Insights into the physiological role of pig liver esterase: Isoenzymes show differences in the demethylation of prenylated proteins

Brüsehaber, Elke; Böttcher, Dominique; Bornscheuer, Uwe T.

doi:10.1016/j.bmc.2009.10.033

Cited by 13 publications

(14 citation statements)

References 31 publications

(39 reference statements)

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“…Esterases and lipases are successfully used in organic synthesis9 for the preparation of various optically active alcohols, acids, and amines. Their natural function, however, might be totally different, as shown for pig liver esterase, which plays a role in signal transduction by ester cleavage of methylated and prenylated proteins 10…”

Section: Methodsmentioning

confidence: 99%

Revealing the Structural Basis of Promiscuous Amine Transaminase Activity

et al. 2012

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One lock for different keys: A flexible arginine in the active site allows γ‐aminobutyrate:pyruvate transaminases to bind the chemically different substrates L‐alanine and γ‐aminobutyric acid. Moreover, a flexible arginine residue facilitates the promiscuous conversion of (S)‐amines and ketones. The degree of promiscuity can be related to distinct key amino acids lying at the surface of the active site.

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Section: Methodsmentioning

confidence: 99%

Revealing the Structural Basis of Promiscuous Amine Transaminase Activity

et al. 2012

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“…The observation of dramatic changes in the methylation status of RhoA after just 30 min of thrombin treatment strongly suggested that an esterase was involved. The existence of a esterase that could demethylate CaaX proteins and thereby allow dynamic modulation of localization/function of the proteins has been proposed by several groups, but most studies have only shown that a particular esterase was capable of acting on a prenylcysteine methyl ester (17), and data that the process actually occurs in cells have been lacking. The best evidence for a biologically relevant esterase acting on prenyl proteins comes from studies in plants, where an Arabidopsis gene acting counter to the Icmt of the organism has been identified (18,19).…”

Section: Elevation Of Icmt Activity Impacts Morphology Of Mda-mb-231mentioning

confidence: 99%

Control of RhoA Methylation by Carboxylesterase I

Cushman

Potter

et al. 2013

Journal of Biological Chemistry

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Background: Methylation of Rho proteins by isoprenylcysteine carboxylmethyltransferase impacts their function. Results: RhoA methylation is dynamic and impacted by carboxylesterase 1 activity. Conclusion: Carboxylesterase 1 plays a role in controlling the methylation status and activation of RhoA and impacts cell morphology. Significance: This study demonstrates that C-terminal methylation is under acute control and plays a major role in cell signaling.

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“…Many esters show appreciable rates of enzyme-independent hydrolysis, and cellular esterases show broad substrate reactivity (13,14). Both of these pathways can degrade cell specificity of an ester-masked small molecule by leading to accumulation of the unmasked compound in all cells.…”

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confidence: 99%

Selective esterase–ester pair for targeting small molecules with cellular specificity

Tian

Yang

Wysocki

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

163

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Small molecules are important tools to measure and modulate intracellular signaling pathways. A longstanding limitation for using chemical compounds in complex tissues has been the inability to target bioactive small molecules to a specific cell class. Here, we describe a generalizable esterase-ester pair capable of targeted delivery of small molecules to living cells and tissue with cellular specificity. We used fluorogenic molecules to rapidly identify a small ester masking motif that is stable to endogenous esterases, but is efficiently removed by an exogenous esterase. This strategy allows facile targeting of dyes and drugs in complex biological environments to label specific cell types, illuminate gap junction connectivity, and pharmacologically perturb distinct subsets of cells. We expect this approach to have general utility for the specific delivery of many small molecules to defined cellular populations. cellular imaging | microscopy | enzyme substrates | fluorophores | pharmacological agents C hemical probes are essential tools in biology for measuring and manipulating cellular properties. Optimization of the structural and electronic features of small molecules allows the fine-tuning of molecular recognition specificity for a particular cellular target. Even with high molecular specificity, however, the application of small molecules in complex biological environments is frequently limited by poor cellular specificity. The inability to target small molecules, such as imaging or pharmacological agents, to defined cellular populations can confound the evaluation and control of discrete subsets of cells within a multicellular environment. A general and efficient strategy for cell-specific targeting, combining the molecular specificity of small molecules with the cellular specificity of genetics, would allow intracellular pathways in defined cell types to be selectively probed in complex tissues.An attractive approach for general cell-specific delivery of small molecules employs selective enzyme-substrate pairs. In this strategy, compounds are masked by attachment of a standard, disposable blocking group that is stable to native cellular enzymes, but labile to a specific exogenous enzyme. Expression of such a protein in a genetically defined cell population permits unmasking of the small molecule with cellular specificity. To be useful across experimental paradigms, such a system should utilize an enzyme that unmasks molecules with high efficiency, expresses in different cell types, and exhibits low cellular toxicity. The cognate masking group must be modular, synthetically efficient, and allow molecules to diffuse passively across the cellular membrane, while also exhibiting favorable solubility and stability in aqueous solution.To date only a few enzyme-substrate pairs have been used as targeted delivery systems for small molecules, and none meet all the criteria outlined above. Strategies employing enzymes encoded by common reporter genes (1) have found some success in targeting small molecules (2-4), ...

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Insights into the physiological role of pig liver esterase: Isoenzymes show differences in the demethylation of prenylated proteins

Cited by 13 publications

References 31 publications

Revealing the Structural Basis of Promiscuous Amine Transaminase Activity

Revealing the Structural Basis of Promiscuous Amine Transaminase Activity

Control of RhoA Methylation by Carboxylesterase I

Selective esterase–ester pair for targeting small molecules with cellular specificity

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