NDLI: AlkB Dioxygenase Preferentially Repairs Protonated Substrates SPECIFICITY AGAINST EXOCYCLIC ADDUCTS AND MOLECULAR MECHANISM OF ACTION

Content Provider	Journal of Biological Chemistry (JBC)
Author	Maciejewska, Agnieszka M. Poznański, Jarosław Kaczmarska, Zuzanna Krowisz, Beata Nieminuszczy, Jadwiga Polkowska-Nowakowska, Agnieszka Grzesiuk, Elżbieta Kuśmierek, Jarosław T.
Abstract	Efficient repair by Escherichia coli AlkB dioxygenase of exocyclic DNA adducts 3,N4-ethenocytosine, 1,N6-ethenoadenine, 3,N4-α-hydroxyethanocytosine, and reported here for the first time 3,N4-α-hydroxypropanocytosine requires higher Fe(II) concentration than the reference 3-methylcytosine. The pH optimum for the repair follows the order of pKa values for protonation of the adduct, suggesting that positively charged substrates favorably interact with the negatively charged carboxylic group of Asp-135 side chain in the enzyme active center. This interaction is supported by molecular modeling, indicating that 1,N6-ethenoadenine and 3,N4-ethenocytosine are bound to AlkB more favorably in their protonated cationic forms. An analysis of the pattern of intermolecular interactions that stabilize the location of the ligand points to a role of Asp-135 in recognition of the adduct in its protonated form. Moreover, ab initio calculations also underline the role of substrate protonation in lowering the free energy barrier of the transition state of epoxidation of the etheno adducts studied. The observed time courses of repair of mixtures of stereoisomers of 3,N4-α-hydroxyethanocytosine or 3,N4-α-hydroxypropanocytosine are unequivocally two-exponential curves, indicating that the respective isomers are repaired by AlkB with different efficiencies. Molecular modeling of these adducts bound by AlkB allowed evaluation of the participation of their possible conformational states in the enzymatic reaction.
Related Links	http://www.jbc.org/content/288/1/432.abstract
Ending Page	441
Starting Page	432
Page Count	10
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	1
Volume Number	288
DOI	10.1074/jbc.M112.353342
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2013-01-04
Access Restriction	Open
Subject Keyword	DNA Enzymes DNA Repair Docking Enzyme Mechanisms Ligand-binding Protein Molecular Modeling AlkB Dioxygenase Etheno Adducts to DNA Bases Exocyclic Adducts to DNA Bases DNA and Chromosomes
Alternative Title	AlkB Dioxygenase Preferentially Repairs Protonated Substrates
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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