Prenylcysteine Lyase Deficiency in Mice Results in the Accumulation of Farnesylcysteine and Geranylgeranylcysteine in Brain and Liver

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

doi:10.1074/jbc.m205183200

Cited by 23 publications

(17 citation statements)

References 24 publications

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“…However, our studies suggest that production of isoprenoid phosphates from FOH and GGOH is up-regulated and therefore might become important when the mevalonate pathway is inhibited. Although FOH and GGOH are not produced directly by the mevalonate pathway, they can be formed by degradation of isoprenylated proteins catalyzed by prenylcysteine lyases (23), so localized or cell-specific recycling of isoprenols may be a more important source of precursors for this pathway than circulating isoprenols. In particular, we and others have described phosphatase activities and identified at least one integral membrane enzyme that can dephosphorylate FPP and GGPP.…”

Section: Discussionmentioning

confidence: 99%

Efficient Use of Exogenous Isoprenols for Protein Isoprenylation by MDA-MB-231 Cells Is Regulated Independently of the Mevalonate Pathway

Onono

Subramanian

Sunkara

et al. 2013

Journal of Biological Chemistry

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Background: Stable isotope/chemical probe mass spectrometry was used to monitor cancer cell metabolism of exogenous isoprenols. Results: Efficient use of exogenous isoprenols for protein isoprenylation was undiminished by genetic or pharmacological inhibition of HMG-CoA reductase. Conclusion: Exogenous isoprenols are metabolized independently of the mevalonate pathway. Significance: This study identifies and quantitates a pathway of isoprenol metabolism with potential relevance to cancer progression.

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Section: Discussionmentioning

confidence: 99%

Efficient Use of Exogenous Isoprenols for Protein Isoprenylation by MDA-MB-231 Cells Is Regulated Independently of the Mevalonate Pathway

Onono

Subramanian

Sunkara

et al. 2013

Journal of Biological Chemistry

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“…[␣-32 P]dCTP-labeled cDNA probes were prepared with All-in-One random prime labeling mixture (Sigma). Standard prehybridization, hybridization, and washing procedures were used (21).…”

Section: Fig 1 Insertional Mutation In Aclymentioning

confidence: 99%

ATP-Citrate Lyase Deficiency in the Mouse

Beigneux

Kosinski

Gavino

et al. 2004

Journal of Biological Chemistry

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131

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ATP-citrate lyase (Acly) is one of two cytosolic enzymes that synthesize acetyl-coenzyme A (CoA). Because acetyl-CoA is an essential building block for cholesterol and triglycerides, Acly has been considered a therapeutic target for hyperlipidemias and obesity. To define the phenotype of Acly-deficient mice, we created Acly knockout mice in which a ␤-galactosidase marker is expressed from Acly regulatory sequences. We also sought to define the cell type-specific expression patterns of Acly to further elucidate the in vivo roles of the enzyme. Homozygous Acly knockout mice died early in development. Heterozygous mice were healthy, fertile, and normolipidemic on both chow and high fat diets, despite expressing half-normal amounts of Acly mRNA and protein. Fibroblasts and hepatocytes from heterozygous Acly mice contained half-normal amounts of Acly mRNA and protein, but this did not perturb triglyceride and cholesterol synthesis or the expression of lipid biosynthetic genes regulated by sterol regulatory elementbinding proteins. The expression of acetyl-CoA synthetase 1, another cytosolic enzyme for producing acetylCoA, was not up-regulated. As judged by ␤-galactosidase staining, Acly was expressed ubiquitously but was expressed particularly highly in tissues with high levels of lipogenesis, such as in the livers of mice fed a highcarbohydrate diet. ␤-Galactosidase staining was intense in the developing brain, in keeping with the high levels of de novo lipogenesis of the tissue. In the adult brain, ␤-galactosidase staining was in general much lower, consistent with reduced levels of lipogenesis; however, ␤-galactosidase expression remained very high in cholinergic neurons, likely reflecting the importance of Acly in generating acetyl-CoA for acetylcholine synthesis. The Acly knockout allele is useful for identifying cell types with a high demand for acetyl-CoA synthesis. ATP-citrate lyase (Acly)1 is a cytosolic enzyme that catalyzes the formation of acetyl-coenzyme A (CoA) and oxaloacetate from citrate and CoA, with the hydrolysis of ATP to ADP and phosphate. Acetyl-CoA is the key building block for de novo lipogenesis. Acly is not, however, the sole source of acetyl-CoA in the cytosol. Another enzyme, acetyl-CoA synthetase 1 (Acs1), generates acetyl-CoA from acetate and CoA, with the hydrolysis of ATP to AMP and diphosphate (1). Whether Asc1 might be sufficient in the setting of a genetic deficiency in Acly is not known. The expression of both Acly and Acs1 is controlled by the sterol regulatory element-binding protein (SREBP)-1c, a transcriptional regulator of fatty acid synthesis (2, 3).An important role for Acly in lipid biosynthesis in the liver has been suggested by studies with the Acly inhibitor hydroxycitrate. In rats treated with hydroxycitrate, the rate of fatty acid and cholesterol synthesis in the liver fall (4). Those experiments and studies with other inhibitors (5-10) have suggested that Acly could represent a therapeutic target for elevated plasma lipid levels. As with other genes involved in lipid...

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“…Knockout mice with targeted disruption of the PCL gene demonstrated no significant physiological effects (37), although PCL activity in knockout cells was substantially reduced. Farnesylcysteine and geranylgeranylcysteine accumulated to high levels in knockout tissues.…”

Section: Prenylated Proteins: Prenylcysteine Lyase a Unique Flavin Amentioning

confidence: 97%

Thematic review series: Lipid Posttranslational Modifications. Lysosomal metabolism of lipid-modified proteins

Hofmann

2006

Journal of Lipid Research

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Much is now understood concerning the synthesis of prenylated and palmitoylated proteins, but what is known of their metabolic fate? This review details metabolic pathways for the lysosomal degradation of S-fatty acylated and prenylated proteins. Central to these pathways are two lysosomal enzymes, palmitoyl-protein thioesterase (PPT1) and prenylcysteine lyase (PCL). PPT1 is a soluble lipase that cleaves fatty acids from cysteine residues in proteins during lysosomal protein degradation. Notably, deficiency in the enzyme causes a neurodegenerative lysosomal storage disorder, infantile neuronal ceroid lipofuscinosis. PCL is a membrane-associated flavin-containing lysosomal monooxygenase that metabolizes prenylcysteine to prenyl aldehyde through a completely novel mechanism.The eventual metabolic fates of other lipidated proteins (such as glycosylphosphatidylinositol-anchored and N-myristoylated proteins) are poorly understood, suggesting directions for future research.

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Prenylcysteine Lyase Deficiency in Mice Results in the Accumulation of Farnesylcysteine and Geranylgeranylcysteine in Brain and Liver

Cited by 23 publications

References 24 publications

Efficient Use of Exogenous Isoprenols for Protein Isoprenylation by MDA-MB-231 Cells Is Regulated Independently of the Mevalonate Pathway

Efficient Use of Exogenous Isoprenols for Protein Isoprenylation by MDA-MB-231 Cells Is Regulated Independently of the Mevalonate Pathway

ATP-Citrate Lyase Deficiency in the Mouse

Thematic review series: Lipid Posttranslational Modifications. Lysosomal metabolism of lipid-modified proteins

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