WordNet

the 1st letter of the Roman alphabet (同)a
the blood group whose red cells carry the A antigen (同)type_A, group A
a nuclease that cleaves nucleic acids at interior bonds and so produces fragments of various sizes

PrepTutorEJDIC

answer / ampere
antipersonnel / (またA.P.)Associated Press

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/03/25 06:54:16」(JST)

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Ribbon diagram of APE1. PDB = 1de9.^[1]

Apurinic/apyrimidinic (AP) endonuclease (BRENDA = 4.2.99.18) is an enzyme that is involved in the DNA base excision repair pathway (BER). Its main role in the repair of damaged or mismatched nucleotides in DNA is to create a nick in the phosphodiester backbone of the AP site created when DNA glycosylase removes the damaged base. There are four types of AP endonucleases that have been classified according to their sites of incision. Class I and class II AP endonucleases incise DNA at the phosphate groups 3´ and 5´ to the baseless site leaving 3´-OH and 5´-phosphate termini. Class III and class IV AP endonucleases also cleave DNA at the phosphate groups 3´ and 5´to the baseless site, but they generate a 3´-phosphate and a 5´-OH.^[2] Human AP Endonuclease (APE1), like most AP endonucleases, is of class II and requires an Mg²⁺ in its active site in order to carry out its role in base excision repair. The yeast homolog of this enzyme is APN1.^[3]

Structure of APE1

Positive residues on the surface of the APE1 protein (in blue) anchor and bend DNA though interactions with DNA's negative phosphate groups. PDB 1de9.^[1]

Hydrogen bonding among key amino acid residues help stabilize active site structure. Moreover, a negatively charged residue (Glue 96) helps hold the Mg2+ also needed to stabilize the AP site in place PDB 1de9^[1]..

APE1 contains several amino acid residues that enable it to react selectively with AP sites. Three APE1 residues (Arg73, Ala74, and Lys78) contact three consecutive DNA phosphates on the strand opposite the one containing the AP site while Tyr128 and Gly127 span and widen the minor groove, anchoring the DNA for the extreme kinking caused by the interaction between positive residues found in four loops and one α-helix and the negative phosphate groups found in the phosphodiester backbone of DNA.

This extreme kinking forces the baseless portion of DNA into APE1’s active site. This active site is bordered by Phe266, Trp280, and Leu282, which pack tightly with the hydrophobic side of the AP site, discriminating against sites that do have bases. The AP site is then further stabilized through hydrogen bonding of the phosphate group 5´ to the AP site with Asn174, Asn212, His309, and the Mg²⁺ ion while its orphan base partner is stabilized through hydrogen bonding with Met270. The phosphate group 3' to the AP site is stabilized through hydrogen bonding to Arg177. Meanwhile, an Asp210 in the active site, which is made more reactive due to the increase in its pK_a (or the negative log of acid dissociation constant) caused through its stabilization through its hydrogen bonding between Asn68 and Asn212, activates the nucleophile that attacks and cleaves the phosphodiester backbone and probably results in the observed maximal APE1 activity at a pH of 7.5.^[1]

Mechanism

The APE1 enzyme creates a nick in the phosphodiester backbone at a abasic(baseless) site through a simple acyl substitution mechanism. First, the Asp210 residue in the active site deprotonates a water molecule, which can then perform a nucleophilic attack on the phosphate group located 5´ to the AP site. Next, electrons from one of the oxygen atom in the phosphate group moves down, kicking off one of the other oxygen to create a free 5´ phosphate group on the AP site and a free 3´-OH on the normal nucleotide, both of which are stabilized by the Mg²⁺ ion.^[1]

Inhibition of APE1

Lucanthone

Known inhibitors of APE1 include 7-nitroindole-2-carboxylic acid (NCA) and lucanthone.^[4] Both of these structures possess rings attached to short chains, which appear similar to the deoxyribose sugar ring without a base attached and phosphodiester bond in DNA. Both also contain lots of H-bond acceptors which may interact with the H-bond donors in the active site of APE1, causing these inhibitors to stick in the active site and preventing the enzyme from catalyzing other reactions.

APE1 as Chemopreventive Target

Because APE1 performs an essential function in DNA base-excision repair pathway, it has become a target for researchers looking for means to prevent cancer cells from surviving chemotherapy. Not only is APE1 needed in and of itself to create the nick in the DNA backbone so that the enzymes involved later in the BER pathway can recognize the AP-site, it also has a redox function that helps activate other enzymes involved in DNA repair. As such, knocking down APE1 could lead to tumor cell sensitivity, thus preventing cancer cells from persisting after chemotherapy.^[5]

External links

Basic Definition
AP endonucleases family 1 in PROSITE
AP endonucleases family 2 in PROSITE
Application in Long Patch Base Excision Repair
Purification and characterization of an apurinic/apyrimidinic endonuclease from HeLa cells

References

Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081).^[6]

^ ^a ^b ^c ^d ^e Clifford D. Mol, Tahide Izumi, Sankar Mitra, and John A. Tainer (2000). "DNA-bound structures and mutants reveal abasic DNA binding by APE1 DNA repair and coordination". Nature 403 (6768): 451–456. doi:10.1038/35000249. PMID 10667800.
^ Gary M. Myles and Aziz Sancar (1989). "DNA Repair". Chemical Research in Toxicology 2 (4): 197–226. doi:10.1021/tx00010a001. PMID 2519777.
^ George W. Teebor, Dina R. Marensein, and David M. Wilson III (2004). "Human AP endonuclease (APE1) demonstrates endonucleolytic activity against AP sites in single-stranded DNA". DNA Repair 3 (5): 527–533. doi:10.1016/j.dnarep.2004.01.010. PMID 15084314.
^ Mark R. Kelley and Melissa L. Fishel (2007). "The DNA base excision repair protein Ape1/Ref-1 as a Therapeutic and chemopreventive target". Molecular Aspects of Medicine 28 (3-4): 375–395. doi:10.1016/j.mam.2007.04.005. PMID 17560642.
^ Mark R. Kelley, Meihua Luo, Sarah Delaphlane, Aihua Jiang, April Reed, Ying He, Melissa Fishel, Rodney L. Nyland II, Richard F. Broch, Xizoxi Qiao, Millie M. Georgiadis (2008). "Role of the Multifunctional DNA Repair and Redox Signaling Protein Ape1/Ref-1 in Cancer and Endothelial Cells: Small-Molecule Inhibition of the Redox Function of Ape1". Antioxidants & Redox Signaling 10: 1–12.
^ E.F. Pettersen, T.D. Goddard, C.C. Huang, G.S. Couch, D.M. Greenblat, E.C. Meng, and T.E. Ferrin (2004). "UCSF Chimera - A Visualization System for Exploratory Research and Analysis". J. Comput. Chem. 25 12: 1605–1612.

UpToDate Contents

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English Journal

Association between genetic variants of DNA repair genes and coronary artery disease.

Gokkusu C, Cakmakoglu B, Dasdemir S, Tulubas F, Elitok A, Tamer S, Seckin S, Umman B.Source1 Department of Biochemistry, Istanbul University , Istanbul, Turkey .
Genetic testing and molecular biomarkers.Genet Test Mol Biomarkers.2013 Apr;17(4):307-13. doi: 10.1089/gtmb.2012.0383. Epub 2013 Jan 31.
Polymorphisms in DNA repair genes may be associated with differences in the repair efficiency of DNA damage and may influence an individual's risk of atherosclerosis. Genetic research on coronary artery disease (CAD) has traditionally focused on investigation aimed at identifying disease-susceptibil
PMID 23368530

Apurinic/Apyrimidinic Endonuclease 1 Is the Essential Nuclease during Immunoglobulin Class Switch Recombination.

Masani S, Han L, Yu K.SourceDepartment of Microbiology and Molecular Genetics, Michigan State University, East Lansing, Michigan, USA.
Molecular and cellular biology.Mol Cell Biol.2013 Apr;33(7):1468-73. doi: 10.1128/MCB.00026-13. Epub 2013 Feb 4.
Immunoglobulin (Ig) class switch recombination (CSR) is initiated by activation-induced cytidine deaminase (AID) that catalyzes numerous DNA cytosine deaminations within switch regions. The resulting uracils are processed by uracil base excision and/or mismatch repair enzymes that ultimately generat
PMID 23382073

Conserved Structural Chemistry for Incision Activity in Structurally Non-homologous Apurinic/Apyrimidinic Endonuclease APE1 and Endonuclease IV DNA Repair Enzymes.

Tsutakawa SE, Shin DS, Mol CD, Izumi T, Arvai AS, Mantha AK, Szczesny B, Ivanov IN, Hosfield DJ, Maiti B, Pique ME, Frankel KA, Hitomi K, Cunningham RP, Mitra S, Tainer JA.SourceFrom the Lawrence Berkeley National Laboratory, Berkeley, California 94720.
The Journal of biological chemistry.J Biol Chem.2013 Mar 22;288(12):8445-55. doi: 10.1074/jbc.M112.422774. Epub 2013 Jan 25.
Non-coding apurinic/apyrimidinic (AP) sites in DNA form spontaneously and as DNA base excision repair intermediates are the most common toxic and mutagenic in vivo DNA lesion. For repair, AP sites must be processed by 5' AP endonucleases in initial stages of base repair. Human APE1 and bacterial Nfo
PMID 23355472

Japanese Journal

P-078 高度好熱菌Thermus thermophilus crtBレポーターベクターを用いたAP endonucleaseの発現様式解析(ポスターセッション)

相原玲子,平澤佑啓,平津圭一郎,布柴達男
日本環境変異原学会大会プログラム・要旨集 (42), 113, 2013-10-30
NAID 110009732491

活性酸素種生成に関与するシトクロームP450の病態生理学的役割

嶋本典夫
薬学雑誌. 乙号 133(4), 435-450, 2013
… Increased ROS activates ERK and AP-1 by inhibition of tyrosine phosphatase, and inhibits BimEL degradation by proteasome. … These results in the accumulation of mitochondrial BimEL, which then induces the release of cytochrome c and endonuclease G (EndoG). …
NAID 130003361937

Structural and functional properties of CiNTH, an endonuclease Ⅲ homologue of the ascidian Ciona intestinalis : critical role of N-terminal region

, , [他], , ,
Genes & genetic systems 87(2), 115-124, 2012-04-25
… Endonuclease III (Nth), a major DNA glycosylase, mainly excises oxidatively damaged pyrimidines from DNA. … CiNTH was bifunctional, with DNA glycosylase and AP lyase activities. …
NAID 10030616613

Related Pictures

★リンクテーブル★

リンク元	「脱プリン脱ピリミジン部位エンドヌクレアーゼ」「AP lyase」「apurinic-apyrimidinic endonuclease」「apurinic endonuclease」
関連記事	「AP」「A」「endonuclease」