Prenylcysteine lyase deficiency in mice results in the accumulation of farnesylcysteine and geranylgeranylcysteine in brain and liver

Anne Beigneux, Shannon K. Withycombe, Jennifer A. Digits, William R. Tschantz, Carolyn A. Weinbaum, Stephen M Griffey, Martin Bergo, Patrick J. Casey, Stephen G. Young

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

In in vitro experiments, prenylcysteine lyase (Pcly) cleaves the thioether bond of prenylcysteines to yield free cysteine and the aldehyde of the isoprenoid lipid. However, the importance of this enzyme has not yet been fully defined at the biochemical or physiologic level. In this study, we show that Pcly is expressed at high levels in mouse liver, kidney, heart, and brain. To test whether Pcly deficiency would cause prenylcysteines to accumulate in tissues and result in pathologic consequences, we produced Pcly-deficient cell lines and Pcly-deficient mice (Pcly-/-). Pcly activity levels were markedly reduced in Pcly-/- cells and tissues. Pcly-/-fibroblasts were more sensitive than wild-type fibroblasts to growth inhibition when prenylcysteines were added to the cell culture medium. To determine if the reduced Pcly enzyme activity levels led to an accumulation of prenylcysteines within cells, mass spectrometry was used to measure farnesylcysteine and geranylgeranylcysteine levels in the tissues of Pcly-/- mice and wild-type controls. These studies revealed a striking accumulation of both farnesylcysteine and geranylgeranylcysteine in the brain and liver of Pcly-/- mice. This accumulation did not appear to be accompanied by significant pathologic consequences. Pcly-/- mice were healthy and fertile, and surveys of more than 30 tissues did not uncover any abnormalities. We conclude that prenylcysteine lyase does play a physiologic role in cleaving prenylcysteines in mammals, but the absence of this activity does not lead to major pathologic consequences.

Original languageEnglish (US)
Pages (from-to)38358-38363
Number of pages6
JournalJournal of Biological Chemistry
Volume277
Issue number41
DOIs
StatePublished - Oct 11 2002
Externally publishedYes

Fingerprint

Liver
Brain
Tissue
Fibroblasts
geranylgeranylcysteine
prenylcysteine lyase
Terpenes
Mammals
Sulfides
Enzymes
Enzyme activity
Aldehydes
Cysteine
Cell culture
Culture Media
Mass Spectrometry
Mass spectrometry
Cell Culture Techniques
prenylcysteine
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

Prenylcysteine lyase deficiency in mice results in the accumulation of farnesylcysteine and geranylgeranylcysteine in brain and liver. / Beigneux, Anne; Withycombe, Shannon K.; Digits, Jennifer A.; Tschantz, William R.; Weinbaum, Carolyn A.; Griffey, Stephen M; Bergo, Martin; Casey, Patrick J.; Young, Stephen G.

In: Journal of Biological Chemistry, Vol. 277, No. 41, 11.10.2002, p. 38358-38363.

Research output: Contribution to journalArticle

Beigneux, A, Withycombe, SK, Digits, JA, Tschantz, WR, Weinbaum, CA, Griffey, SM, Bergo, M, Casey, PJ & Young, SG 2002, 'Prenylcysteine lyase deficiency in mice results in the accumulation of farnesylcysteine and geranylgeranylcysteine in brain and liver', Journal of Biological Chemistry, vol. 277, no. 41, pp. 38358-38363. https://doi.org/10.1074/jbc.M205183200
Beigneux, Anne ; Withycombe, Shannon K. ; Digits, Jennifer A. ; Tschantz, William R. ; Weinbaum, Carolyn A. ; Griffey, Stephen M ; Bergo, Martin ; Casey, Patrick J. ; Young, Stephen G. / Prenylcysteine lyase deficiency in mice results in the accumulation of farnesylcysteine and geranylgeranylcysteine in brain and liver. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 41. pp. 38358-38363.
@article{01a09846eca84834b1d20bc84f7c3f98,
title = "Prenylcysteine lyase deficiency in mice results in the accumulation of farnesylcysteine and geranylgeranylcysteine in brain and liver",
abstract = "In in vitro experiments, prenylcysteine lyase (Pcly) cleaves the thioether bond of prenylcysteines to yield free cysteine and the aldehyde of the isoprenoid lipid. However, the importance of this enzyme has not yet been fully defined at the biochemical or physiologic level. In this study, we show that Pcly is expressed at high levels in mouse liver, kidney, heart, and brain. To test whether Pcly deficiency would cause prenylcysteines to accumulate in tissues and result in pathologic consequences, we produced Pcly-deficient cell lines and Pcly-deficient mice (Pcly-/-). Pcly activity levels were markedly reduced in Pcly-/- cells and tissues. Pcly-/-fibroblasts were more sensitive than wild-type fibroblasts to growth inhibition when prenylcysteines were added to the cell culture medium. To determine if the reduced Pcly enzyme activity levels led to an accumulation of prenylcysteines within cells, mass spectrometry was used to measure farnesylcysteine and geranylgeranylcysteine levels in the tissues of Pcly-/- mice and wild-type controls. These studies revealed a striking accumulation of both farnesylcysteine and geranylgeranylcysteine in the brain and liver of Pcly-/- mice. This accumulation did not appear to be accompanied by significant pathologic consequences. Pcly-/- mice were healthy and fertile, and surveys of more than 30 tissues did not uncover any abnormalities. We conclude that prenylcysteine lyase does play a physiologic role in cleaving prenylcysteines in mammals, but the absence of this activity does not lead to major pathologic consequences.",
author = "Anne Beigneux and Withycombe, {Shannon K.} and Digits, {Jennifer A.} and Tschantz, {William R.} and Weinbaum, {Carolyn A.} and Griffey, {Stephen M} and Martin Bergo and Casey, {Patrick J.} and Young, {Stephen G.}",
year = "2002",
month = "10",
day = "11",
doi = "10.1074/jbc.M205183200",
language = "English (US)",
volume = "277",
pages = "38358--38363",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "41",

}

TY - JOUR

T1 - Prenylcysteine lyase deficiency in mice results in the accumulation of farnesylcysteine and geranylgeranylcysteine in brain and liver

AU - Beigneux, Anne

AU - Withycombe, Shannon K.

AU - Digits, Jennifer A.

AU - Tschantz, William R.

AU - Weinbaum, Carolyn A.

AU - Griffey, Stephen M

AU - Bergo, Martin

AU - Casey, Patrick J.

AU - Young, Stephen G.

PY - 2002/10/11

Y1 - 2002/10/11

N2 - In in vitro experiments, prenylcysteine lyase (Pcly) cleaves the thioether bond of prenylcysteines to yield free cysteine and the aldehyde of the isoprenoid lipid. However, the importance of this enzyme has not yet been fully defined at the biochemical or physiologic level. In this study, we show that Pcly is expressed at high levels in mouse liver, kidney, heart, and brain. To test whether Pcly deficiency would cause prenylcysteines to accumulate in tissues and result in pathologic consequences, we produced Pcly-deficient cell lines and Pcly-deficient mice (Pcly-/-). Pcly activity levels were markedly reduced in Pcly-/- cells and tissues. Pcly-/-fibroblasts were more sensitive than wild-type fibroblasts to growth inhibition when prenylcysteines were added to the cell culture medium. To determine if the reduced Pcly enzyme activity levels led to an accumulation of prenylcysteines within cells, mass spectrometry was used to measure farnesylcysteine and geranylgeranylcysteine levels in the tissues of Pcly-/- mice and wild-type controls. These studies revealed a striking accumulation of both farnesylcysteine and geranylgeranylcysteine in the brain and liver of Pcly-/- mice. This accumulation did not appear to be accompanied by significant pathologic consequences. Pcly-/- mice were healthy and fertile, and surveys of more than 30 tissues did not uncover any abnormalities. We conclude that prenylcysteine lyase does play a physiologic role in cleaving prenylcysteines in mammals, but the absence of this activity does not lead to major pathologic consequences.

AB - In in vitro experiments, prenylcysteine lyase (Pcly) cleaves the thioether bond of prenylcysteines to yield free cysteine and the aldehyde of the isoprenoid lipid. However, the importance of this enzyme has not yet been fully defined at the biochemical or physiologic level. In this study, we show that Pcly is expressed at high levels in mouse liver, kidney, heart, and brain. To test whether Pcly deficiency would cause prenylcysteines to accumulate in tissues and result in pathologic consequences, we produced Pcly-deficient cell lines and Pcly-deficient mice (Pcly-/-). Pcly activity levels were markedly reduced in Pcly-/- cells and tissues. Pcly-/-fibroblasts were more sensitive than wild-type fibroblasts to growth inhibition when prenylcysteines were added to the cell culture medium. To determine if the reduced Pcly enzyme activity levels led to an accumulation of prenylcysteines within cells, mass spectrometry was used to measure farnesylcysteine and geranylgeranylcysteine levels in the tissues of Pcly-/- mice and wild-type controls. These studies revealed a striking accumulation of both farnesylcysteine and geranylgeranylcysteine in the brain and liver of Pcly-/- mice. This accumulation did not appear to be accompanied by significant pathologic consequences. Pcly-/- mice were healthy and fertile, and surveys of more than 30 tissues did not uncover any abnormalities. We conclude that prenylcysteine lyase does play a physiologic role in cleaving prenylcysteines in mammals, but the absence of this activity does not lead to major pathologic consequences.

UR - http://www.scopus.com/inward/record.url?scp=0037064133&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037064133&partnerID=8YFLogxK

U2 - 10.1074/jbc.M205183200

DO - 10.1074/jbc.M205183200

M3 - Article

C2 - 12151402

AN - SCOPUS:0037064133

VL - 277

SP - 38358

EP - 38363

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 41

ER -