Suicide Substrates, Mechanism-Based Enzyme Inactivators: Recent Developments

Ct, Walsh

doi:10.1146/annurev.bi.53.070184.002425

Cited by 299 publications

(125 citation statements)

References 46 publications

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“…TGZ reactive metabolites appear relatively stable and are able to diffuse from the active site of P450 to react with GSH. These features are different from typical mechanism-based inactivators that form highly reactive intermediates bound covalently at the enzyme active site in such a way that GSH could not completely prevent covalent binding (Walsh, 1984;He et al, 1999). The location of the glutathionyl moiety in the molecule of the TGZ-GSH adduct was determined to be the C5 position of the thiazolidinedione ring by LC-MS/MS and NMR.…”

Section: Discussionmentioning

confidence: 88%

Metabolic Activation of Troglitazone: Identification of a Reactive Metabolite and Mechanisms Involved

He¹,

Talaat²,

Pool³

et al. 2004

Drug Metab Dispos

109

107

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Section: Discussionmentioning

confidence: 88%

Metabolic Activation of Troglitazone: Identification of a Reactive Metabolite and Mechanisms Involved

He¹,

Talaat²,

Pool³

et al. 2004

Drug Metab Dispos

109

107

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“…They have further shown that the herbicide was rapidly metabolized in pea but only gradually in cucumber and ryegrass (11). Other possibilities could involve the modification ofthe target enzyme to reduce its affinity to the inhibitor, or an increase in the level of the relevant enzyme (14). The increase of GLA in S. platensis and EPA in P. cruentum may be attributed to one of the last two mechanisms.…”

Section: Resultsmentioning

confidence: 99%

Overproduction of γ-Linolenic and Eicosapentaenoic Acids by Algae

Cohen¹,

Didi²,

Heimer³

1992

Plant Physiol.

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The pharmaceutical interest and limited availability of y-linolenic acid (GLA) and eicosapentaenoic acid (EPA) prompted the search for genetic means for increasing the production of these fatty acids from algal sources. Cell lines of Spirulina platensis and Porphyridium cruentum resistant to the growth inhibition of the herbicide Sandoz 9785 were selected by serial transfers of the culture in the presence of increasing concentrations of the herbicide. The resistant cell lines of S. platensis overproduced GLA and those of P. cruentum overproduced EPA and were stable for at least 50 generations in the absence of the inhibitor.The recent pharmaceutical interest in the polyunsaturated fatty acids, EPA2 and GLA (7,17) and the limitations of their current availability (2, 5) triggered the search for potential new sources for these fatty acids. We (1,5) have previously demonstrated that the marine red microalga Porphyridium cruentum and the cyanobacterium Spirulina platensis are among the best producers of EPA and GLA, respectively. Strain selection and manipulation of physiological and environmental conditions brought about an increased content of these polyunsaturated fatty acids (1, 2, 4-6). Yet, the inherent limitation ofthese approaches prompted us to look for genetic means that could result in even higher contents of EPA and GLA.A possible approach for increasing the content of particular cell metabolites is the use of inhibitors of specific steps in biosynthetic pathways or analogs of specific products. Generally, such inhibitors and analogs inhibit growth as well. Thus, resistance to the inhibitor could be achieved by overproduction of the inhibited metabolites. It was indeed shown in higher plants that some lines selected for resistance to the growth inhibition are overproducers of the metabolite in question (8,10,15 ence of proline analogs (12). Similar results were obtained in the cyanobacterium Nostoc (9) and the alga Nannochloris bacilaris (13).Several herbicides of the substituted pyridazinone family were shown to inhibit fatty acid desaturation. Of these, SAN 9785 is the most effective inhibitor of w3 desaturation (11), and its effect on reduction of 18:3w3 levels in the glycolipids of higher plants and algae was widely studied. Recently, we (1) found this herbicide to be an effective inhibitor also for A6 desaturation of linoleic acid in Spirulina. Although SAN 9785 has a certain inhibitory effect on photosynthesis, it was shown that the effect on fatty acid desaturation is a direct inhibition of the desaturase ( 16).In the present paper, we describe the successful selection of P. cruentum and S. platensis cell lines that display stable resistance to the growth inhibition of SAN 9785. These cell lines over produced EPA and GLA, respectively. To the best of our knowledge, this is the first report of a fatty acid overproduction in either higher or lower plants induced by perturbation of fatty acid metabolism. MATERIALS AND METHODS Organisms and Culture ConditionsSpirulina platensis strain 2340 wa...

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“…The high degradation rate of proteins has previously been explained based on specific features of a protein fold that enables rapid degradation in protein abundance, e.g., the auxin degron (Nishimura et al, 2009), or the irreversible binding of inhibitors to a protein domain or due to an enzymatic mechanism that damages an active site (e.g., selfhydrolyzing enzymes, reactive oxygen species damage, cosubstrate enzymes, or catalysis with suicide substrates) (Walsh, 1984;Chatterjee et al, 2011). To test systematically for domains in Arabidopsis proteins linked to degradation rate, we searched for differences in protein degradation rate distributions between protein sets with common protein domains.…”

Section: Intrinsic Protein Properties Linked To Degradation Ratementioning

confidence: 99%

Protein Degradation Rate in Arabidopsis thaliana Leaf Growth and Development

et al. 2017

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We applied 15 N labeling approaches to leaves of the Arabidopsis thaliana rosette to characterize their protein degradation rate and understand its determinants. The progressive labeling of new peptides with 15 N and measuring the decrease in the abundance of >60,000 existing peptides over time allowed us to define the degradation rate of 1228 proteins in vivo. We show that Arabidopsis protein half-lives vary from several hours to several months based on the exponential constant of the decay rate for each protein. This rate was calculated from the relative isotope abundance of each peptide and the fold change in protein abundance during growth. Protein complex membership and specific protein domains were found to be strong predictors of degradation rate, while N-end amino acid, hydrophobicity, or aggregation propensity of proteins were not. We discovered rapidly degrading subunits in a variety of protein complexes in plastids and identified the set of plant proteins whose degradation rate changed in different leaves of the rosette and correlated with leaf growth rate. From this information, we have calculated the protein turnover energy costs in different leaves and their key determinants within the proteome.

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Suicide Substrates, Mechanism-Based Enzyme Inactivators: Recent Developments

Cited by 299 publications

References 46 publications

Metabolic Activation of Troglitazone: Identification of a Reactive Metabolite and Mechanisms Involved

Metabolic Activation of Troglitazone: Identification of a Reactive Metabolite and Mechanisms Involved

Overproduction of γ-Linolenic and Eicosapentaenoic Acids by Algae

Protein Degradation Rate in Arabidopsis thaliana Leaf Growth and Development

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