Lithium and valproate decrease the membrane phosphatidylinositol/phosphatidylcholine ratio

Ding, Daobin; Greenberg, Miriam L.

doi:10.1046/j.1365-2958.2003.03284.x

Cited by 20 publications

(17 citation statements)

References 48 publications

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“…While these data suggest that Crg1 may be regulated via the CWI pathway and is transcriptionally responsive to numerous cell wall stressing agents (Figure S9B), we did not detect any drastic fitness defects when crg1 mutants were grown in the presence of cell wall perturbing agents (Figure S9B). However, overexpression of CRG1 in the crg1Δ/Δ mutant did confer resistance to lithium chloride and fenpropimorph, both of which are known perturbants of the cell membrane and other lipid processes (Figure S9C) [53]–[58]. Together these results supports a model in which Crg1 is involved in lipid-related processes that indirectly impinges on cell wall integrity.…”

Section: Resultssupporting

confidence: 58%

A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis

et al. 2011

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Using small molecule probes to understand gene function is an attractive approach that allows functional characterization of genes that are dispensable in standard laboratory conditions and provides insight into the mode of action of these compounds. Using chemogenomic assays we previously identified yeast Crg1, an uncharacterized SAM-dependent methyltransferase, as a novel interactor of the protein phosphatase inhibitor cantharidin. In this study we used a combinatorial approach that exploits contemporary high-throughput techniques available in Saccharomyces cerevisiae combined with rigorous biological follow-up to characterize the interaction of Crg1 with cantharidin. Biochemical analysis of this enzyme followed by a systematic analysis of the interactome and lipidome of CRG1 mutants revealed that Crg1, a stress-responsive SAM-dependent methyltransferase, methylates cantharidin in vitro. Chemogenomic assays uncovered that lipid-related processes are essential for cantharidin resistance in cells sensitized by deletion of the CRG1 gene. Lipidome-wide analysis of mutants further showed that cantharidin induces alterations in glycerophospholipid and sphingolipid abundance in a Crg1-dependent manner. We propose that Crg1 is a small molecule methyltransferase important for maintaining lipid homeostasis in response to drug perturbation. This approach demonstrates the value of combining chemical genomics with other systems-based methods for characterizing proteins and elucidating previously unknown mechanisms of action of small molecule inhibitors.

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Section: Resultssupporting

confidence: 58%

A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis

et al. 2011

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“…This is of interest because PtdIns is a key modulator in several signaling cascades (59) and is a candidate therapeutic target for drugs used to treat bipolar disorder, a disorder that where EPA may be efficacious (60–64). Therefore, an interesting aspect of this study was to examine if EPA in PtdIns would increase upon MEP treatment.…”

Section: Discussionmentioning

confidence: 99%

The low levels of eicosapentaenoic acid in rat brain phospholipids are maintained via multiple redundant mechanisms

Chen

Domenichiello

Trépanier

et al. 2013

Journal of Lipid Research

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Brain eicosapentaenoic acid (EPA) levels are 250- to 300-fold lower than docosahexaenoic acid (DHA), at least partly, because EPA is rapidly β-oxidized and lost from brain phospholipids. Therefore, we examined if β-oxidation was necessary for maintaining low EPA levels by inhibiting β-oxidation with methyl palmoxirate (MEP). Furthermore, because other metabolic differences between DHA and EPA may also contribute to their vastly different levels, this study aimed to quantify the incorporation and turnover of DHA and EPA into brain phospholipids. Fifteen-week-old rats were subjected to vehicle or MEP prior to a 5 min intravenous infusion of 14C-palmitate, 14C-DHA, or 14C-EPA. MEP reduced the radioactivity of brain aqueous fractions for 14C-palmitate-, 14C-EPA-, and 14C-DHA-infused rats by 74, 54, and 23%, respectively; while it increased the net rate of incorporation of plasma unesterified palmitate into choline glycerophospholipids and phosphatidylinositol and EPA into ethanolamine glycerophospholipids and phosphatidylserine. MEP also increased the synthesis of n-3 docosapentaenoic acid (n-3 DPA) from EPA. Moreover, the recycling of EPA into brain phospholipids was 154-fold lower than DHA. Therefore, the low levels of EPA in the brain are maintained by multiple redundant pathways including β-oxidation, decreased incorporation from plasma unesterified FA pool, elongation/desaturation to n-3 DPA, and lower recycling within brain phospholipids.

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“…Both drugs cause a decrease in intracellular myo-inositol and an increase in expression of INO1 as well as the regulatory gene INO2 required for inositol biosynthesis (20). In addition, both drugs lead to a decrease in the phosphatidylinositol/phosphatidylcholine ratio (38). Furthermore, VPA abrogates the normal response to inositol depletion of inositol-responsive genes and leads to aberrant synthesis of phospholipids (39).…”

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confidence: 99%

Human 1-D-myo-Inositol-3-phosphate Synthase Is Functional in Yeast

Shaltiel

Shamir

et al. 2004

Journal of Biological Chemistry

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We have cloned, sequenced, and expressed a human cDNA encoding 1-D-myo-inositol-3-phosphate (MIP) synthase (hINO1). The encoded 62-kDa human enzyme converted D-glucose 6-phosphate to 1-D-myo-inositol 3-phosphate, the rate-limiting step for de novo inositol biosynthesis. Activity of the recombinant human MIP synthase purified from Escherichia coli was optimal at pH 8.0 at 37°C and exhibited K m values of 0.57 mM and 8 M for glucose 6-phosphate and NAD ؉ , respectively. NH 4 ؉ and K ؉ were better activators than other cations tested (Na ؉ , Li ؉ , Mg 2؉ , Mn 2؉ ), and Zn 2؉ strongly inhibited activity. Expression of the protein in the yeast ino1⌬ mutant lacking MIP synthase (ino1⌬/hINO1) complemented the inositol auxotrophy of the mutant and led to inositol excretion. MIP synthase activity and intracellular inositol were decreased about 35 and 25%, respectively, when ino1⌬/hINO1 was grown in the presence of a therapeutically relevant concentration of the anti-bipolar drug valproate (0.6 mM). However, in vitro activity of purified MIP synthase was not inhibited by valproate at this concentration, suggesting that inhibition by the drug is indirect. Because inositol metabolism may play a key role in the etiology and treatment of bipolar illness, functional conservation of the key enzyme in inositol biosynthesis underscores the power of the yeast model in studies of this disorder.

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Lithium and valproate decrease the membrane phosphatidylinositol/phosphatidylcholine ratio

Cited by 20 publications

References 48 publications

A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis

A Systems Biology Approach Reveals the Role of a Novel Methyltransferase in Response to Chemical Stress and Lipid Homeostasis

The low levels of eicosapentaenoic acid in rat brain phospholipids are maintained via multiple redundant mechanisms

Human 1-D-myo-Inositol-3-phosphate Synthase Is Functional in Yeast

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