A new enzyme and pathway in cardiolipin synthesis

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Pathways for the synthesis of cardiolipin in E

Thematic Review Series: Glycerolipids. Cardiolipin synthesis for the assembly of bacterial and mitochondrial membranes*

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A Pseudomonas putida cardiolipin synthesis mutant …

The reaction of synthesis involves the conversion of phosphatidylethanolamine and glycerol into PG and is catalyzed by ClsB, a phospholipase D-type cardiolipin synthase.

Biosynthesis of Phosphatidic Acid (PA) and Cardiolipin (CL)

N2 - CDP-diacylglycerol (CDP-DAG) is central to the phospholipid biosynthesis pathways in cells. A prevailing view is that only one CDP-DAG synthase named Cds1 is present in both the endoplasmic reticulum (ER) and mitochondrial inner membrane (IM) and mediates generation of CDP-DAG from phosphatidic acid (PA) and CTP. However, we demonstrate here by using yeast Saccharomyces cerevisiae as a model organism that Cds1 resides in the ER but not in mitochondria, and that Tam41, a highly conserved mitochondrial maintenance protein, directly catalyzes the formation of CDP-DAG from PA in the mitochondrial IM. We also find that inositol depletion by overexpressing an arrestin-related protein Art5 partially restores the defects of cell growth and CL synthesis in the absence of Tam41. The present findings unveil the missing step of the cardiolipin synthesis pathway in mitochondria as well as the flexibile regulation of phospholipid biosynthesis to respond to compromised CDP-DAG synthesis in mitochondria.

isolation of a mutant deficient in cardiolipin synthesis

In eukaryotic cells, cardiolipin synthesis takes places in the mitochondrion

Streptococcus mutans, a causative agent of dental caries in humans, adapts to changing environmental conditions, such as pH, in order to survive and cause disease in the oral cavity. Previously, we have shown that S. mutans increases the proportion of monounsaturated membrane fatty acids as part of its acid-adaptive strategy. Membrane lipids function as carriers of membrane fatty acids and therefore it was hypothesized that lipid backbones themselves could participate in the acid adaptation process. Lipids have been shown to protect other bacterial species from rapid changes in their environment, such as shifts in osmolality and the need for long-term survival. In the present study, we have determined the contribution of cardiolipin (CL) to acid resistance in S. mutans. Two ORFs have been identified in the S. mutans genome that encode presumptive synthetic enzymes for the acidic phospholipids: phosphatidylglycerol (PG) synthase (pgsA, SMU.2151c) and CL synthase (cls, SMU.988), which is responsible for condensing two molecules of PG to create CL. A deletion mutant of the presumptive cls gene was created using PCR-mediated cloning; however, attempts to delete pgsA were unsuccessful, indicating that pgsA may be essential. Loss of the presumptive cls gene resulted in the inability of the mutant strain to produce CL, indicating that SMU.988 encodes CL synthase. The defect in cls rendered the mutant acid sensitive, indicating that CL is required for acid adaptation in S. mutans. Addition of exogenous CL to the mutant strain alleviated acid sensitivity. MS indicated that S. mutans could assimilate exogenous CL into the membrane, halting endogenous CL incorporation. This phenomenon was not due to repression, as a cls gene transcriptional reporter fusion exhibited elevated activity when cells were supplemented with exogenous CL. Lipid analysis, via MS, indicated that CL is a reservoir for monounsaturated fatty acids in S. mutans. We demonstrated that the cls mutant exhibits elevated F-ATPase activity but it is nevertheless unable to maintain the normal membrane proton gradient, indicating cytoplasmic acidification. We conclude that the control of lipid backbone synthesis is part of the acid-adaptive repertoire of S. mutans.

Since the phospholipid cardiolipin (CL) is required for function of the mitochondrial respiratory chain, we examined the dynamics of CL synthesis in growing Hela cells immediately after and 12 h post-fusion.

The dynamics of cardiolipin synthesis post …

Phosphatidylglycerol is a precursor in the synthesis of both cardiolipin and PI ..

Genes in the S. mutans genome encoding synthetic enzymes for the major acidic lipids are phosphatidylglycerol (PG) synthase (pgsA, encoded by SMU.2151c) and cardiolipin (CL) synthase (cls, encoded by SMU.988) (). PG is a phospholipid containing a glycerol-3-phosphate backbone with two acyl groups attached to carbons 1 and 2 through ester linkages. The other predominant acidic lipid, CL, consists of two PG molecules linked by a central glycerol; thus it contains four acyl groups and two phosphate molecules ().

AB - CDP-diacylglycerol (CDP-DAG) is central to the phospholipid biosynthesis pathways in cells. A prevailing view is that only one CDP-DAG synthase named Cds1 is present in both the endoplasmic reticulum (ER) and mitochondrial inner membrane (IM) and mediates generation of CDP-DAG from phosphatidic acid (PA) and CTP. However, we demonstrate here by using yeast Saccharomyces cerevisiae as a model organism that Cds1 resides in the ER but not in mitochondria, and that Tam41, a highly conserved mitochondrial maintenance protein, directly catalyzes the formation of CDP-DAG from PA in the mitochondrial IM. We also find that inositol depletion by overexpressing an arrestin-related protein Art5 partially restores the defects of cell growth and CL synthesis in the absence of Tam41. The present findings unveil the missing step of the cardiolipin synthesis pathway in mitochondria as well as the flexibile regulation of phospholipid biosynthesis to respond to compromised CDP-DAG synthesis in mitochondria.

is a precursor in the synthesis of both cardiolipin and PI (Phosphatidylinositol).
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  • Lipogenesis: the pathway of fatty acid synthesis

    Figure 1: Cardiolipin synthesis and remodeling pathway in humans and yeast

  • The role of phospholipids in cell function - ScienceDirect

    Impaired Cardiolipin Biosynthesis Prevents Hepatic Steatosis and Diet-Induced Obesity

  • THE ROLE OF PHOSPHOLIPIDS IN CELL FUNCTION William Dowhan lo II

    In Vivo and in Vitro Synthesis of Phosphatidylglycerol by an Escherichia coli Cardiolipin Synthase

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Cardiac + Myopathy; Cardiomyopathy

Thomas Whitfield, of Oxford University and Oxford BioLabs found that “L-carnitine stimulates energy production and cardiolipin synthesis within the cell membranes of hair follicles.

Carnitine metabolism: General principles

CDP-diacylglycerol (CDP-DAG) is central to the phospholipid biosynthesis pathways in cells. A prevailing view is that only one CDP-DAG synthase named Cds1 is present in both the endoplasmic reticulum (ER) and mitochondrial inner membrane (IM) and mediates generation of CDP-DAG from phosphatidic acid (PA) and CTP. However, we demonstrate here by using yeast Saccharomyces cerevisiae as a model organism that Cds1 resides in the ER but not in mitochondria, and that Tam41, a highly conserved mitochondrial maintenance protein, directly catalyzes the formation of CDP-DAG from PA in the mitochondrial IM. We also find that inositol depletion by overexpressing an arrestin-related protein Art5 partially restores the defects of cell growth and CL synthesis in the absence of Tam41. The present findings unveil the missing step of the cardiolipin synthesis pathway in mitochondria as well as the flexibile regulation of phospholipid biosynthesis to respond to compromised CDP-DAG synthesis in mitochondria.

Parkview Health Laboratory: Test Directory

In hepatocytes, mTORC2 stimulates in particular the production of two lipid species important for cell growth: sphingolipids and cardiolipins. The first are structural components of cell membranes, which have to be continuously supplied in rapidly proliferating cells. Cardiolipins are located in the cellular powerhouse, the mitochondria, and are involved in energy production. By enhancing cardiolipin synthesis, the energy-hungry tumor cells ensure their energy supply. "Cancer cells depend on the new synthesis of fatty acids and lipids; if you turn off the tap, you stop the development of tumors."

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