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Toxicity and repair of DNA adducts produced by the natural product yatakemycin.
Mullins EA, Shi R, Eichman BF
(2017) Nat Chem Biol 13: 1002-1008
MeSH Terms: Biological Products, DNA Adducts, DNA Damage, DNA Repair, Drug Resistance, Bacterial, Duocarmycins, Indoles, Molecular Structure, Pyrroles
Show Abstract · Added August 26, 2019
Yatakemycin (YTM) is an extraordinarily toxic DNA alkylating agent with potent antimicrobial and antitumor properties and is the most recent addition to the CC-1065 and duocarmycin family of natural products. Though bulky DNA lesions the size of those produced by YTM are normally removed from the genome by the nucleotide-excision repair (NER) pathway, YTM adducts are also a substrate for the bacterial DNA glycosylases AlkD and YtkR2, unexpectedly implicating base-excision repair (BER) in their elimination. The reason for the extreme toxicity of these lesions and the molecular basis for the way they are eliminated by BER have been unclear. Here, we describe the structural and biochemical properties of YTM adducts that are responsible for their toxicity, and define the mechanism by which they are excised by AlkD. These findings delineate an alternative strategy for repair of bulky DNA damage and establish the cellular utility of this pathway relative to that of NER.
0 Communities
1 Members
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9 MeSH Terms
The DNA glycosylase AlkD uses a non-base-flipping mechanism to excise bulky lesions.
Mullins EA, Shi R, Parsons ZD, Yuen PK, David SS, Igarashi Y, Eichman BF
(2015) Nature 527: 254-8
MeSH Terms: Bacillus cereus, Base Pairing, Biocatalysis, Catalytic Domain, Crystallography, X-Ray, DNA Adducts, DNA Damage, DNA Glycosylases, DNA Repair, Duocarmycins, Indoles, Models, Molecular, Pyrroles
Show Abstract · Added November 10, 2015
Threats to genomic integrity arising from DNA damage are mitigated by DNA glycosylases, which initiate the base excision repair pathway by locating and excising aberrant nucleobases. How these enzymes find small modifications within the genome is a current area of intensive research. A hallmark of these and other DNA repair enzymes is their use of base flipping to sequester modified nucleotides from the DNA helix and into an active site pocket. Consequently, base flipping is generally regarded as an essential aspect of lesion recognition and a necessary precursor to base excision. Here we present the first, to our knowledge, DNA glycosylase mechanism that does not require base flipping for either binding or catalysis. Using the DNA glycosylase AlkD from Bacillus cereus, we crystallographically monitored excision of an alkylpurine substrate as a function of time, and reconstructed the steps along the reaction coordinate through structures representing substrate, intermediate and product complexes. Instead of directly interacting with the damaged nucleobase, AlkD recognizes aberrant base pairs through interactions with the phosphoribose backbone, while the lesion remains stacked in the DNA duplex. Quantum mechanical calculations revealed that these contacts include catalytic charge-dipole and CH-π interactions that preferentially stabilize the transition state. We show in vitro and in vivo how this unique means of recognition and catalysis enables AlkD to repair large adducts formed by yatakemycin, a member of the duocarmycin family of antimicrobial natural products exploited in bacterial warfare and chemotherapeutic trials. Bulky adducts of this or any type are not excised by DNA glycosylases that use a traditional base-flipping mechanism. Hence, these findings represent a new model for DNA repair and provide insights into catalysis of base excision.
1 Communities
1 Members
0 Resources
13 MeSH Terms
The structural basis for in situ activation of DNA alkylation by duocarmycin SA.
Smith JA, Bifulco G, Case DA, Boger DL, Gomez-Paloma L, Chazin WJ
(2000) J Mol Biol 300: 1195-204
MeSH Terms: Alkylating Agents, Alkylation, Antibiotics, Antineoplastic, Base Sequence, Binding Sites, DNA Adducts, Duocarmycins, Indoles, Kinetics, Models, Molecular, Molecular Conformation, Nuclear Magnetic Resonance, Biomolecular, Oligodeoxyribonucleotides, Pyrroles, Stereoisomerism, Structure-Activity Relationship, Thermodynamics
Show Abstract · Added December 10, 2013
Duocarmycin SA is a member of a growing class of interesting lead compounds for chemotherapy, distinguished by the manner in which they bind to and react with DNA substrates. The first three-dimensional structure of a DNA adduct of an unnatural enantiomer from this family has been determined by (1)H NMR methods. Comparison to the previously determined structure of the natural enantiomer bound in the same DNA-binding site provides unique insights into the similarities and critical distinctions producing the respective alkylation products and site selectivities. The results also support the hypothesis that the duocarmycin SA alkylation reaction is catalyzed by the binding to DNA, and provide a deeper understanding of the structural basis for this unique mode of activation.
Copyright 2000 Academic Press.
0 Communities
1 Members
0 Resources
17 MeSH Terms
High resolution solution structure of a DNA duplex alkylated by the antitumor agent duocarmycin SA.
Eis PS, Smith JA, Rydzewski JM, Case DA, Boger DL, Chazin WJ
(1997) J Mol Biol 272: 237-52
MeSH Terms: Antineoplastic Agents, Alkylating, Binding Sites, DNA, Duocarmycins, Indoles, Ligands, Magnetic Resonance Spectroscopy, Models, Molecular, Nucleic Acid Conformation, Pyrroles
Show Abstract · Added December 10, 2013
The three-dimensional solution structure of duocarmycin SA in complex with d-(G1ACTAATTGAC11).d-(G12TCATTAGTC22) has been determined by restrained molecular dynamics and relaxation matrix calculations using experimental NOE distance and torsion angle constraints derived from 1H NMR spectroscopy. The final input data consisted of a total of 858 distance and 189 dihedral angle constraints, an average of 46 constraints per residue. In the ensemble of 20 final structures, there were no distance constraint violations >0.06 A or torsion angle violations >0.8 degrees. The average pairwise root mean square deviation (RMSD) over all 20 structures for the binding site region is 0.57 A (average RMSD from the mean: 0.39 A). Although the DNA is very B-like, the sugar-phosphate backbone torsion angles beta, epsilon, and zeta are distorted from standard values in the binding site region. The structure reveals site-specific bonding of duocarmycin SA at the N3 position of adenine 19 in the AT-rich minor groove of the duplex and binding stabilization via hydrophobic interactions. Comparisons have been made to the structure of a closely related complex of duocarmycin A bound to an AT-rich DNA duplex. These results provide insights into critical aspects of the alkylation site selectivity and source of catalysis of the DNA alkylating agents, and the unusual stability of the resulting adducts.
Copyright 1997 Academic Press Limited.
0 Communities
1 Members
0 Resources
10 MeSH Terms