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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2007-1-16
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pubmed:abstractText |
Trichomonas vaginalis is a parasitic protozoan purine auxotroph possessing a unique purine salvage pathway consisting of a bacterial type purine nucleoside phosphorylase (PNP) and a purine nucleoside kinase. Thus, T. vaginalis PNP (TvPNP) functions in the reverse direction relative to the PNPs in other organisms. Immucillin-A (ImmA) and DADMe-Immucillin-A (DADMe-ImmA) are transition state mimics of adenosine with geometric and electrostatic features that resemble early and late transition states of adenosine at the transition state stabilized by TvPNP. ImmA demonstrates slow-onset tight-binding inhibition with TvPNP, to give an equilibrium dissociation constant of 87 pM, an inhibitor release half-time of 17.2 min, and a Km/Kd ratio of 70,100. DADMe-ImmA resembles a late ribooxacarbenium ion transition state for TvPNP to give a dissociation constant of 30 pM, an inhibitor release half-time of 64 min, and a Km/Kd ratio of 203,300. The tight binding of DADMe-ImmA supports a late SN1 transition state. Despite their tight binding to TvPNP, ImmA and DADMe-ImmA are weak inhibitors of human and P. falciparum PNPs. The crystal structures of the TvPNP x ImmA x PO4 and TvPNP x DADMe-ImmA x PO4 ternary complexes differ from previous structures with substrate analogues. The tight binding with DADMe-ImmA is in part due to a 2.7 A ionic interaction between a PO4 oxygen and the N1' cation of the hydroxypyrrolidine and is weaker in the TvPNP x ImmA x PO4 structure at 3.5 A. However, the TvPNP x ImmA x PO4 structure includes hydrogen bonds between the 2'-hydroxyl and the protein that are not present in TvPNP x DADMe-ImmA x PO4. These structures explain why DADMe-ImmA binds tighter than ImmA. Immucillin-H is a 12 nM inhibitor of TvPNP but a 56 pM inhibitor of human PNP. And this difference is explained by isotope-edited difference infrared spectroscopy with [6-18O]ImmH to establish that O6 is the keto tautomer in TvPNP x ImmH x PO4, causing an unfavorable leaving-group interaction.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/17223688-10080389,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17223688-10673349,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17223688-11337031,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/17223688-5651329,
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http://linkedlifedata.com/resource/pubmed/commentcorrection/17223688-9628722
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0006-2960
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pubmed:author |
pubmed-author:AlmoSteven CSC,
pubmed-author:DengHuaH,
pubmed-author:EvansGary BGB,
pubmed-author:FurneauxRichard HRH,
pubmed-author:GhanemMahmoudM,
pubmed-author:GuptaArtiA,
pubmed-author:Rinaldo-MatthisAgnesA,
pubmed-author:SchrammVern LVL,
pubmed-author:TylerPeter CPC,
pubmed-author:WangChing CCC,
pubmed-author:WingCorinC,
pubmed-author:WuPengP
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pubmed:issnType |
Print
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pubmed:day |
23
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pubmed:volume |
46
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
659-68
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pubmed:dateRevised |
2011-9-26
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pubmed:meshHeading |
pubmed-meshheading:17223688-Adenine,
pubmed-meshheading:17223688-Animals,
pubmed-meshheading:17223688-Catalytic Domain,
pubmed-meshheading:17223688-Crystallization,
pubmed-meshheading:17223688-Crystallography, X-Ray,
pubmed-meshheading:17223688-Models, Molecular,
pubmed-meshheading:17223688-Purine-Nucleoside Phosphorylase,
pubmed-meshheading:17223688-Pyrrolidines,
pubmed-meshheading:17223688-Substrate Specificity,
pubmed-meshheading:17223688-Trichomonas vaginalis
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pubmed:year |
2007
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pubmed:articleTitle |
Inhibition and structure of Trichomonas vaginalis purine nucleoside phosphorylase with picomolar transition state analogues.
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pubmed:affiliation |
Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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