Linked Life Data

11966438

Source:http://linkedlifedata.com/resource/pubmed/id/11966438

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2002-4-22
pubmed:abstractText
Benzamide riboside (BR) is a nucleoside prodrug that is phosphorylated to its 5'-monophosphate (BRMP) and then converted to its active metabolite, BAD (benzamide adenine dinucleotide), an analogue of NAD by the action of NMN adenylyltransferase (NMNAT). BAD is a potent, reversible, and noncompetitive inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH) resulting in depletion of guanylates (GTP and dGTP). IMPDH inhibitors such as BR induce differentiation and apoptosis as a consequence of GTP depletion. Tiazofurin (TR) and selenazofurin (SR) require similar metabolism by NMNAT. NMNAT is the rate-limiting step in the synthesis of NAD and NAD analogues. BR- and TR-sensitive leukemic cells contain high NMNAT activity, whereas resistant clones have greatly downregulated NMNAT activity (<0.1% of wild type). Perhaps the applicability of BR and analogues could be enhanced if combined with NMNAT gene expression in BR-resistant leukemic blasts. NAD has important regulatory role in repair of DNA damage and cell growth since it is a substrate for poly(ADP-ribose) polymerase (PARP). PARP appears to direct short-patch base excision repair and induce p53 upregulation leading to apoptosis. BR inhibits PARP at high concentrations when assayed in permeabilized leukemic cells. Several other IMPDH inhibitors (TR, mycophenolic acid, and ribavirin) exhibit similar PARP inhibitory activity. Although this inhibition was reversible, it was not prevented by the addition of guanosine, GTP, or its nonhydrolyzable analog gamma-S-GTP. Therefore, it can be concluded that IMPDH inhibitors directly inhibit PARP. Presumably, the shared IMP-NAD active site of IMPDH has a similar architecture to the NAD-binding pocket of PARP.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0929-8673
pubmed:author
pubmed:issnType
Print
pubmed:volume
9
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
749-58
pubmed:dateRevised
2007-2-12
pubmed:meshHeading
pubmed:year
2002
pubmed:articleTitle
Modulation of cytotoxicity of benzamide riboside by expression of NMN adenylyltransferase.
pubmed:affiliation
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS4053, Indianapolis 46202-5122, USA.
pubmed:publicationType
Journal Article, Review