PXD024455

PXD024455 is an original dataset announced via ProteomeXchange.

Title	Comprehensive Structure-Activity Profiling of Micheliolide and its Targeted Proteome in Leukemia Cells via Probe-Guided Late-Stage C—H Functionalization
Description	The plant-derived sesquiterpene lactone micheliolide was recently found to possess promising antileukemic activity, including the ability to target and kill leukemia stem cells. Efforts toward improving the biological activity of micheliolide and investigating its mechanism of action have been hindered by the paucity of preexisting functional groups amenable for late-stage derivatization of this molecule. Here, we report the implementation of a probe-based P450 fingerprinting strategy to rapidly evolve engineered P450 catalysts useful for the regio- and stereoselective hydroxylation of micheliolide at two previously inaccessible aliphatic positions in this complex natural product. Via P450-mediated chemoenzymatic synthesis, a broad panel of novel micheliolide analogs could thus be obtained to gain structure-activity insights into the effect of C2, C4, and C14 substitutions on the anti-leukemic activity of micheliolide, ultimately leading to the discovery of ‘micheliologs’ with improved potency against acute myelogenic leukemia cells. These late-stage C—H functionalization routes could be further leveraged to generate a panel of affinity probes for conducting a comprehensive analysis of the protein targeting profile of micheliolide in leukemia cells via pull-down experiments and proteomic analyses. These studies introduce new micheliolide-based anti-leukemic agents and shed light onto the biomolecular targets and mechanism of action of micheliolide in leukemia cells. More broadly, this work showcases the value of the present P450-mediated C—H functionalization strategy for streamlining late-stage diversification and elucidation of the biomolecular targets of a complex bioactive natural product.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-16_16:21:45.772.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Kevin Welle
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-01 22:42:16	ID requested
⏵ 1	2022-02-16 16:21:46	announced

Alwaseem H, Giovani S, Crotti M, Welle K, Jordan CT, Ghaemmaghami S, Fasan R, Comprehensive Structure-Activity Profiling of Micheliolide and its Targeted Proteome in Leukemia Cells via Probe-Guided Late-Stage C-H Functionalization. ACS Cent Sci, 7(5):841-857(2021) [pubmed]

submitter keyword: C-H functionalization, biocatalysis, leukemia stem cells, sesquiterpene lactones, multi-probe proteomics, competitive pull-down

Rudi Fasan
contact affiliation	Department of Chemistry, University of Rochester, United States
contact email	rudi.fasan@rochester.edu
lab head
Kevin Welle
contact affiliation	University of Rochester
contact email	kevin_welle@urmc.rochester.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024455
     1. Label: PRIDE project
     2. Name: Comprehensive Structure-Activity Profiling of Micheliolide and its Targeted Proteome in Leukemia Cells via Probe-Guided Late-Stage C—H Functionalization