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translocation between cytosol and membrane fractions of the cell. In this context, CCT acts as a sensor for the physical structure of the endoplasmic reticulum membrane. Hydrolysis of PC alters the inherent curvature of the membrane and decreases its stored elastic energy, enabling CCT to bind and thus replenish membrane PC.

The spatial pathway of phospholipid synthesis is illustrated schematically in Figure 4 for the type 2 epithelial cell of the lung alveolus, which synthesizes and secretes lung surfactant. Initial synthesis of phos-pholipids on the endoplasmic reticulum is followed by a complex series of events that include modification of esterified fatty acid groups by a process of acyl remodeling, selective transport between different intracellular membranes, and uptake of selected phos-pholipids into lamellar bodies. These lamellar bodies are intracellular stores of surfactant that, when secreted in response to cell stretch, are actively secreted into the alveolar space where they adsorb to the air-liquid interface, oppose surface tension forces within the lungs, and prevent alveolar collapse. In addition, inactive surfactant is recycled by type 2 cells into endosomes that fuse into multivesicular bodies and subsequently into lamellar bodies.

Although the phospholipid metabolism of the type 2 cell is complex compared to that of most cell types, it demonstrates very well the various stages in phospholipid synthesis, transport, and metabolism with potential for modification of molecular compositions.

A limited number of conditions are known in which alterations to the processes of phospholipid synthesis and metabolism have profound effects on health and survival. In human subjects, the inability to synthesise the major phospholipids, such as PC and PE, is incompatible with life, so most genetic abnormalities have been identified in abundances of more minor phospholipids. For instance, Barth's syndrome is an X-linked recessive disorder characterised by childhood onset of cardiomyopathy, neutropenia, and abnormal mito-chondrial structure and function. The gene affected is the tafazzin gene, responsible for acyl remodeling in cardiolipin synthesis. Cardiolipin is a minor phospho-lipid enriched within the heart and in mitochondria that contains four fatty acid and two phosphate moieties and is synthesised on the endoplasmic reticulum predominately with four oleoyl (Cig-i) chains. Patients with Barth's syndrome are unable to convert this tetra-oleoyl form into the more functional tetralinoleoyl (C18:2) cardiolipin species. This is the only condition

type 2 cell

Figure 4 Synthesis and secretion of lung surfactant phospholipid by the type 2 epithelial cell of the lung alveolus. Phospholipid synthesized in the endoplasmic reticulum (ER) is routed through the Golgi apparatus for uptake and packaging into intracellular storage vesicles called lamellar bodies. In response to cell stretch, lamellar bodies fuse with the plasma membrane and secrete their contents into the alveolar space. After processes of adsorption and desorption from the air-liquid interface, inactive surfactant is recycled into lamellar bodies via endosomes and multivesicular bodies (MVB). Metabolically active type 2 cells occupy only approximately 5% of the surface area of the alveolus, with the thin type 1 cells responsible for gas exchange contributing the other 95%.

type 2 cell

Figure 4 Synthesis and secretion of lung surfactant phospholipid by the type 2 epithelial cell of the lung alveolus. Phospholipid synthesized in the endoplasmic reticulum (ER) is routed through the Golgi apparatus for uptake and packaging into intracellular storage vesicles called lamellar bodies. In response to cell stretch, lamellar bodies fuse with the plasma membrane and secrete their contents into the alveolar space. After processes of adsorption and desorption from the air-liquid interface, inactive surfactant is recycled into lamellar bodies via endosomes and multivesicular bodies (MVB). Metabolically active type 2 cells occupy only approximately 5% of the surface area of the alveolus, with the thin type 1 cells responsible for gas exchange contributing the other 95%.

identified in which the inability to synthesize a precise composition of an individual phospholipid class is apparently responsible for clinical symptoms.

In addition to modification of synthetic mechanisms, alterations to transport and uptake processes can result in severe disease and mortality. ABCA3 is a membrane protein member of the ATP-binding cassette (ABC) family of proteins, which includes the multidrug resistance protein and the ABCA1 protein responsible for reverse cholesterol transport. ABCA3 is though to be involved in the selective uptake and processing of phospholipids destined for lung surfactant assembly within lamellar bodies. Mutations in the ABCA3 gene cause fatal surfactant deficiency in newborn infants and have been recognized as major contributors to lung disease and respiratory failure in infants delivered full term.

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