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Mechanism, function, and inhibition of peptide deformylase

Nguyen, Kiet T.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1110038706

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Ohio State Biochemistry Program.
Peptide deformylase (PDF) was originally thought as unique and essential only to the prokaryotes and apparently was absent from the eukaryotes. In this work, two peptide deformylase homologs from the eukaryotic Plasmodium falciparum (PfPDF) and Homo Sapiens (HsPDF) were cloned and characterized. Both proteins were found to be active and contained similar properties to the Escherichia coli peptide deformylase. Expression of the PfPDF protein was detected inside the Plasmodium cell, and potent PDF inhibitors were found to reduce cell growth. The HsPDF was fused with green fluorescence protein (GFP) and revealed mitochondrial localization. Human cell growth study was carried out and was unaffected by potent PDF inhibitors. This work provides evidence that PDF indeed exists in the eukaryotes. However, the role for deformylation in humans was apparently unnecessary, and this work may validate the support for a PDF drug target, as well as providing some preliminary evidence that PDF inhibitors are not toxic to human cells. The next project involved the identification of a novel class of macrocyclic PDF inhibitors, which tailored from the traditional PDF inhibitors in being acyclic and peptide-like in nature. This new class of PDF inhibitors exhibited potent inhibition and antibacterial properties, against both the Gram-negative and Gram-positive bacteria. The cyclization effect improved the PDF inhibition selectivity and biostability. Here, this work may provide a lead toward more effective PDF inhibitors more resistant to proteolysis and demonstrating improved specificity. The final part of this work involved the purification and identification enzymes degrading chemotactic f-Met-Leu-Phe peptide (fMLF) released from bacteria. This area of study encompasses the PDF drug effect presented by the commensal bacteria within the mammalian intestines. N-acylpeptide hydrolase and N-acylase 1A from rat small intestine mucosal layer were isolated and identified to degrade the fMLF chemopeptide and other N-formylmethionine peptides. The results may provide support for better understanding the host defense mechanism against the commensal bacteria and to identify the potential problems that may encounter as PDF makes an attractive novel therapeutic drug target.
Dehua Pei (Advisor)
188 p.
Chemistry, Biochemistry
Peptide deformylase; Human peptide deformylase; Plasmodium peptide deformylase; Peptide deformylase inhibitor; Deformylation

Recommended Citations

Citations

  • Nguyen, K. T. (2005). Mechanism, function, and inhibition of peptide deformylase [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1110038706

    APA Style (7th edition)

  • Nguyen, Kiet. Mechanism, function, and inhibition of peptide deformylase. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1110038706.

    MLA Style (8th edition)

  • Nguyen, Kiet. "Mechanism, function, and inhibition of peptide deformylase." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1110038706

    Chicago Manual of Style (17th edition)

osu1110038706
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.