Inhibition of ricin by an rna stem-loop containing a ribo-oxycarbonium mimic

Xiangyang Chen, Todd M. Link, Vern L. Schramm

Research output: Contribution to journalArticle

Abstract

Ricin A-chain (RTA), the catalytic subunit of ricin, catalyzes the hydrolysis of a specific adenine from a stem-loop region of ribosomal RNA, to destroy cell protein synthesis. Conjugates of RTA are in clinical trials as toxinchemotherapy agents, but also exhibit general toxicity. The purpose of this study is to design specific inhibitors as rescue agents in toxin chemotherapy. Phenyliminoribitol (X), a transition-state analogue for N- ribohydrolases, was incorporated into a 14-base stem-loop RNA with a GXGA tetraloop. Inhibition against RTA was evaluated with a 10-base stem-loop RNA, CGC GAGA GCG (A-10) as the RTA substrate. The results demonstrated that A-10 has a A'm of 6.2 pM and a kcat of 1.7 minl under optimized reaction conditions, while the stem- loop RNA containing phenyliminoribitol at the depurination site gave an inhibition constant of 0.7 M, a 10-fold increase in binding compared to interactions with similar stem-loop substrates. The stem- loop motif is required to achieve inhibition since X alone and XG dinucleotide were not inhibitory.

Original languageEnglish (US)
JournalFASEB Journal
Volume10
Issue number6
StatePublished - 1996

Fingerprint

ricin
Ricin
Rapid thermal annealing
antineoplaston A10
RNA
stems
Ribosomal RNA
Adenine
Chemotherapy
Catalytic Domain
Hydrolysis
Substrates
Clinical Trials
Toxicity
Drug Therapy
protein subunits
adenine
drug therapy
clinical trials
Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

Cite this

Inhibition of ricin by an rna stem-loop containing a ribo-oxycarbonium mimic. / Chen, Xiangyang; Link, Todd M.; Schramm, Vern L.

In: FASEB Journal, Vol. 10, No. 6, 1996.

Research output: Contribution to journalArticle

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