RGD Reference Report - Motexafin gadolinium, a tumor-selective drug targeting thioredoxin reductase and ribonucleotide reductase. - Rat Genome Database

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Motexafin gadolinium, a tumor-selective drug targeting thioredoxin reductase and ribonucleotide reductase.

Authors: Hashemy, SI  Ungerstedt, JS  Zahedi Avval, F  Holmgren, A 
Citation: Hashemy SI, etal., J Biol Chem. 2006 Apr 21;281(16):10691-7. Epub 2006 Feb 14.
RGD ID: 5133691
Pubmed: PMID:16481328   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M511373200   (Journal Full-text)

Motexafin gadolinium (MGd) is a chemotherapeutic drug that selectively targets tumor cells and mediates redox reactions generating reactive oxygen species. Thioredoxin (Trx), NADPH, and thioredoxin reductase (TrxR) of the cytosol/nucleus or mitochondria are major thiol-dependent reductases with many functions in cell growth, defense against oxidative stress, and apoptosis. Mammalian TrxRs are selenocysteine-containing flavoenzymes; MGd was an NADPH-oxidizing substrate for human or rat TrxR1 with a Km value of 8.65 microM (kcat/Km of 4.86 x 10(4) M(-1) s(-1)). The reaction involved redox cycling of MGd by oxygen producing superoxide and hydrogen peroxide. MGd acted as a non-competitive inhibitor (IC50 of 6 microM) for rat TrxR. In contrast, direct reaction between MGd and reduced human Trx was negligible. The corresponding reaction with reduced Escherichia coli Trx was also negligible, but MGd was a better substrate (kcat/Km of 2.23 x 10(5) M(-1) s(-1)) for TrxR from E. coli and a strong inhibitor of Trx-dependent protein disulfide reduction. Ribonucleotide reductase (RNR), a 1:1 complex of the non-identical R1- and R2-subunits, catalyzes the essential de novo synthesis of deoxyribonucleotides for DNA synthesis using electrons from Trx and TrxR. MGd inhibited recombinant mouse RNR activity with either 3 microM reduced human Trx (IC50 2 microM) or 4 mM dithiothreitol (IC50 6 microM) as electron donors. Our results demonstrate MGd-induced enzymatic generation of reactive oxygen species by TrxR plus a powerful inhibition of RNR. This may explain the effects of the drug on cancer cells, which often overproduce TrxR and have induced RNR for replication and repair.

Gene Ontology Annotations    Click to see Annotation Detail View

Molecular Function
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
NAD(P)H oxidase H2O2-forming activity  IDA 5133691 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Txnrd1  (thioredoxin reductase 1)


Additional Information