A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1

Mitchell J Riley; Colleen C Mitchell; Sarah E Ernst; Eric B Taylor; Michael J Welsh

doi:10.1073/pnas.2318956121

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A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1

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A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1

Mitchell J Riley, Colleen C Mitchell, Sarah E Ernst, Eric B Taylor and Michael J Welsh

Proceedings of the National Academy of Sciences - PNAS, Vol.121(9), e2318956121

02/27/2024

DOI: 10.1073/pnas.2318956121

PMCID: PMC10907273

PMID: 38377207

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Abstract

The drug terazosin (TZ) binds to and can enhance the activity of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and can increase ATP levels. That finding prompted studies of TZ in Parkinson's disease (PD) in which decreased neuronal energy metabolism is a hallmark feature. TZ was neuroprotective in cell-based and animal PD models and in large epidemiological studies of humans. However, how TZ might increase PGK1 activity has remained a perplexing question because structural data revealed that the site of TZ binding to PGK1 overlaps with the site of substrate binding, predicting that TZ would competitively inhibit activity. Functional data also indicate that TZ is a competitive inhibitor. To explore the paradoxical observation of a competitive inhibitor increasing enzyme activity under some conditions, we developed a mass action model of TZ and PGK1 interactions using published data on PGK1 kinetics and the effect of varying TZ concentrations. The model indicated that TZ-binding introduces a bypass pathway that accelerates product release. At low concentrations, TZ binding circumvents slow product release and increases the rate of enzymatic phosphotransfer. However, at high concentrations, TZ inhibits PGK1 activity. The model explains stimulation of enzyme activity by a competitive inhibitor and the biphasic dose-response relationship for TZ and PGK1 activity. By providing a plausible mechanism for interactions between TZ and PGK1, these findings may aid development of TZ or other agents as potential therapeutics for neurodegenerative diseases. The results may also have implications for agents that interact with the active site of other enzymes.

Animals

Glycolysis

Humans

Parkinson Disease - drug therapy

Phosphoglycerate Kinase - metabolism

Prazosin - analogs & derivatives

Prazosin - pharmacology

Details

Title: Subtitle: A model for stimulation of enzyme activity by a competitive inhibitor based on the interaction of terazosin and phosphoglycerate kinase 1
Creators: Mitchell J Riley - University of Iowa
Colleen C Mitchell - University of Iowa
Sarah E Ernst - University of Iowa
Eric B Taylor - University of Iowa
Michael J Welsh - University of Iowa
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.121(9), e2318956121
DOI: 10.1073/pnas.2318956121
PMID: 38377207
PMCID: PMC10907273
NLM abbreviation: Proc Natl Acad Sci U S A
eISSN: 1091-6490
Grant note: 1 / CSRD VA
Language: English
Date published: 02/27/2024
Academic Unit: Neurology; Molecular Physiology and Biophysics; Pulmonary, Critical Care, and Occupational Medicine; Fraternal Order of Eagles Diabetes Research Center; Mathematics; Neurosurgery; Internal Medicine
Record Identifier: 9984560488302771

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