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

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1333-6. doi: 10.1016/j.bmcl.2015.12.079. Epub 2015 Dec 22.

Authors

Benjamin C Jennings¹, Amy M Danowitz², Yen-Chih Wang³, Richard A Gibbs⁴, Mark D Distefano⁵, Carol A Fierke⁶

Affiliations

¹ Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Chemistry and Biochemistry, Mercyhurst University, Erie, PA 16546, USA.
³ Department of Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
⁴ Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA.
⁵ Department of Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, USA; Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, USA.
⁶ Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: fierke@umich.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alkyl and Aryl Transferases / metabolism*
Alkynes / chemistry
Click Chemistry
Kinetics
Peptides / chemistry
Peptides / metabolism
Polyisoprenyl Phosphates / chemistry
Polyisoprenyl Phosphates / metabolism*
Protein Prenylation
Sesquiterpenes / chemistry
Sesquiterpenes / metabolism*
Substrate Specificity

Substances

Alkynes
Peptides
Polyisoprenyl Phosphates
Sesquiterpenes
farnesyl pyrophosphate
Alkyl and Aryl Transferases
p21(ras) farnesyl-protein transferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding