Sphingomyelin, a phospholipid based on sphingosine, can be found in cell membranes as well as in the myelin sheath. The synthesis of sphingomyelin is illustrated in Figure 17.10. In brief, serine and palmitoyl CoA combine, resulting in the loss of CoA and the carboxyl group of serine as CO2. Pyridoxal phosphate, a coenzyme derived from vitamin B6, is required for this reaction, similar to the decarboxylation reactions involved in the synthesis of PE from PS and regulators from amino acids. Following this, the product undergoes a reduction reaction that requires nicotinamide adenine dinucleotide phosphate (NADPH), resulting in the formation of sphinganine (dihydrosphingosine). Sphinganine is then acylated with a long-chain fatty acid (LCFA) at the amino group and subsequently desaturated to produce ceramide, which is the immediate precursor of sphingomyelin and other sphingolipids. Ceramides are crucial for maintaining the skin's water-permeability barrier, and a decrease in ceramide levels is associated with various skin diseases. The addition of phosphorylcholine from PC to ceramide leads to the production of sphingomyelin and DAG. It is worth noting that sphingomyelin in the myelin sheath primarily contains longer-chain fatty acids such as lignoceric acid and nervonic acid, while the gray matter of the brain has sphingomyelin consisting mainly of stearic acid. Moving on to phospholipid degradation, phospholipases, which are present in all tissues and pancreatic juice, are responsible for breaking down phosphoglycerides. Certain toxins, venoms, and pathogenic bacteria produce phospholipases that can dissolve cell membranes and facilitate the spread of infection. Sphingomyelin, on the other hand, is degraded by a lysosomal phospholipase called sphingomyelinase. Phospholipases act by hydrolyzing the phosphodiester bonds of phosphoglycerides, each enzyme cleaving the phospholipid at a specific site. Figure 17.11 illustrates the major phospholipases involved. Phospholipases not only break down phospholipids but also participate in their remodeling. For instance, phospholipases A1 and A2 remove specific fatty acids from membrane-bound phospholipids, which can then be replaced with different fatty acids using fatty acyl CoA transferase. This mechanism is utilized to create the unique lung surfactant DPCC and to ensure that carbon 2 of PI (and sometimes PC) is bound to arachidonic acid. It should be noted that Barth syndrome, an uncommon X-linked disorder characterized by cardiomyopathy, muscle weakness, and neutropenia, arises from defects in cardiolipin remodeling. Phospholipases release molecules that can serve as second messengers, such as DAG and IP3, or can be utilized as substrates for the synthesis of messengers, such as arachidonic acid.
Sphingomyelin, a sphingosine-based phospholipid, is found in cell membranes and in the myelin sheath. The synthesis of sphingomyelin is shown in Figure 17.10. Briefly, palmitoyl CoA condenses with serine, as CoA and the carboxyl group (as CO2) of serine are lost. [Note: This reaction, like the decarboxylation reactions involved in the synthesis of PE from PS and of regulators from amino acids (for example, the catecholamines from tyrosine; see p. 286), requires pyridoxal phosphate (a derivative of vitamin B6) as a coenzyme.] The product is reduced in a nicotinamide adenine dinucleotide phosphate (NADPH)-requiring reaction to sphinganine (dihydrosphingosine). The sphinganine is acylated at the amino group with one of a variety of LCFA and then desaturated to produce a ceramide, the immediate precursor of sphingomyelin (and other sphingolipids, as described on p. 208).
Ceramides play a key role in maintaining the skin’s water-permeability barrier. Decreased ceramide levels are associated with a number of skin diseases.
Phosphorylcholine from PC is transferred to the ceramide, producing sphingomyelin and DAG. [Note: Sphingomyelin of the myelin sheath contains predominantly longer-chain FA such as lignoceric acid and nervonic acid, whereas gray matter of the brain has sphingomyelin that contains primarily stearic acid.]
IV. PHOSPHOLIPID DEGRADATION
The degradation of phosphoglycerides is performed by phospholipases found in all tissues and pancreatic juice. [Note: For a discussion of phospholipid digestion, see p. 175.] 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 B. 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 FA 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 FA from membrane-bound phospholipids, which can be replaced with different FA using fatty acyl CoA transferase. This mechanism is used as one way to create the unique lung surfactant DPCC (see p. 204) 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.] phosphatidylinositol 4,5-bisphosphate; R1 and R2 = fatty acids; X = an alcohol.
B. Sphingomyelin