Probe Development Summary of Inhibitors of Bacillus subtilis Sfp phosphopantetheinyl transferase (PPTase)
The covalent attachment of a phosphopantetheinyl (4'-PP) arm to a variety of synthases and other proteins is a key posttranslational protein modification. The 4'-PP is installed on the proteins post-translationally from coenzyme A (CoA) on a conserved serine residue by action of phosphopantetheinyl transferase (PPTase) enzymes. Phosphopantetheinylation is essential for synthase activity, and more ..
Source: NIH Chemical Genomics Center [NCGC]
Assay Submitter: Michael Burkart, University of California, San Diego
Screening Center PI: Christopher P. Austin, NIH
Probe Development: NIH Chemical Genomics Center [NCGC]
NIH Grant Number: MH083266-01
The covalent attachment of a phosphopantetheinyl (4'-PP) arm to a variety of synthases and other proteins is a key posttranslational protein modification. The 4'-PP is installed on the proteins post-translationally from coenzyme A (CoA) on a conserved serine residue by action of phosphopantetheinyl transferase (PPTase) enzymes. Phosphopantetheinylation is essential for synthase activity, and removal of the PPTase gene precludes natural product synthesis in microorganisms, or in the case of fatty acid biosynthesis, renders the organism unviable. PPTase enzymes belong to a distinct structural superfamily. Within bacteria, these enzymes are grouped into two classes based upon primary structure, the AcpS-Type and Sfp-Type PPTases.
Sfp-type PPTases, corresponding to an activator of surfactin production in Bacillus subtilis, are responsible for modifying type I polyketide and nonribosomal peptide synthases of prokaryotes. Sfp-type PPTases are responsible for the activation of a variety of pathogen-associated virulence factors. Among these compounds are toxins such as mycolactone from Mycobacterium ulcerans, siderophores such as vibriobactin from Vibrio cholerae or mycobactin from Mycobacterium tuberculosis, as well as the mycolic acids which form the waxy cell wall of Mycobacteria. The biosyntheses of these natural products are considered attractive targets for drug design.
This BioAssay summarizes the development of novel small molecule Sfp-PPTase inhibitors and their follow-up characterization.
Please see related BioAssays for all protocols relevant to this probe development project: AIDs 1490
AID 1490: This assays is a validation of a quantitative high throughput screening (qHTS) protocol tested against 1,113 samples.
This summary assay will be updated as additional screens are run and small molecule probes have been developed.
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML267
PubChem Substance ID (SID) for probe 1: 124398570
PubChem Compound ID (CID) for probe 1: 53257126
IC50/EC50 (nM) for probe 1: 290
Target for probe 1: Sfp-PPTase (gi: 10954339)
Anti-target for probe 1: Cytotoxicity (HepG2 Cells)
Fold selectivity for probe 1: >196
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK169448/ (ID: 3060720)
Grant number for probe 1: MH083266-01
PubMed Publication ID (PMID) for probe 1: 24450337
NCBI Book chapter title for probe 1: Discovery of ML 267 as a Novel Inhibitor of Pathogenic Sfp phosphopantetheinyl transferase (PPTase)