Biochemist India: Biochemist India: Methylenetetrahydrofolate reductase gene polymorph...

Tuesday, October 25, 2011

Biochemist India: Methylenetetrahydrofolate reductase gene polymorph...

Biochemist India: Methylenetetrahydrofolate reductase gene polymorph...: Cerebral palsy (CP) covers a group of non-progressive chronic disorders of motor function and posture caused by lesions of the developing fe...

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Lipid of the week : Sphingomyelin

Not merely membrane building blocks, sphingomyelin species carry out important signaling roles as precursor molecules and by providing localized platforms.

Sphingomyelin species comprise a ceramide unit and a phosphorylcholine or phosphoethanolamine polar headgroup. Typically, sphingosine is the long-chain base component of ceramide, although other long-chain bases can be present; differences in the sphingoid base and the fatty acid components (which are very-long-chain saturated and monounsaturated) confer great variability on the composition of sphingomyelins¹.

As a major constituent of cell membranes, sphingomyelin is found at particularly high concentrations in the membranes of nerve cells (in the myelin sheaths) and red blood cells. It was previously thought to have a purely structural role, similar to the function of phosphatidylcholine, through intermolecular interactions mediated by the 2-amide group, the 3-hydroxy group and the 4,5-trans double bond of the sphingoid base. However, it is now appreciated that sphingomyelin has a high affinity for cholesterol and that these two lipids pack tightly into liquid-ordered domains among a liquid-disordered phase to form lipid rafts¹². These membrane microdomains are thought to function as signaling platforms that regulate the localization and interactions of proteins. But sphingomyelin does not just influence signaling as a component of lipid rafts — it is also a precursor to ceramides and other sphingolipid metabolites that comprise the sphingomyelin cycle or sphingolipid network.

Sphingomyelin biosynthesis begins in the Golgi but continues in the plasma membrane. Sphingomyelin synthase catalyzes the transfer of phosphorylcholine from phosphatidylcholine to ceramide. The consequent decrease in ceramide levels is accompanied by an increase in the levels of sphingomyelin and the release of the well-known signaling molecule diacylglycerol. Alternatively, ceramide can also first be converted to ethanolamine phosphorylceramide through the transfer of the head group from phosphatidylethanolamine followed by sequential methylation of the ethanolamine moiety to a choline group, although whether this pathway is physiologically relevant is unknown¹.

Conversely, sphingomyelin can be metabolized to ceramide (and further, to other biologically active sphingolipids such as sphingosine and sphingosine-1-phosphate) by sphingomyelinases. The function of ceramide as a proapoptotic molecule is well known, although the exact mechanism through which this lipid induces cell death is not fully understood. By contrast, a decrease in ceramide levels accompanies the accumulation of sphingomyelin in cells of the brain, spleen and liver that occurs as a consequence of a deficiency in sphingomyelinase in Niemann–Pick disease types A and B¹. Notably, levels of cholesterol are also elevated in Niemann–Pick disease, which is consistent with reports suggesting that the metabolism, as well as the distribution, of these two lipids is linked, which has clear implications for several other diseases.

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Tuesday, October 25, 2011

Biochemist India: Methylenetetrahydrofolate reductase gene polymorph...

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