Glycerophospholipid biosynthesis

Stable Identifier
R-HSA-1483206
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Pathway
Species
Homo sapiens
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Glycerophospholipids are important structural and functional components of biological membranes and constituents of serum lipoproteins and the pulmonary surfactant. In addition, glycerophospholipids act as precursors of lipid mediators such as platelet-activating factor and eicosanoids. Cellular membranes contains a distinct composition of various glycerophospholipids such as phosphatidic acid (PA), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), cardiolipin (CL), lysophosphatidic acid (LPA) and lysobisphosphatidic acid (also known as bis(monoacylglycerol) hydrogen phosphate - BMP).

Glycerophospholipids are first formed by the de novo (Kennedy) pathway using fatty acids activated as acyl-CoA donors. However, the acyl groups of glycerophospholipids are highly diverse and distributed in an asymmetric manner. Saturated and monounsaturated fatty acids are usually esterified at the sn-1 position, whereas polyunsaturated acyl groups are esterified at the sn-2 position. Subsequent acyl chain remodeling (Lands cycle) generates the diverse glycerophospholipid composition and asymmetry characteristic of cell membranes.

In the de novo pathway of glycerophospholipid biosynthesis, lysophosphatidic acid (LPA) is initially formed from glycerol 3-phosphate (G3P). Next, LPA is converted to PA by a LPA acyltransferase (AGPAT, also known as LPAAT), then PA is metabolized into two types of glycerol derivatives. The first is diacylglycerol (DAG) which is converted to triacylglycerol (TAG), PC, and PE. Subsequently, PS is synthesized from PC or PE. The second is cytidine diphosphate-diacylglycerol (CDP-DAG), which is processed into PI, PG, CL, and BMP. Each glycerophospholipid is involved in acyl chain remodeling via cleavage by phospholipases followed by reacylation by an acyltransferase.

Most of the glycerophospholipids are synthesized at the endoplasmic reticulum (ER), however, some, most notably cardiolipin, and BMP are synthesized in the mitochondrial and endosomal membranes respectively. Since the most of the glycerophospholipids are found in all membrane compartments, there must be extensive network of transport of glycerophospholipids from one membrane compartment to another via various mechanisms including diffusion through the cytosol, formation of transportation complexes, and diffusion via membrane contact sites (MCS) (Osman et al. 2011, Lebiedzinska et al. 2009, Lev 2010, Scherer & Schmitz 2011, Orso et al. 2011, Hermansson et al. 2011, Vance & Vance 2008).

Literature References
PubMed ID Title Journal Year
21683693 Oxidized LDL-induced endolysosomal phospholipidosis and enzymatically modified LDL-induced foam cell formation determine specific lipid species modulation in human macrophages

Orsó, E, Grandl, M, Schmitz, G

Chem Phys Lipids 2011
19703651 Interactions between the endoplasmic reticulum, mitochondria, plasma membrane and other subcellular organelles

Lebiedzinska, M, Szabadkai, G, Jones, AW, Duszynski, J, Wieckowski, MR

Int J Biochem Cell Biol 2009
21704024 Metabolism, function and mass spectrometric analysis of bis(monoacylglycero)phosphate and cardiolipin

Scherer, M, Schmitz, G

Chem Phys Lipids 2011
  Biochemistry of Lipids, Lipoproteins and Membranes, 5th Edition

Vance, DE, Vance, JE

  2008
20823909 Non-vesicular lipid transport by lipid-transfer proteins and beyond

Lev, S

Nat Rev Mol Cell Biol 2010
21382416 Mechanisms of glycerophospholipid homeostasis in mammalian cells

Hermansson, M, Hokynar, K, Somerharju, P

Prog Lipid Res 2011
21220505 Making heads or tails of phospholipids in mitochondria

Osman, C, Voelker, DR, Langer, T

J Cell Biol 2011
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