also known as NAD(+) ADP-ribosyltransferase 1(ADPRT), is a chromatin-associated enzyme which modifies various nuclear proteins by poly(ADP-ribosyl)ation. The ADP-D-ribosyl group of NAD+ is transferred to an acceptor carboxyl group on a histone or the enzyme itself, and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units. The poly(ADP-ribosyl)ation modification is critical for a wide range of processes, including DNA repair, regulation of chromosome structure, transcriptional regulation, mitosis and apoptosis. PARP1 is demonstrateed to mediate the (ADP-ribose) ation of APLF (aprataxin PNK-like factor) and CHFR (checkpoint protein with FHA and RING domains), two representative proteins involved in the DNA damage response and checkpoint regulation. Further, It has been suggested that DNA-dependent protein kinase (DNA-PK), another component of DNA repair, suppresses PARP activity, probably through direct binding and/or sequestration of DNA-ends which serve as an important stimulator for both enzymes. PARP1 inhibitors is thus proposed as a targeted cancer therapy for recombination deficient cancers, such as BRCA2 tumors**.**


 * Proven Inhibitors, use for comparison in enzyme assay?:**

4-Amino-1,8-Napthalimide (Catalog # [|4667-50-09])
Inhibitor of poly(ADP-ribose) polymerase (PARP). Can be used with PARP Assay.

6(5H)-Phenanthridinone (Catalog # [|4667-50-10])
Inhibitor of poly(ADP-ribose) polymerase (PARP) and displays immunosuppressive activity. Can be used with PARP Assay.

6-Biotin-17-NAD (Catalog # [|4670-500-01])
Non-isotopic alternative to radiolabeled NAD for studies requiring this substrate. Can be used with PARP Assay.

Benzamide (Catalog # [|4667-50-11])
A potent inhibitor of poly(ADP-ribose) polymerase (PARP). It is able to prevent nuclear fragmentation and apoptotic-body formation without affecting DNA fragmentation during apoptosis. Can be used with PARP Assay.

PARP is found in the cell’s nucleus, the main role is to detect and signal single strand DNA breaks (SSB) to the enzymatic machinery involved in the SSB repair. PARP activation is an immediate cellular response to metabolic, chemical, or radiation-induced DNA SSB damage. Once PARP detects a SSB it binds to the DNA, and, after a structural change, begin the synthesis of a poly(ADP-ribose)chain (PAR)as a signal for the other DNA repairing enzymes such as DNA ligase III (LigIII), DNA polymerase beta (polβ) and scaffolding proteins such as x-ray cross complementing gene 1 (XRCC1). After repairing, the PAR chains are degraded via PAR glycohydrolase (PARG). Interestingly, NAD+ is required as substrate for generating ADP-ribose monomers. The overactivation of PARP may deplete the stores of cellular NAD+ and induce a progressive ATP depletion, since glucose oxidation is inhibited, and necrotic cell death. In this regard, PARP is inactivated by caspase-3 cleavage (in a specific domain of the enzyme) during programmed cell death. PARP enzymes are essential in a number of cellular functions, including expression of inflammatory genes : PARP1 is required for the induction of ICAM-1 gene expression by smooth muscle cells, in response to TNF.
 * Function-**


 * Image of protein from PDB:**

code format="genbank" 1 aggcatcagc aatctatcag ggaacggcgg tggccggtgc ggcgtgttcg gtggcggctc 61 tggccgctca ggcgcctgcg gctgggtgag cgcacgcgag gcggcgaggc ggcagcgtgt 121 ttctaggtcg tggcgtcggg cttccggagc tttggcggca gctaggggag gatggcggag 181 tcttcggata agctctatcg agtcgagtac gccaagagcg ggcgcgcctc ttgcaagaaa 241 tgcagcgaga gcatccccaa ggactcgctc cggatggcca tcatggtgca gtcgcccatg 301 tttgatggaa aagtcccaca ctggtaccac ttctcctgct tctggaaggt gggccactcc 361 atccggcacc ctgacgttga ggtggatggg ttctctgagc ttcggtggga tgaccagcag 421 aaagtcaaga agacagcgga agctggagga gtgacaggca aaggccagga tggaattggt 481 agcaaggcag agaagactct gggtgacttt gcagcagagt atgccaagtc caacagaagt 541 acgtgcaagg ggtgtatgga gaagatagaa aagggccagg tgcgcctgtc caagaagatg 601 gtggacccgg agaagccaca gctaggcatg attgaccgct ggtaccatcc aggctgcttt 661 gtcaagaaca gggaggagct gggtttccgg cccgagtaca gtgcgagtca gctcaagggc 721 ttcagcctcc ttgctacaga ggataaagaa gccctgaaga agcagctccc aggagtcaag 781 agtgaaggaa agagaaaagg cgatgaggtg gatggagtgg atgaagtggc gaagaagaaa 841 tctaaaaaag aaaaagacaa ggatagtaag cttgaaaaag ccctaaaggc tcagaacgac 901 ctgatctgga acatcaagga cgagctaaag aaagtgtgtt caactaatga cctgaaggag 961 ctactcatct tcaacaagca gcaagtgcct tctggggagt cggcgatctt ggaccgagta 1021 gctgatggca tggtgttcgg tgccctcctt ccctgcgagg aatgctcggg tcagctggtc 1081 ttcaagagcg atgcctatta ctgcactggg gacgtcactg cctggaccaa gtgtatggtc 1141 aagacacaga cacccaaccg gaaggagtgg gtaaccccaa aggaattccg agaaatctct 1201 tacctcaaga aattgaaggt taaaaaacag gaccgtatat tccccccaga aaccagcgcc 1261 tccgtggcgg ccacgcctcc gccctccaca gcctcggctc ctgctgctgt gaactcctct 1321 gcttcagcag ataagccatt atccaacatg aagatcctga ctctcgggaa gctgtcccgg 1381 aacaaggatg aagtgaaggc catgattgag aaactcgggg ggaagttgac ggggacggcc 1441 aacaaggctt ccctgtgcat cagcaccaaa aaggaggtgg aaaagatgaa taagaagatg 1501 gaggaagtaa aggaagccaa catccgagtt gtgtctgagg acttcctcca ggacgtctcc 1561 gcctccacca agagccttca ggagttgttc ttagcgcaca tcttgtcccc ttggggggca 1621 gaggtgaagg cagagcctgt tgaagttgtg gccccaagag ggaagtcagg ggctgcgctc 1681 tccaaaaaaa gcaagggcca ggtcaaggag gaaggtatca acaaatctga aaagagaatg 1741 aaattaactc ttaaaggagg agcagctgtg gatcctgatt ctggactgga acactctgcg 1801 catgtcctgg agaaaggtgg gaaggtcttc agtgccaccc ttggcctggt ggacatcgtt 1861 aaaggaacca actcctacta caagctgcag cttctggagg acgacaagga aaacaggtat 1921 tggatattca ggtcctgggg ccgtgtgggt acggtgatcg gtagcaacaa actggaacag 1981 atgccgtcca aggaggatgc cattgagcac ttcatgaaat tatatgaaga aaaaaccggg 2041 aacgcttggc actccaaaaa tttcacgaag tatcccaaaa agttctaccc cctggagatt 2101 gactatggcc aggatgaaga ggcagtgaag aagctgacag taaatcctgg caccaagtcc 2161 aagctcccca agccagttca ggacctcatc aagatgatct ttgatgtgga aagtatgaag 2221 aaagccatgg tggagtatga gatcgacctt cagaagatgc ccttggggaa gctgagcaaa 2281 aggcagatcc aggccgcata ctccatcctc agtgaggtcc agcaggcggt gtctcagggc 2341 agcagcgact ctcagatcct ggatctctca aatcgctttt acaccctgat cccccacgac 2401 tttgggatga agaagcctcc gctcctgaac aatgcagaca gtgtgcaggc caaggtggaa 2461 atgcttgaca acctgctgga catcgaggtg gcctacagtc tgctcagggg agggtctgat 2521 gatagcagca aggatcccat cgatgtcaac tatgagaagc tcaaaactga cattaaggtg 2581 gttgacagag attctgaaga agccgagatc atcaggaagt atgttaagaa cactcatgca 2641 accacacaca atgcgtatga cttggaagtc atcgatatct ttaagataga gcgtgaaggc 2701 gaatgccagc gttacaagcc ctttaagcag cttcataacc gaagattgct gtggcacggg 2761 tccaggacca ccaactttgc tgggatcctg tcccagggtc ttcggatagc cccgcctgaa 2821 gcgcccgtga caggctacat gtttggtaaa gggatctatt tcgctgacat ggtctccaag 2881 agtgccaact actgccatac gtctcaggga gacccaatag gcttaatcct gttgggagaa 2941 gttgcccttg gaaacatgta tgaactgaag cacgcttcac atatcagcaa gttacccaag 3001 ggcaagcaca gtgtcaaagg tttgggcaaa actacccctg atccttcagc taacattagt 3061 ctggatggtg tagacgttcc tcttgggacc gggatttcat ctggtgtgaa tgacacctct 3121 ctactatata acgagtacat tgtctatgat attgctcagg taaatctgaa gtatctgctg 3181 aaactgaaat tcaattttaa gacctccctg tggtaattgg gagaggtagc cgagtcacac 3241 ccggtggctc tggtatgaat tcacccgaag cgcttctgca ccaactcacc tggccgctaa 3301 gttgctgatg ggtagtacct gtactaaacc acctcagaaa ggattttaca gaaacgtgtt 3361 aaaggttttc tctaacttct caagtccctt gttttgtgtt gtgtctgtgg ggaggggttg 3421 ttttggggtt gtttttgttt tttcttgcca ggtagataaa actgacatag agaaaaggct 3481 ggagagagat tctgttgcat agactagtcc tatggaaaaa accaagcttc gttagaatgt 3541 ctgccttact ggtttcccca gggaaggaaa aatacacttc cacccttttt tctaagtgtt 3601 cgtctttagt tttgattttg gaaagatgtt aagcatttat ttttagttaa aaataaaaac 3661 taatttcata ctatttagat tttctttttt atcttgcact tattgtcccc tttttagttt 3721 tttttgtttg cctcttgtgg tgaggggtgt gggaagacca aaggaaggaa cgctaacaat 3781 ttctcatact tagaaacaaa aagagctttc cttctccagg aatactgaac atgggagctc 3841 ttgaaatatg tagtattaaa agttgcattt gaaattcttg actttcttat gggcactttt 3901 gtcttccaaa ttaaaactct accacaaata tacttaccca agggctaata gtaatactcg 3961 attaaaaatg cagatgcctt ctctaaaaaa aaaaaaaaaa a code
 * CDS Gene Sequence:**

1014 amino acids
 * Amino Acid Sequence:**

MAESSDKLYRVEYAKSGRASCKKCSESIPKDSLRMAIMVQSPMFDGKVPHWYHFSCFWKVGHSIRHPDVEVDGFSELRWDDQQKVKKTAE AGGVTGKGQDGIGSKAEKTLGDFAAEYAKSNRSTCKGCMEKIEKGQVRLSKKMVDPEKPQLGMIDRWYHPGCFVKNREELGFRPEYSASQ LKGFSLLATEDKEALKKQLPGVKSEGKRKGDEVDGVDEVAKKKSKKEKDKDSKLEKALKAQNDLIWNIKDELKKVCSTNDLKELLIFNKQ QVPSGESAILDRVADGMVFGALLPCEECSGQLVFKSDAYYCTGDVTAWTKCMVKTQTPNRKEWVTPKEFREISYLKKLKVKKQDRIFPPE TSASVAATPPPSTASAPAAVNSSASADKPLSNMKILTLGKLSRNKDEVKAMIEKLGGKLTGTANKASLCISTKKEVEKMNKKMEEVKEAN IRVVSEDFLQDVSASTKSLQELFLAHILSPWGAEVKAEPVEVVAPRGKSGAALSKKSKGQVKEEGINKSEKRMKLTLKGGAAVDPDSGLE HSAHVLEKGGKVFSATLGLVDIVKGTNSYYKLQLLEDDKENRYWIFRSWGRVGTVIGSNKLEQMPSKEDAIEHFMKLYEEKTGNAWHSKN FTKYPKKFYPLEIDYGQDEEAVKKLTVNPGTKSKLPKPVQDLIKMIFDVESMKKAMVEYEIDLQKMPLGKLSKRQIQAAYSILSEVQQAV SQGSSDSQILDLSNRFYTLIPHDFGMKKPPLLNNADSVQAKVEMLDNLLDIEVAYSLLRGGSDDSSKDPIDVNYEKLKTDIKVVDRDSEE AEIIRKYVKNTHATTHNAYDLEVIDIFKIEREGECQRYKPFKQLHNRRLLWHGSRTTNFAGILSQGLRIAPPEAPVTGYMFGKGIYFADM VSKSANYCHTSQGDPIGLILLGEVALGNMYELKHASHISKLPKGKHSVKGLGKTTPDPSANISLDGVDVPLGTGISSGVNDTSLLYNEYI VYDIAQVNLKYLLKLKFNFKTSLW

[] Dr. B