Degradation of Phospholipids

DEGRADATION OF PHOSPHOLIPIDS

The degradation of phosphoglycerides is performed by phospholipases found in all tissues and pancreatic juice (for a discussion of phospholipid digestion). A number of toxins and venoms have phospholipase activity, and several pathogenic bacteria produce phospholipases that dissolve cell membranes and allow the spread of infection. Sphingomyelin is degraded by the lysosomal phospholipase, sphingomyelinase (see below).

A. Phosphoglycerides

Phospholipases hydrolyze the phosphodiester bonds of phosphoglycerides, with each enzyme cleaving the phospholipid at a specific site. The major phospholipases are shown in Figure 17.11 . [Note: Removal of the fatty acid from carbon 1 or 2 of a phosphoglyceride produces a lysophosphoglyceride, which is the substrate for lysophospholipases. ] Phospholipases release molecules that can serve as second messengers (for example, DAG and IP₃) or that are the substrates for synthesis of messengers (for example, arachidonic acid). Phospholipases are responsible not only for degrading phospholipids, but also for “remodeling” them. For example, phospholipases A₁ and A₂ remove specific fatty acids from membrane-bound phospholipids, which can be replaced with different fatty acids using fatty acyl CoA transferase. This mechanism is used as one way to create the unique lung surfactant DPCC and to insure that carbon 2 of PI (and sometimes of PC) is bound to arachidonic acid. [Note: Barth syndrome, a rare X-linked disorder characterized by cardiomyopathy, muscle weakness, and neutropenia, is the result of defects in cardiolipin remodeling.]

Figure 17.11 Degradation of glycerophospholipids by phospholipases. PIP₂ = phosphatidylinositol 4,5-bisphosphate; R₁ and R₂ = fatty acids; X = an alcohol.

B. Sphingomyelin

Sphingomyelin is degraded by sphingomyelinase, a lysosomal enzyme that hydrolytically removes phosphorylcholine, leaving a ceramide. The ceramide is, in turn, cleaved by ceramidase into sphingosine and a free fatty acid (Figure 17.12 ). [Note: The ceramide and sphingosine released regulate signal transduction pathways, in part by influencing the activity of protein kinase C and, thus, the phosphorylation of its protein substrates. They also promote apoptosis.] Niemann-Pick disease (Types A and B is an autosomal-recessive disease caused by the inability to degrade sphingomyelin due to a deficiency of sphingomyelinase, a type of phospholipase C. In the severe infantile form (Type A, which shows less than 1% of normal enzymic activity), the liver and spleen are the primary sites of lipid deposits and are, therefore, greatly enlarged. The lipid consists primarily of the sphingomyelin that cannot be degraded (Figure 17.13). Infants with this lysosomal storage disease experience rapid and progressive neurodegeneration as a result of deposition of sphingomyelin in the CNS, and they die in early childhood. A less severe variant (Type B, which shows 5% or more of normal activity) with a later age of onset and a longer survival time causes little to no damage to neural tissue, but lungs, spleen, liver, and bone marrow are affected, resulting in a chronic form of the disease. Although Niemann-Pick disease occurs in all ethnic groups, Type A occurs with greater frequency in the Ashkenazi Jewish population.

Figure 17.12 Degradation of sphingomyelin. [Note: Type B is the nonneuropathic form. It has a later age of onset and a longer survival time than Type A.]

Figure 17.13 Accumulation of lipids in spleen cells from a patient with Niemann-Pick disease.