Sandbox GGC15: Difference between revisions
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== Structure == | == Structure == | ||
'''Human topo 1 is composed of 765 amino acids <ref name="Redinbo" />. The enzyme consist of 4 regions which are the NH2-terminal, core, linker, and COOH-terminal domains<ref name="Redinbo" />. The NH2-terminal is approximately 210 residues long, it is highly charged, disordered, and contains few hydrophobic amino acids<ref name="Redinbo" />. The COOH-terminal domain is made up of residues 713 to 765 and contains the important amino aside Tyrosine | '''Human topo 1 is composed of 765 amino acids <ref name="Redinbo" />. The enzyme consist of 4 regions which are the NH2-terminal, core, linker, and COOH-terminal domains<ref name="Redinbo" />. The NH2-terminal is approximately 210 residues long, it is highly charged, disordered, and contains few hydrophobic amino acids<ref name="Redinbo" />. The <scene name='78/781215/04_27_structure_cooh/1'>COOH-terminal</scene> domain is made up of residues 713 to 765 and contains the important amino aside Tyrosine 723<ref name="Redinbo"/>. The location of the active site is at this amino acid<ref name="Redinbo" />. Residues 636 to 712[Turquoise Color] form the linker domain and they contribute to the enzyme catalytic activity but are not required<ref name="Redinbo" />. The core and the COOH-terminal domain are very important for the catalytic activity<ref name="Redinbo" />.''' | ||
== Active Site == | == Active Site == | ||
Revision as of 03:26, 28 April 2021
DNA TOPOISOMERASE IDNA TOPOISOMERASE I
Eukaryotic DNA topoisomerase I (topo I) is a protein that reduces the strain from the supercoils that are caused during transcription and translation[1]. There are two types of topoisomerases. Type 1 topoisomerases are monomeric and break one strand of DNA[2]. Type 2 topoisomerases are dimeric, meaning that they made up of two units and break both strands of the DNA helix[2]. They are able to pass another part of the duplex through the cut, and close the cut using ATP[1].
StructureHuman topo 1 is composed of 765 amino acids [2]. The enzyme consist of 4 regions which are the NH2-terminal, core, linker, and COOH-terminal domains[2]. The NH2-terminal is approximately 210 residues long, it is highly charged, disordered, and contains few hydrophobic amino acids[2]. The domain is made up of residues 713 to 765 and contains the important amino aside Tyrosine 723[2]. The location of the active site is at this amino acid[2]. Residues 636 to 712[Turquoise Color] form the linker domain and they contribute to the enzyme catalytic activity but are not required[2]. The core and the COOH-terminal domain are very important for the catalytic activity[2]. Active SiteTopo 1 reduces stress in DNA by causing a transient single strand nick in the the DNA helix[1]. This nick enables the cut to rotate around its intact complement, thus eliminating proximal supercoils[1].
The active site of Topo 1 is catalytic and it is the location where the nicking or cutting occurs[2]. The nicking occurs from the trans-esterification of Tyr-723 at a DNA phophodiester bond forming a 3'-phosphotyrosine covalent enzyme–DNA complex [1]. After the DNA is relaxed, the covalent intermediate is reversed when the released 5'-OH of the broken strand reattacks the phosphotyrosine intermediate in a second transesterification reaction[1].
RelevanceMany anticancer drugs target topo 1 enzymes. This enzyme is the target of camptothecin (CPT) family of anticancer drugs[2]. These drugs work by increasing the duration of the nicked intermediate in the topo I reaction [2]. The stabilized intermediates prevent transcription and replication to continue in the cancer cells[2]. This eventually leads to DNA damage and cell death[2]. MutationsA mutation at amino acid 532 to Alanine almost abolishes enzyme activity[5]. The location of Lys 532 to the scissile phosphate and other active site amino acids could be the reason why a mutation of this amino acid abolishes the enzyme activity[5].
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ReferencesReferences
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L. The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15387-92. Epub 2002 Nov 8. PMID:12426403 doi:10.1073/pnas.242259599
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WG. Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science. 1998 Mar 6;279(5356):1504-13. PMID:9488644
- ↑ D'yakonov, V. A., Dzhemileva, L. U., & Dzhemilev, U. M. (2017). Advances in the Chemistry of Natural and Semisynthetic Topoisomerase I/II Inhibitors. Studies in Natural Products Chemistry, 21–86. https://doi.org/10.1016/b978-0-444-63929-5.00002-4
- ↑ Stewart, L. (1998). A Model for the Mechanism of Human Topoisomerase I. Science, 279(5356), 1534–1541. https://doi.org/10.1126/science.279.5356.1534
- ↑ 5.0 5.1 Interthal H, Quigley PM, Hol WG, Champoux JJ. The role of lysine 532 in the catalytic mechanism of human topoisomerase I. J Biol Chem. 2004 Jan 23;279(4):2984-92. Epub 2003 Oct 31. PMID:14594810 doi:10.1074/jbc.M309959200