Phosphate Binding in PNP Alters Transition-State Analogue Affinity and Subunit Cooperativity
Purine nucleoside phosphorylases (PNPs) catalyze the phosphorolysis of 6-oxypurine nucleosides with an HPO42- dianion nucleophile. Nucleosides and phosphate occupy distinct pockets in the PNP active site. Evaluation of the HPO42- site by mutagenesis, cooperative binding studies, and thermodynamic and structural analysis demonstrate that alterations in the HPO42- binding site can render PNP inactive and significantly impact subunit cooperativity and binding to transition-state analogue inhibitors. Cooperative interactions between the cationic transition-state analogue and the anionic HPO42- nucleophile demonstrate the importance of reforming the transition-state ensemble for optimal inhibition with transition-state analogues. Altered phosphate binding in the catalytic site mutants helps to explain one of the known lethal PNP deficiency syndromes in humans.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:62 |
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| Enthalten in: |
Biochemistry - 62(2023), 21 vom: 07. Nov., Seite 3116-3125 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Minnow, Yacoba V T [VerfasserIn] |
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| Links: |
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| Themen: |
EC 2.4.2.1 |
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| Anmerkungen: |
Date Completed 08.11.2023 Date Revised 11.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.biochem.3c00264 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM363057536 |
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| 100 | 1 | |a Minnow, Yacoba V T |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Phosphate Binding in PNP Alters Transition-State Analogue Affinity and Subunit Cooperativity |
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| 500 | |a Date Revised 11.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Purine nucleoside phosphorylases (PNPs) catalyze the phosphorolysis of 6-oxypurine nucleosides with an HPO42- dianion nucleophile. Nucleosides and phosphate occupy distinct pockets in the PNP active site. Evaluation of the HPO42- site by mutagenesis, cooperative binding studies, and thermodynamic and structural analysis demonstrate that alterations in the HPO42- binding site can render PNP inactive and significantly impact subunit cooperativity and binding to transition-state analogue inhibitors. Cooperative interactions between the cationic transition-state analogue and the anionic HPO42- nucleophile demonstrate the importance of reforming the transition-state ensemble for optimal inhibition with transition-state analogues. Altered phosphate binding in the catalytic site mutants helps to explain one of the known lethal PNP deficiency syndromes in humans | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
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| 650 | 7 | |a Phosphates |2 NLM | |
| 700 | 1 | |a Schramm, Vern L |e verfasserin |4 aut | |
| 700 | 1 | |a Almo, Steven C |e verfasserin |4 aut | |
| 700 | 1 | |a Ghosh, Agnidipta |e verfasserin |4 aut | |
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