Biosynthesis choline

Properties Wh. cryst. sol. in water m.w. 257.22 m.p. 142.5-143 C sinters 141 C Toxicology LD50 (oral, mouse) >13 g/kg, (IV, mouse) > 650 mg/kg Storage Extremely hygroscopic Uses Precursor in choline biosynthesis intermediate in catabolic pathway of phosphatidylchoiine natural raw material for pharmaceuticals Manuf./Distrib. Sigma... 

Vitamin Bj 2 is concerned in the biosynthesis of methyl groups of choline and methionine. 

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP, hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26). 

Figure 24-2. Biosynthesis of triaq/lglycerol and phospholipids. ( , Monoacylglycerol pathway (D, glycerol phosphate pathway.) Phosphatidylethanolamine may be formed from ethanolamine by a pathway similar to that shown for the formation of phosphatidylcholine from choline.

The biosynthesis and storage of ACh can be divided into three processes that allow for recovery of hydrolyzed transmitter by choline transport back into the nerve ending, conversion by acetylation to active transmitter and then storage in a vesicle for subsequent release [16-21] (Fig. 11-4). 

Figure 3. Inhibition of phosphatidylcholine biosynthesis by apoptosis-inducing compounds. The target enzyme for the inhibition of PC biosynthesis is shown for several compounds that have further in common that they all induce apoptosis. Abbreviations are as follows CK, choline kinase CPT, cholinephosphotransferase CT, CTP phosphocholine cytidylyltransferase PC, phosphatidylcholine.

Citicoline (cytidinediphosphate-choline/CDP-choline 26) is an intermediate in the biosynthesis of acetylcholine. It has been extensively used for the treatment of neurodegenerative disorders associated with head trauma, stroke, brain aging, and AD. Studies in mice have indicated a protective effect of citicohne against memory impairment induced by adverse environments. A human study recruited 30 patients with mild to moderate AD in a double-blind, randomized and placebo-controlled clinical trial... 

Orotic acid added to rat diet also provokes an. excessive biosynthesis of porphyrins in liver, erythrocytes and bone marrow. Administration of adenine monophosphate (AMP) counteracted this effect of orotic acid intoxication [165]. Haemorrhagic renal necrosis in rats, caused by choline deficiency, can be relieved by orotic acid [166], Simultaneous supplementation of the diet with adenine does not influence the protective effect of orotic acid. It has been suggested that orotic acid may lower the body requirement for choline through a metabolic interaction—orotic acid may stimulate the cytidine phosphate choline pathway of lecthin biosynthesis [166]. 

Transfer of a phosphocholine residue to the free OH group gives rise to phosphatidylcholine (lecithin enzyme l-alkyl-2-acetyl-glycerolcholine phosphotransferase 2.7.8.16). The phosphocholine residue is derived from the precursor CDP-choline (see p. 110). Phos-phatidylethanolamine is similarly formed from CDP-ethanolamine and DAG. By contrast, phosphatidylserine is derived from phosphatidylethanolamine by an exchange of the amino alcohol. Further reactions serve to interconvert the phospholipids—e.g., phosphatidylserine can be converted into phosphatidylethanolamine by decarboxylation, and the latter can then be converted into phosphatidylcholine by methylation with S-adenosyl methionine (not shown see also p. 409). The biosynthesis of phosphatidylino-sitol starts from phosphatidate rather than DAG. 

Fig. 6.11. Formation and function of diacylglycerol. The figure schematically shows two main pathways for formation of diacylglycerol (DAG). DAG can be formed from PtdInsP2 by the action of phospholipase C (PL-C). Another pathway starts from phosphatidyl chohne. Phospholipase D (PL-D) converts phosphatidyl choline to phosphatidic add (Ptd), and the action of phosphatases results in DAG. Arachidonic add, the starting point of biosynthesis of prostaglandins and other intracellular and extracellular messenger substances, can be cleaved from DAG. PKC protein kinase C Ptdins phosphatidyl inositol.

Write the sequence of steps and the net reaction for the biosynthesis of phosphatidylcholine by the salvage pathway from oleate, palmitate, dihydroxyacetone phosphate, and choline. Starting from these precursors, what is the cost (in number of ATPs) of the synthesis of phosphatidylcholine by the salvage pathway ... 

Lysophospholipids have been found in butter serum by Cho et al. (1977). They characterized the sn-1 and -2 lysophosphatidylcholines and phosphatidylethanolamines. It is not known if these compounds are products of degradation or remnants of biosynthesis. Cho et al. (1977) searched for, but did not find, another possible product of enzymatic degradation of milk, phosphatidic acid. Phosphatidic acid can be formed by the action of phospholipase D on phosphatidylcholine, for example, but this enzymatic activity was not detected. The compound is also an important intermediate in the biosynthesis of lipids, but the concentration in tissue is always very low. The amount is also low in milk. Cho et al. (1977) found 1.2 and 0.9 (percent of total lipid P) of the lyso compounds above. The quantities of the other phospholipids were phosphatidylethanolamine, 27.3 -choline, 29.1 -serine, 13.4 -inositol, 2.5 and sphingomyelin, 25.6. 

The pathway for the synthesis of dipalmitoyl-phos-phatidylcholine is illustrated in figure 19.5. The starting species of phosphatidylcholine is made by the CDP-choline pathway (see fig. 19.4). The fatty acid at the sn-2 position, which is usually unsaturated, is hydrolyzed by phospholi-pase A2, and the lysophosphatidylcholine is reacylated with palmitoyl-CoA. This modification permits alteration of the properties of the phospholipid without resynthesis of the entire molecule, a strategy called remodeling. Deacylation-reacylation of phosphatidylcholine occurs in other tissues and provides an important route for alteration of the fatty acid substituents at both the sn-1 and sn-2 positions. For example, fatty acids at the sn-2 position can be replaced by arachidonic acid, which is stored there until needed for eicosanoid biosynthesis, as we discuss later in this chapter. 

Additional regulation of phosphatidylcholine and phosphatidylethanolamine biosynthesis occurs at the second step in the biosynthetic sequence (see fig. 19.4) where either CDP-choline or CDP-ethanolamine are made. For phosphatidylcholine biosynthesis, the activity of CTP phos-phocholine cytidylyltransferase (which makes CDP-choline) is governed by an unusual mechanism. The enzyme... 

Holub, B.J., Piekarski, J. and Leatherland, J.F. (1977). Differential biosynthesis of molecular species of 1,2-diacyl-glycerols and phosphatidyl cholines in cold and warm acclimated goldfish. Lipids 12,316-318. 

Zwingelstein, G., Malak, A.N. and Brichon, G. (1978). Effect of environmental temperature on biosynthesis of liver phosphatidyl choline in the trout. Journal of Thermal Biology 3,229-233. 

Sher, R. B., Aoyama, C., Huebsch, K. A., Ji, S., Kerner, J., Yang, Y., et al. (2006) A rostrocaudal muscular dystrophy caused by a defect in choline kinase beta, the first enzyme in phosphatidylcholine biosynthesis. J Biol Chem 281, 4938-4948. 

Phosphoglycerides may be synthesized either from phosphatidic add or by the so-called salvage pathway. Phosphatidic acid is also an intermediate in triglyceride biosynthesis (Figure 19.4). The phosphatidic acid pathway is relatively minor in eukaryotes phosphatidic acid reacts with CTP to form CDP diglyceride (see Figure 19.15), and the latter may then react with choline or inositol to form phosphatidylinositol or phosphatidylcholine, as in Equations (19.14) and (19.15). 

---