Human Alkyladenine DNA Glycosylase: Difference between revisions
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The process of recognition of damaged lesions involves initial nonspecific binding followed by diffusion along the DNA. Formed the AAG-DNA complex, it occurs a redundant process of search because of the long lifetime of this complex, while AAG search many adjacent sites in a DNA molecule in a single binding. This provides ample opportunity to recognize and excise lesions that minimally perturb the structure of the DNA.<ref>{{Cite web|url = http://deepblue.lib.umich.edu/handle/2027.42/110472|title = Specificity and Searching Mechanism of Alkyladenine DNA Glycosylase.|date = |accessdate = |website = |publisher = |last = Zhang|first = Yaru}}</ref> |
The process of recognition of damaged lesions involves initial nonspecific binding followed by diffusion along the DNA. Formed the AAG-DNA complex, it occurs a redundant process of search because of the long lifetime of this complex, while AAG search many adjacent sites in a DNA molecule in a single binding. This provides ample opportunity to recognize and excise lesions that minimally perturb the structure of the DNA.<ref>{{Cite web|url = http://deepblue.lib.umich.edu/handle/2027.42/110472|title = Specificity and Searching Mechanism of Alkyladenine DNA Glycosylase.|date = |accessdate = |website = |publisher = |last = Zhang|first = Yaru}}</ref> |
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Due to its broad specificity, the Human Alkyladenine DNA Glycosylase (AAG) perfoms the substrate selection through a combination of selectivity filters. <ref>Hedglin, Mark; O'Brien, Patrick J. (2008) "Human Alkyladenine DNA Glycosylase employs a processive search for dNA damage". ''Biochemistry'' 47: 11434-11445.</ref> |
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* The first selectivity filter occurs at the [[DNA base flipping|nucleotide flipping]] step of unsable base pairs that present lesions. |
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* The second selectivity filter is constituted by the catalytic mechanism which ensures that only purine bases are excised even though smaller pyrimidines can fit in the AAG’s [[Active site|active site]]. |
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* The third selectivity filter consist of unfavorable steric clashes that allow a preferential recognition of purine lesions lacking exocyclic amino groups of guanine and adenine. |
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==Reference== |
==Reference== |
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Revision as of 13:32, 18 October 2015
Human Alkyladenine DNA Glycosylase (also known as AAG), alternatively named 3-methyladenine DNA glycosylase, MPG or ANPG, is an specific type of DNA glycosylase enzyme. This type correspond to a family of monofunctional glycosylases involved in the recognition of a variety of base lesions, including alkylated and deaminated purines, and initiating their repair via the base excision repair pathway.[1] In addition, AAG is the only glycosylase identified to date in human cells that excises alkylation-damaged bases.
Function
It is estimated that 104 appear in a typical human cell per day. Although it seems to be an insignificant percentage considering the extension of the DNA (1010 nucleotids), DNA bases are subject to a large number of anomalies: spontaneous alkylation or oxidative deamination. These mutations lead to changes in the structure and coding potencial of the DNA, affecting processes of replication and transcription. In human cells,[2] Alkyladenine DNA Glycosylase is the enzyme responsible for recognition and repair.
Structure
Human Alkyladenine DNA Glycosylase is a monomeric protein compounded by 298 amino acids. It folds into a single domain of mixed α/β structure with seven α helices and eight β strands. The core of the protein consists of a curved, antiparallel β sheet with a protruding β hairpin (β3β4) that inserts into the minor groove of the bound DNA. A series of α helices and connecting loops form the remainder of the DNA binding interface[4]. It lacks the helix-hairpin-helix motif associated with other base excision-repair proteins and, in fact, it does not resemble any other model in the Protein Data Bank[5].
Its formula weight is 32.869 Da.
Location
In eukaryotic cells (in this case in human cells), Human Alkyladenine Glycosylase localizes to the mitochondria, nucleus and cytoplasm.
Mechanism
Human Alkyladenine DNA Glycosylase (AAG) is part of the family of enzymes that follow the BER, acting on specific substrates according to BER steps.
The process of recognition of damaged lesions involves initial nonspecific binding followed by diffusion along the DNA. Formed the AAG-DNA complex, it occurs a redundant process of search because of the long lifetime of this complex, while AAG search many adjacent sites in a DNA molecule in a single binding. This provides ample opportunity to recognize and excise lesions that minimally perturb the structure of the DNA.[6]
Due to its broad specificity, the Human Alkyladenine DNA Glycosylase (AAG) perfoms the substrate selection through a combination of selectivity filters. [7]
- The first selectivity filter occurs at the nucleotide flipping step of unsable base pairs that present lesions.
- The second selectivity filter is constituted by the catalytic mechanism which ensures that only purine bases are excised even though smaller pyrimidines can fit in the AAG’s active site.
- The third selectivity filter consist of unfavorable steric clashes that allow a preferential recognition of purine lesions lacking exocyclic amino groups of guanine and adenine.
Reference
- ^ Hedglin, Mark; O'Brien, Patrick J. (2008) "Human Alkyladenine DNA Glycosylase employs a processive search for dNA damage". Biochemistry 47: 11434-11445.
- ^ O'Brie, Patrick J.; Ellenberger, Tom. "Human Alkyladenine DNA Glycosylase Uses Acid−Base Catalysis for Selective Excision of Damaged Purines †". Biochemistry. 42 (42): 12418–12429. doi:10.1021/bi035177v.
- ^ Hollis, Thomas; Lau, Albert; Ellenberger, Tom (2000-08-30). "Structural studies of human alkyladenine glycosylase and E. coli 3-methyladenine glycosylase". Mutation Research/DNA Repair. 460 (3–4): 201–210. doi:10.1016/S0921-8777(00)00027-6.
- ^ Lau, Albert Y.; Schärer, Orlando D.; Samson, Leona; Verdine, Gregory L.; Ellenberger, Tom. "Crystal Structure of a Human Alkylbase-DNA Repair Enzyme Complexed to DNA". Cell. 95 (2): 249–258. doi:10.1016/S0092-8674(00)81755-9. ISSN 0092-8674. PMID 9790531.
- ^ Hollis, Thomas; Lau, Albert; Ellenberger, Tom (2000-08-30). "Structural studies of human alkyladenine glycosylase and E. coli 3-methyladenine glycosylase". Mutation Research/DNA Repair. 460 (3–4): 201–210. doi:10.1016/S0921-8777(00)00027-6.
- ^ Zhang, Yaru. "Specificity and Searching Mechanism of Alkyladenine DNA Glycosylase".
- ^ Hedglin, Mark; O'Brien, Patrick J. (2008) "Human Alkyladenine DNA Glycosylase employs a processive search for dNA damage". Biochemistry 47: 11434-11445.