Publications by authors named "Amie R Michie"

2 Publications

  • Page 1 of 1

The acute myeloid leukemia variant DNMT3A Arg882His is a DNMT3B-like enzyme.

Nucleic Acids Res 2020 04;48(7):3761-3775

Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.

We have previously shown that the highly prevalent acute myeloid leukemia (AML) mutation, Arg882His, in DNMT3A disrupts its cooperative mechanism and leads to reduced enzymatic activity, thus explaining the genomic hypomethylation in AML cells. However, the underlying cause of the oncogenic effect of Arg882His in DNMT3A is not fully understood. Here, we discovered that DNMT3A WT enzyme under conditions that favor non-cooperative kinetic mechanism as well as DNMT3A Arg882His variant acquire CpG flanking sequence preference akin to that of DNMT3B, which is non-cooperative. We tested if DNMT3A Arg882His could preferably methylate DNMT3B-specific target sites in vivo. Rescue experiments in Dnmt3a/3b double knockout mouse embryonic stem cells show that the corresponding Arg878His mutation in mouse DNMT3A severely impairs its ability to methylate major satellite DNA, a DNMT3A-preferred target, but has no overt effect on the ability to methylate minor satellite DNA, a DNMT3B-preferred target. We also observed a previously unappreciated CpG flanking sequence bias in major and minor satellite repeats that is consistent with DNMT3A and DNMT3B specificity suggesting that DNA methylation patterns are guided by the sequence preference of these enzymes. We speculate that aberrant methylation of DNMT3B target sites could contribute to the oncogenic potential of DNMT3A AML variant.
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http://dx.doi.org/10.1093/nar/gkaa139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144950PMC
April 2020

Lipophilic efficient phenylthiazoles with potent undecaprenyl pyrophosphatase inhibitory activity.

Eur J Med Chem 2019 Aug 27;175:49-62. Epub 2019 Apr 27.

Department of Pharmaceutical Organic Chemistry, College of Pharmacy, Al-Azhar University, Cairo, 11884, Egypt; University of Science and Technology, Nanoscience Program, Zewail City of Science and Technology, October Gardens, 6th of October, Giza, 12578, Egypt. Electronic address:

Antibiotic resistance remains a pressing medical challenge for which novel antibacterial agents are urgently needed. The phenylthiazole scaffold represents a promising platform to develop novel antibacterial agents for drug-resistant infections. However, enhancing the physicochemical profile of this class of compounds remains a challenging endeavor to address to successfully translate these molecules into novel antibacterial agents in the clinic. We extended our understanding of the SAR of the phenylthiazoles' lipophilic moiety by exploring its ability to accommodate a hydrophilic group or a smaller sized hetero-ring with the objective of enhancing the physicochemical properties of this class of novel antimicrobials. Overall, the 2-thienyl derivative 20 and the hydroxyl-containing derivative 31 emerged as the most promising antibacterial agents inhibiting growth of drug-resistant Staphylococcus aureus at a concentration as low as 1 μg/mL. Remarkably, compound 20 suppressed bacterial undecaprenyl pyrophosphatase (UppP), the molecular target of the phenylthiazole compounds, in a sub nano-molar concentration range (almost 20,000 times more potent than the lead compounds 1a and 1b). Compound 31 possessed the most balanced antibacterial and physicochemical profile. The compound exhibited rapid bactericidal activity against S. aureus, and successfully cleared intracellular S. aureus within infected macrophages. Furthermore, insertion of the hydroxyl group enhanced the aqueous solubility of 31 by more than 50-fold relative to the first-generation lead 1c.
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http://dx.doi.org/10.1016/j.ejmech.2019.04.063DOI Listing
August 2019