topoisomerase I

ト・イソメラーゼI

関

DNA topoisomerase、DNA topoisomerase I、type I DNA topoisomerase

WordNet

1. the 9th letter of the Roman alphabet (同)i

PrepTutorEJDIC

1. 『私は』私が
2. iodineの化学記号

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/10/02 10:31:05」(JST)

wiki en

[Wiki en表示]

VirDNA-topo-I_N
amino terminal 9kda domain of vaccinia virus dna topoisomerase i residues 1-77, experimental electron density for residues 1-77
Identifiers
Symbol	VirDNA-topo-I_N
Pfam	PF09266
InterPro	IPR015346
SCOP	1vcc
SUPERFAMILY	1vcc
Available protein structures: Pfam structures PDB RCSB PDB; PDBe PDBsum structure summary

Type I topoisomerases cut one strand of double-stranded DNA, relax the strand, and reanneal the strands. They are further subdivided into two structurally and mechanistically distinct topoisomerases: type IA and type IB.

• Type IA topoisomerases change the linking number of a circular DNA strand by units of strictly 1.
• Type IB topoisomerases change the linking number by multiples of 1 (n).

Historically, type IA topoisomerases are referred to as prokaryotic topo I, while type IB topoisomerases are referred to as eukaryotic topoisomerase. This distinction, however, no longer applies as type IA and type IB topoisomerases exist in all domains of life.

Functionally, these subclasses perform very specialized functions. Prokaryotic topoisomerase I (topo IA) can only relax negative supercoiled DNA, whereas eukaryotic topoisomerase I (topo IB) can introduce positive supercoils, decatenate single-stranded DNA, and relax DNA.

Function

These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis.

Structure

This domain assumes a beta(2)-alpha-beta-alpha-beta(2) fold, with a left-handed crossover between strands beta2 and beta3. It has a four criss-crossed beta-strands surrounded by four alpha-helices that are arranged in a Rossmann fold

Mechanisms

Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA.

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks.

Classes

DNA topoisomerases are divided into two classes: type I enzymes (EC; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (EC; topoisomerases II, IV and VI) break double-strand DNA.

Type IA topoisomerses

Structure of topo III bound to single stranded DNA (pdb ID 1I7D). Note that the DNA resembles B-form DNA

Introduction
Type IA topoisomerases, historically said to be found in prokaryotes, creates a single break in DNA, and passes a second strand or duplex through the break. This strand passage mechanism shares several features with type IIA topoisomerases. They both form a 5' phosphotyrosine intermediate, and require a divalent metal ion to perform its work. Unlike type II topoisomerases, type IA topoisomerases do not use energy to do its work (with the notable exception of reverse gyrase, see below).

Structure
Type IA topoisomerases have several domains, often number Domain 1-4. Domain I contains a Toprim domain (a Rossman fold known to coordinate Magnesium ions), domain IV and domain III each consist of a helix-turn-helix (HTH) domain; the catalytic tyrosine resides on the HTH of domain III. Domain II is a flexible bridge between domains III and IV. The structure of type IA topoisomerase resembles a lock, with Domains I, III and IV lie on the bottom of the structure. The structure of topo III (see below) bound to single-stranded DNA (pdb id = 1I7D) shows how the HTH and Toprim domain are coordinated about the DNA.

Type IA topo variants
There are several variants of Type IA topoisomerases, differing by appendages attached to the main core (sometimes referred to as the "topo-fold"). Members of this subclass include topo I, topo III (which contain additional Zinc-binding motifs), and reverse gyrase. Reverse gyrase is particularly interesting because an ATPase domain, which resembles the helicase-like domain of the Rho transcription factor, is attached (the structure of reverse gyrase was solved by Rodriguez and Stock, EMBO J 2002). The enzyme uses the hydrolysis of ATP to introduce positive supercoils and overwinds DNA, a feature attractive in hyperthermophiles, in which reverse gyrase is known to exist. Rodriguez and Stock have done further work to identify a "latch" that is involved in communicating the hydroylsis of ATP to the introduction of positive supercoils.

The topo III variant is likewise very interesting because it has zinc-binding motifs that is thought to bind single-stranded DNA. Topo III has been identified to be associated with the BLM (for Bloom Syndrome) helicase during recombination.

Mechanism
Type IA topoisomerases operate through a strand-passage mechanism, using a single gate (in contrast with type II topoisomerases). First, the single-stranded DNA binds domain III and I. The catalytic tyrosine cleaves the DNA backbone, creating a transient 5' phosphotyrosine intermediate. The break is then separated, using domain II as a hinge, and a second duplex or strand of DNA is passed through. Domain III and I close and the DNA is re-annealed.

Type IB topoisomerases

Introduction
In contrast to type IA topoisomerases, type 1B Topoisomerase solves the problem of overwound and underwound (also referred to as positively or negatively supercoiled) DNA through a hindered rotary mechanism. Crystal structures, biochemistry, and single molecule experiments have contributed to a general mechanism. The enzyme first wraps around DNA and creates a single, 3' phosphotyrosine intermediate. The 5' end is then free to rotate, twisting it about the other strand, to relax DNA until the topoisomerase religates the broken strands.

Structure
The structure of topo IB bound to DNA has been solved (pdb id = 1A36). Topo IB is composed of an NTD, a capping lobe, a catalytic lobe, and a C-terminal domain. The capping lobe and catalytic lobe wrap around the DNA.

Mechanism
Relaxation is not an active process in the sense that energy (in the form of ATP) is not spent during the nicking or ligation steps; this is because the reaction between the tyrosine residue at the active site of the enzyme with the phosphodiester DNA backbone simply replaces one phosphomonoester bond with another. The topoisomerase also does not use ATP during uncoiling of the DNA; rather, the torque present in the DNA drives the uncoiling and proceeds on average energetically downhill. Recent single molecule experiments have confirmed what bulk-plasmid relaxation experiments have proposed earlier, which is that uncoiling of the DNA is torque-driven and proceeds until religation occurs. No data suggest that Topo IB "controls" the swiveling insofar as that it has a mechanism in place that triggers religation after a specific number of supercoils removed. On the contrary, single-molecule experiments suggest that religation is a random process and has some probability of occurring each time the swiveling 5'-OH end comes in close proximity with the attachment site of the enzyme-linked 3'-end.

Type IB topoisomerases were originally identified in eukaryotes and in viruses. Viral topo I is unique because it binds DNA in a sequence-specific manner.

Important active site residues of Topoisomerase IB. DNA is colored raspberry.

Active site of Topoisomerase IB. DNA is colored raspberry with a light-blue backbone. (PDB ID = 1A36)

Type IC topoisomerases

A third type of topoisomerase I was identified, topo V, in the archaeon Methanopyrus kandleri. Topo V is the founding member, and so far the only member, of the type IC topoisomerase, although some authors suggest it may have viral origins. The crystal structure of topo V was solved. Type IC topoisomerases work through a controlled rotary mechanism, much like type IB topoisomerases (pdb ID = 2CSB and 2CSD), but the fold is unique.

Intermediates

All topoisomerases form a phosphotyrosine intermediate between the catalytic tyrosine of the enzyme and the scissile phosphoryl of the DNA backbone.

• Type IA topoisomerases form a covalent linkage between the catalytic tyrosine and the 5'-phosphoryl.
• Type IB enzymes form a covalent 3'-phosphotyrosine intermediate.
• Type 1C topoisomerases form a covalent 3'-phosphotyrosine intermediate.

This intermediate is isoenergetic, meaning that the forward cleavage reaction and the backward religation reaction are both energetically equal. As such, no outside energy source is necessary to conduct this reaction.

Inhibition

As topoisomerases generate breaks in DNA, they are targets of small-molecule inhibitors that inhibit the enzyme. Type 1 topoisomerase is inhibited by irinotecan, topotecan and camptothecin.

Autoantibodies

Main article: Anti-Scl-70 antibodies

Autoantibodies targeted against type I topoisomerase are called anti-Scl-70 antibodies, named by the association with scleroderma and the 70 kD extractable immunoreactive fragment that can be obtained from the otherwise larger (100-105 kD) target topoisomerase antigen (called the SCL-70 Antigen) of the antibodies.

References

External links

• DNA+Topoisomerases,+Type+I at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 強皮症の概要および分類 overview and classification of scleroderma disorders
• 2. 乳癌におけるHER2と治療の効果予測 her2 and predicting response to therapy in breast cancer
• 3. 急性骨髄性白血病における細胞遺伝学 cytogenetics in acute myeloid leukemia
• 4. 全身性硬化症（強皮症）の危険因子および考えられる原因 risk factors for and possible causes of systemic sclerosis scleroderma
• 5. 様々な抗核抗体 miscellaneous antinuclear antibodies

English Journal

• Zinc (II) complex with a cationic Schiff base ligand: Synthesis, characterization, and biological studies.

• Lee SK1, Tan KW2, Ng SW3, Ooi KK4, Ang KP4, Abdah MA4.Author information 1Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia.2Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia. Electronic address: kongwai@um.edu.my.3Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia; Chemistry Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah, Saudi Arabia.4Department of Biomedical Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia.AbstractA cationic Schiff base ligand, TSB (L) and its Zn (II) complex (1) were synthesized and characterized by using CHN, (1)H-NMR, FT-IR, UV, LC-MS, and X-ray methods. Their ability to inhibit topoisomerase I, DNA cleavage activities, and cytotoxicity were studied. X-ray diffraction study shows that the mononuclear complex 1 is four coordinated with distorted tetrahedral geometry. The singly deprotonated Schiff base ligand L acts as a bidentate ON-donor ligand. Complexation of L increases the inhibitory strength on topoisomerase I activity. Complex 1 could fully inhibit topoisomerase I activity at 250μM, while L did not show any inhibitory effect on topoisomerase I activity. In addition, L and complex 1 could cleave pBR322 DNA in a concentration and time dependent profile. Surprisingly, L has better DNA cleavage activity than complex 1. The cleavage of DNA by complex 1 is altered in the presence of hydrogen peroxide. Furthermore, L and complex 1 are mildly cytotoxic towards human ovarian cancer A2780 and hepatocellular carcinoma HepG2.
• Spectrochimica acta. Part A, Molecular and biomolecular spectroscopy.Spectrochim Acta A Mol Biomol Spectrosc.2014 Mar 5;121:101-8. doi: 10.1016/j.saa.2013.10.084. Epub 2013 Oct 28.
• A cationic Schiff base ligand, TSB (L) and its Zn (II) complex (1) were synthesized and characterized by using CHN, (1)H-NMR, FT-IR, UV, LC-MS, and X-ray methods. Their ability to inhibit topoisomerase I, DNA cleavage activities, and cytotoxicity were studied. X-ray diffraction study shows that the
• PMID 24231745

• A3.5 Toll like receptors: a crossroad in scleroderma etiopathogenesis.

• Chighizola C1, Raschi E, Cesana L, Uceda S, Borghi M, Meroni P.Author information 1University of Milan, Milan, Italy.AbstractBACKGROUND AND OBJECTIVE: Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by excessive deposition of extracellular matrix (ECM) components, immune activation and neoangiogenesis. The pathogenesis of scleroderma is still poorly elucidated; however, an increasing burden of evidence suggests involvement of Toll-like Receptors (TLRs). In our working hypothesis, nucleic acid-containing immune complexes (ICs) isolated from scleroderma patients bearing different autoantibody antigenic specificities might activate TLRs, thus inducing several mediators involved in SSc pathogenesis. Therefore, the aim of this study was to characterise the role of TLR3 and TLR9 as potential mediators in the initiator phase of scleroderma.
• Annals of the rheumatic diseases.Ann Rheum Dis.2014 Mar 1;73 Suppl 1:A43-4. doi: 10.1136/annrheumdis-2013-205124.99.
• BACKGROUND AND OBJECTIVE: Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by excessive deposition of extracellular matrix (ECM) components, immune activation and neoangiogenesis. The pathogenesis of scleroderma is still poorly elucidated; however, an increasing burden of evide
• PMID 24489221

• p-Terphenyl O-β-glucuronides, DNA topoisomerase inhibitors from Streptomyces sp. LZ35ΔgdmAI.

• Deng J1, Lu C1, Li S1, Hao H1, Li Z1, Zhu J2, Li Y1, Shen Y3.Author information 1Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China.2School of Life Sciences, Shandong University, No. 27 South Shanda Road, Jinan, Shandong 250100, PR China.3Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong 250012, PR China; School of Life Sciences, Shandong University, No. 27 South Shanda Road, Jinan, Shandong 250100, PR China. Electronic address: yshen@sdu.edu.cn.AbstractThe analysis of genome sequence indicated that Streptomyces sp. LZ35 has the potential of producing many types of secondary metabolites, including p-terphenyls and geldanamycins. The fermentation of LZ35 in laboratory produces geldanamycins as the major components, which hampers the isolation of minor compounds. To clean the background of geldanamycins, the mutant strain LZ35ΔgdmAI of Streptomyces sp. LZ35 was constructed by disrupting the first PKS module of geldanamycin gene cluster (gdm). From this mutant, five novel p-terphenyls bearing glucuronic acid moiety, namely echosides A-E (1-5), were isolated with the aid of chromophore-guided fractionation. The structures of 1-5 were elucidated by the analysis of their HR-ESI-MS and NMR spectroscopic data. DNA relaxation assay indicated that compound 1 had evident inhibitory activity against topoisomerase I. Moreover, the inhibitory activity of compound 3 against topoisomerase IIα is approximately equal to VP16, indicating that p-terphenyl O-β-glucuronides are promising leads for the development of novel inhibitors of topoisomerases.
• Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2014 Mar 1;24(5):1362-5. doi: 10.1016/j.bmcl.2014.01.037. Epub 2014 Jan 25.
• The analysis of genome sequence indicated that Streptomyces sp. LZ35 has the potential of producing many types of secondary metabolites, including p-terphenyls and geldanamycins. The fermentation of LZ35 in laboratory produces geldanamycins as the major components, which hampers the isolation of min
• PMID 24507923

Japanese Journal

• Suppressive effect of topoisomerase inhibitors on JC polyomavirus propagation in human neuroblastoma cells

• Microbiology and immunology 60(4), 253-260, 2016-04
• NAID 40020808909

• DNA-binding activity of rat DNA topoisomerase Ⅱ α C-terminal domain contributes to efficient DNA catenation in vitro

• The journal of biochemistry 159(3), 363-369, 2016-03
• NAID 40020763503

• Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability

• Nature Communications 7, 2016-02-04
• NAID 120005745627

Related Pictures

---

★リンクテーブル★

リンク元	「type I DNA topoisomerase」「トポイソメラーゼI」「DNA topoisomerase」
拡張検索	「DNA topoisomerase I」「DNA topoisomerase II」「anti-topoisomerase I antibody」
関連記事	「I」「Id」

「type I DNA topoisomerase」

　　[★]

I型DNAト・イソメラーゼ、DNAト・イソメラーゼI

関

DNA topoisomerase、DNA topoisomerase I、topoisomerase I

「トポイソメラーゼI」

　　[★]

英

topoisomerase I

関

DNAト・イソメラーゼ、I型DNAト・イソメラーゼ、DNAト・イソメラーゼI

「DNA topoisomerase」

　　[★] DNAトポイソメラーゼ

関

DNA topoisomerase I、topoisomerase I、type I DNA topoisomerase

「DNA topoisomerase I」

　　[★]

DNAト・イソメラーゼI

関

DNA topoisomerase、topoisomerase I、type I DNA topoisomerase

「DNA topoisomerase II」

　　[★]

DNAト・イソメラーゼII

関

topoisomerase II、type II DNA topoisomerase

「anti-topoisomerase I antibody」

　　[★] 抗トポイソメラーゼI抗体

「I」

　　[★]

• イソロイシン isoleucine
• イノシン inosine
• 阻害剤 inhibitor
• iodine
• ヨード iodide
• I因子 factor I

　 　 　

「Id」

　　[★]

• イディオタイプ idiotype idiotypic
• inhibitor of DNA binding