Analogs of farnesyl diphosphate alter CaaX substrate specificity and reactions rates of protein farnesyltransferase

Benjamin C. Jennings; Amy M. Danowitz; Yen Chih Wang; Richard A. Gibbs; Mark D. Distefano; Carol A. Fierke

doi:10.1016/j.bmcl.2015.12.079

Analogs of farnesyl diphosphate alter CaaX substrate specificity and reactions rates of protein farnesyltransferase

Benjamin C. Jennings, Amy M. Danowitz, Yen Chih Wang, Richard A. Gibbs, Mark D. Distefano, Carol A. Fierke

Division of Hematology

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Attempts to identify the prenyl-proteome of cells or changes in prenylation following drug treatment have used 'clickable' alkyne-modified analogs of the lipid substrates farnesyl- and geranylgeranyl-diphosphate (FPP and GGPP). We characterized the reactivity of four alkyne-containing analogs of FPP with purified protein farnesyltransferase and a small library of dansylated peptides using an in vitro continuous spectrofluorimetric assay. These analogs alter prenylation specificity and reactivity suggesting that in vivo results obtained using these FPP analogs should be interpreted cautiously.

Original language	English
Pages (from-to)	1333-1336
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2015.12.079
State	Published - Feb 15 2016

Keywords

Click chemistry
Post-translational modification
Protein farnesylation
Protein prenylation
Substrate analogs

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title = "Analogs of farnesyl diphosphate alter CaaX substrate specificity and reactions rates of protein farnesyltransferase",

abstract = "Attempts to identify the prenyl-proteome of cells or changes in prenylation following drug treatment have used 'clickable' alkyne-modified analogs of the lipid substrates farnesyl- and geranylgeranyl-diphosphate (FPP and GGPP). We characterized the reactivity of four alkyne-containing analogs of FPP with purified protein farnesyltransferase and a small library of dansylated peptides using an in vitro continuous spectrofluorimetric assay. These analogs alter prenylation specificity and reactivity suggesting that in vivo results obtained using these FPP analogs should be interpreted cautiously.",

keywords = "Click chemistry, Post-translational modification, Protein farnesylation, Protein prenylation, Substrate analogs",

author = "Jennings, {Benjamin C.} and Danowitz, {Amy M.} and Wang, {Yen Chih} and Gibbs, {Richard A.} and Distefano, {Mark D.} and Fierke, {Carol A.}",

note = "Funding Information: This work was supported by NIH grants F32GM112317 (B.C.J.), R01GM040602 (C.A.F.), R01CA078819 (R.A.G.), R01GM084152 (M.D.D.) and NSF grant CHE-1308655 (M.D.D.). We thank Andrew Placzek for providing analogs 2 and 3 . The authors publish this manuscript in memoriam to the late Richard Gibbs, who sadly passed away before its completion. Publisher Copyright: {\textcopyright} 2015 Elsevier Ltd. All rights reserved.",

year = "2016",

month = feb,

day = "15",

doi = "10.1016/j.bmcl.2015.12.079",

language = "English",

volume = "26",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Analogs of farnesyl diphosphate alter CaaX substrate specificity and reactions rates of protein farnesyltransferase

AU - Jennings, Benjamin C.

AU - Danowitz, Amy M.

AU - Wang, Yen Chih

AU - Gibbs, Richard A.

AU - Distefano, Mark D.

AU - Fierke, Carol A.

N1 - Funding Information: This work was supported by NIH grants F32GM112317 (B.C.J.), R01GM040602 (C.A.F.), R01CA078819 (R.A.G.), R01GM084152 (M.D.D.) and NSF grant CHE-1308655 (M.D.D.). We thank Andrew Placzek for providing analogs 2 and 3 . The authors publish this manuscript in memoriam to the late Richard Gibbs, who sadly passed away before its completion. Publisher Copyright: © 2015 Elsevier Ltd. All rights reserved.

PY - 2016/2/15

Y1 - 2016/2/15

N2 - Attempts to identify the prenyl-proteome of cells or changes in prenylation following drug treatment have used 'clickable' alkyne-modified analogs of the lipid substrates farnesyl- and geranylgeranyl-diphosphate (FPP and GGPP). We characterized the reactivity of four alkyne-containing analogs of FPP with purified protein farnesyltransferase and a small library of dansylated peptides using an in vitro continuous spectrofluorimetric assay. These analogs alter prenylation specificity and reactivity suggesting that in vivo results obtained using these FPP analogs should be interpreted cautiously.

AB - Attempts to identify the prenyl-proteome of cells or changes in prenylation following drug treatment have used 'clickable' alkyne-modified analogs of the lipid substrates farnesyl- and geranylgeranyl-diphosphate (FPP and GGPP). We characterized the reactivity of four alkyne-containing analogs of FPP with purified protein farnesyltransferase and a small library of dansylated peptides using an in vitro continuous spectrofluorimetric assay. These analogs alter prenylation specificity and reactivity suggesting that in vivo results obtained using these FPP analogs should be interpreted cautiously.

KW - Click chemistry

KW - Post-translational modification

KW - Protein farnesylation

KW - Protein prenylation

KW - Substrate analogs

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 4

ER -

Analogs of farnesyl diphosphate alter CaaX substrate specificity and reactions rates of protein farnesyltransferase

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Keywords

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