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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
24
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pubmed:dateCreated |
1994-1-11
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pubmed:abstractText |
Eucaryotic ribonucleotide reductases (RR) catalyze the reduction of ribonucleoside diphosphates to 2'-deoxyribonucleoside diphosphates. Each has an R1(2)R2(2) quaternary structure with each subunit playing a critical role in catalysis. Separation of the subunits results in loss of activity. Previous studies have demonstrated that peptides corresponding to the C-terminus of R2 disrupt subunit association by competion with R2 and have potential usefulness as therapeutics. Extensive structure-function studies have been carried out on peptide inhibition of herpes simplex RR in an effort to develop antiviral agents based on the observation that the herpes simplex R2 C-terminus, YAGAVVNDL, is quite different from the corresponding mammalian sequence. In this work we report a detailed structure-function analysis of peptide inhibition of mammalian and, to a more limited extent, Saccharomyces cerevisiae RRs. Our results for mammalian RR support the following conclusions with regard to the effect of substitution on inhibitory potency: (a) the N-acetylated R2 C-terminal heptapeptide N-AcPhe384Thr385Leu386Asp387Ala388Asp389Phe390 (N-AcF7TLDADF1) is the minimal core peptide length required; deletion of the N-terminus or of middle positions (resulting in penta- and hexapeptides) results in large losses in inhibitory potency; (b) a free carboxylate is required on the C-terminal Phe; (c) Phe is strongly preferred to Leu in positions 1 and 7 and a bulky aliphatic group is preferred in position 5; (d) neither negative charge in positions 2 or 4 nor a polar side chain in position 6 are required for peptide binding, contrary to what evolutionary patterns in the R2 C-terminus of RR would suggest. S. cerevisiae RR displays a similar length dependence on the corresponding N-acetylated R2 C-terminal heptapeptide, N-AcFTFNEDF. This peptide has a 4-fold higher inhibitory potency toward S. cerevisiae RR than toward mammalian RR. Such selectivity raises the possibility that peptide analogs related to R2 C-termini can be developed as therapeutic agents even against organisms having R2 C-terminal sequences similar to that of mammalian RR.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical | |
pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
0022-2623
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
26
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pubmed:volume |
36
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3859-62
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:8254617-Acetylation,
pubmed-meshheading:8254617-Amino Acid Sequence,
pubmed-meshheading:8254617-Animals,
pubmed-meshheading:8254617-Cattle,
pubmed-meshheading:8254617-Mice,
pubmed-meshheading:8254617-Molecular Sequence Data,
pubmed-meshheading:8254617-Oligopeptides,
pubmed-meshheading:8254617-Ribonucleotide Reductases,
pubmed-meshheading:8254617-Saccharomyces cerevisiae,
pubmed-meshheading:8254617-Species Specificity,
pubmed-meshheading:8254617-Structure-Activity Relationship
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pubmed:year |
1993
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pubmed:articleTitle |
R2 C-terminal peptide inhibition of mammalian and yeast ribonucleotide reductase.
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pubmed:affiliation |
Department of Chemistry, University of Pennsylvania, Philadelphia 19104-6323.
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pubmed:publicationType |
Journal Article,
Comparative Study,
Research Support, Non-U.S. Gov't
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