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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
6
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pubmed:dateCreated |
1990-6-14
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pubmed:abstractText |
The entire family of ATP analogues that are either mono- or disubstituted with imido and methylene bridges in the polyphosphate chain of ATP have been investigated as substrates and inhibitors of S-adenosylmethionine synthetase (ATP:L-methionine S-adenosyltransferase). The disubstituted analogues adenosine 5'-(alpha,beta:beta,gamma-diimidotriphosphate) (AMPNPNP) and adenosine 5'-(alpha,beta:alpha,beta'-diimidotriphosphate) [AMP(NP)2] have been synthesized for the first time, and a new route to adenosine 5'-(alpha,beta:beta,gamma-dimethylenetriphosphate) (AMPCPCP) has been developed. S-Adenosylmethionine synthetase catalyzes a two-step reaction: the intact polyphosphate chain is displaced from ATP, yielding AdoMet and tripolyphosphate, followed normally, but not obligatorily, by the hydrolysis of the tripolyphosphate to pyrophosphate and orthophosphate. Uniformly, the imido mono- or disubstituted derivatives are both better substrates and better inhibitors than their methylene counterparts. AMPNPNP reacts rapidly to give a single equivalent of product per active site, but subsequent turnovers are at least 1000-fold slower, enabling it to be used to quantify enzyme active site concentrations. In contrast, AMPCPCP is not detectably a substrate (less than 10(-5)% of ATP). AMP(NP)2, a branched isomer of linear AMPNPNP, was not a substrate but was a linear competitive inhibitor, greater than 100 fold more potent than ADP, indicating a reasonable degree of bulk tolerance at the alpha-phosphoryl group binding site.(ABSTRACT TRUNCATED AT 250 WORDS)
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pubmed:grant | |
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 |
Feb
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pubmed:issn |
0006-2960
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
13
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pubmed:volume |
29
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1412-6
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pubmed:dateRevised |
2007-11-14
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pubmed:meshHeading |
pubmed-meshheading:2334705-Adenosine Triphosphate,
pubmed-meshheading:2334705-Kinetics,
pubmed-meshheading:2334705-Methionine Adenosyltransferase,
pubmed-meshheading:2334705-Molecular Structure,
pubmed-meshheading:2334705-Polyphosphates,
pubmed-meshheading:2334705-Substrate Specificity,
pubmed-meshheading:2334705-Transferases
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pubmed:year |
1990
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pubmed:articleTitle |
Specificity of S-adenosylmethionine synthetase for ATP analogues mono- and disubstituted in bridging positions of the polyphosphate chain.
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pubmed:affiliation |
Department of Pharmaceutical Chemistry, University of California, San Francisco 94143.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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