Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids

Raymond Hohl, Kriste A. Lewis, Diana M. Cermak, David F. Wiemer

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-α- Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-α- hydroxyfarnesyl- and α-hydroxy-geranylphosphonates. A striking find is that only E,E-α-hydroxy-farnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-α-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-α- hydroxyfarnesylphosphonate is greater in enzyme than intact cell assays. This active compound does not significantly inhibit geranylgeranyl protein transferase I or squalene synthase, nor does it diminish cholesterol synthesis. These results indicate that the length of the terpenoid chain and olefin stereochemistry allow selective inhibition of critical enzymes of terpenoid metabolism. Discrimination was observed between inhibition of farnesyl protein transferase and squalene synthase by E,E-α- hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.

Original languageEnglish (US)
Pages (from-to)39-46
Number of pages8
JournalLipids
Volume33
Issue number1
DOIs
StatePublished - Mar 9 1998

Fingerprint

Phosphorous Acids
Prenylation
Stereochemistry
Terpenes
Farnesyl-Diphosphate Farnesyltransferase
Transferases
Enzyme inhibition
Enzymes
Metabolism
Assays
Proteins
Enzyme Assays
Alkenes
Leukemia
Cholesterol
Substrates
Processing
farnesyl pyrophosphate

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Organic Chemistry
  • Cell Biology

Cite this

Hohl, Raymond ; Lewis, Kriste A. ; Cermak, Diana M. ; Wiemer, David F. / Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids. In: Lipids. 1998 ; Vol. 33, No. 1. pp. 39-46.
@article{dc411def98db449eb82cad792f6ed8d2,
title = "Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids",
abstract = "This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-α- Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-α- hydroxyfarnesyl- and α-hydroxy-geranylphosphonates. A striking find is that only E,E-α-hydroxy-farnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-α-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-α- hydroxyfarnesylphosphonate is greater in enzyme than intact cell assays. This active compound does not significantly inhibit geranylgeranyl protein transferase I or squalene synthase, nor does it diminish cholesterol synthesis. These results indicate that the length of the terpenoid chain and olefin stereochemistry allow selective inhibition of critical enzymes of terpenoid metabolism. Discrimination was observed between inhibition of farnesyl protein transferase and squalene synthase by E,E-α- hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.",
author = "Raymond Hohl and Lewis, {Kriste A.} and Cermak, {Diana M.} and Wiemer, {David F.}",
year = "1998",
month = "3",
day = "9",
doi = "10.1007/s11745-998-0178-x",
language = "English (US)",
volume = "33",
pages = "39--46",
journal = "Lipids",
issn = "0024-4201",
publisher = "Springer Verlag",
number = "1",

}

Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids. / Hohl, Raymond; Lewis, Kriste A.; Cermak, Diana M.; Wiemer, David F.

In: Lipids, Vol. 33, No. 1, 09.03.1998, p. 39-46.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Stereochemistry-dependent inhibition of RAS farnesylation by farnesyl phosphonic acids

AU - Hohl, Raymond

AU - Lewis, Kriste A.

AU - Cermak, Diana M.

AU - Wiemer, David F.

PY - 1998/3/9

Y1 - 1998/3/9

N2 - This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-α- Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-α- hydroxyfarnesyl- and α-hydroxy-geranylphosphonates. A striking find is that only E,E-α-hydroxy-farnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-α-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-α- hydroxyfarnesylphosphonate is greater in enzyme than intact cell assays. This active compound does not significantly inhibit geranylgeranyl protein transferase I or squalene synthase, nor does it diminish cholesterol synthesis. These results indicate that the length of the terpenoid chain and olefin stereochemistry allow selective inhibition of critical enzymes of terpenoid metabolism. Discrimination was observed between inhibition of farnesyl protein transferase and squalene synthase by E,E-α- hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.

AB - This investigation compares the effects of three farnesyl pyrophosphate analogs on selected aspects of isoprenoid metabolism. E,E-α- Hydroxyfarnesylphosphonate was prepared by an improved variation on a literature synthesis, which also gave access to the new Z,E-α- hydroxyfarnesyl- and α-hydroxy-geranylphosphonates. A striking find is that only E,E-α-hydroxy-farnesylphosphonate induces alteration of RAS processing in intact human-derived leukemia cells and inhibits farnesyl protein transferase in enzyme assays, while the Z,E-α-farnesyl- and geranylphosphonates are inactive. The inhibitory activity of E,E-α- hydroxyfarnesylphosphonate is greater in enzyme than intact cell assays. This active compound does not significantly inhibit geranylgeranyl protein transferase I or squalene synthase, nor does it diminish cholesterol synthesis. These results indicate that the length of the terpenoid chain and olefin stereochemistry allow selective inhibition of critical enzymes of terpenoid metabolism. Discrimination was observed between inhibition of farnesyl protein transferase and squalene synthase by E,E-α- hydroxyfarnesylphosphonate, even though both enzymes utilize farnesyl pyrophosphate as their natural substrate.

UR - http://www.scopus.com/inward/record.url?scp=0031933368&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031933368&partnerID=8YFLogxK

U2 - 10.1007/s11745-998-0178-x

DO - 10.1007/s11745-998-0178-x

M3 - Article

C2 - 9470172

AN - SCOPUS:0031933368

VL - 33

SP - 39

EP - 46

JO - Lipids

JF - Lipids

SN - 0024-4201

IS - 1

ER -