Choline synthesis and

The data of the previous section have indicated that brain tissue is able to convert endogenous Ptd-ethanolamine to Ptd-choline by the stepwise methylation pathway. The fact that the addition of exogenous PDE brings about higher rate of Ptd-choline synthesis and the different results obtained at two different pH values with and without PDE addition already indicated that the methyl transferases acting upon membrane-bound Ptd-ethanolamine might be functioning at different pH optima. 

Acetylcholine Precursors. Early efforts to treat dementia using cholinomimetics focused on choline [62-49-7] (12) supplement therapy (Fig. 3). This therapy, analogous to L-dopa [59-92-7] therapy for Parkinson s disease, is based on the hypothesis that increasing the levels of choline in the brain bolsters acetylcholine (ACh) synthesis and thereby reverses deficits in cholinergic function. In addition, because choline is a precursor of phosphatidylcholine as well as ACh, its supplementation may be neuroprotective in conditions of choline deficit (104). 

The neurotransmitter must be present in presynaptic nerve terminals and the precursors and enzymes necessary for its synthesis must be present in the neuron. For example, ACh is stored in vesicles specifically in cholinergic nerve terminals. It is synthesized from choline and acetyl-coenzyme A (acetyl-CoA) by the enzyme, choline acetyltransferase. Choline is taken up by a high affinity transporter specific to cholinergic nerve terminals. Choline uptake appears to be the rate-limiting step in ACh synthesis, and is regulated to keep pace with demands for the neurotransmitter. Dopamine [51 -61-6] (2) is synthesized from tyrosine by tyrosine hydroxylase, which converts tyrosine to L-dopa (3,4-dihydroxy-L-phenylalanine) (3), and dopa decarboxylase, which converts L-dopa to dopamine. 

Die neurological disorder associated with severe vitamin B12 deficiency is termed funicular myelitis. Vitamin B12 deficiency leads to disturbed choline-, phospholipid-, and nucleic-acid synthesis, resulting in spinal marrow damages. Disturbed myelin synthesis finally causes irreversible neurological failure. In addition, there are psychiatric disturbances (disturbed memory, apathy). 

Figure 6.1 Synthesis and metabolism of acetylcholine. Choline is acetylated by reacting with acetyl-CoA in the presence of choline acetyltransferase to form acetylcholine (1). The acetylcholine binds to the anionic site of cholinesterase and reacts with the hydroxy group of serine on the esteratic site of the enzyme (2). The cholinesterase thus becomes acetylated and choline splits off to be taken back into the nerve terminal for further ACh synthesis (3). The acetylated enzyme is then rapidly hydrolised back to its active state with the formation of acetic acid (4)...

Low concentrations of solubilised jS-albumin inhibit ACh release in slices from rat hippocampus and cortex areas which show degeneration in AzD, but not in slices from the striatum which is unaffected. While not totally specific to ACh, since some inhibition of NA and DA and potentiation of glutamate release have been reported, this effect is achieved at concentrations of A/i below those generally neurotoxic. Since jS-amyloid can inhibit choline uptake it is also possible (see Auld, Kar and Quiron 1998) that in order to obtain sufficient choline for ACh synthesis and the continued function of cholinergic neurons, a breakdown of membrane phosphatidyl choline is required leading to cell death (so-called autocannibalism), /i-amyloid can also reduce the secondary effects of Mi receptor activation such as GTPase activity... 

Enhancing its synthesis (and presumed release) through giving the precursor choline... 

Acetylcholine synthesis and neurotransmission requires normal functioning of two active transport mechanisms. Choline acetyltransferase (ChAT) is the enzyme responsible for ACh synthesis from the precursor molecules acetyl coenzyme A and choline. ChAT is the neurochemical phenotype used to define cholinergic neurons although ChAT is present in cell bodies, it is concentrated in cholinergic terminals. The ability of ChAT to produce ACh is critically dependent on an adequate level of choline. Cholinergic neurons possess a high-affinity choline uptake mechanism referred to as the choline transporter (ChT in Fig. 5.1). The choline transporter can be blocked by the molecule hemicholinium-3. Blockade of the choline transporter by hemicholinium-3 decreases ACh release,... 

Another observation on oxalate formation is that other a-keto acids, such as oxalosuccinic acid (74) and a-ketoglutaric acid (106) do not seem to yield oxalate directly but indirectly (123). This appears to be due to the fact that only oxaloacetic acid can function as an acetate donor. In this connection the intervention of Coenzyme A may be considered, since it is reported to function in the acetylation of sulfanilamide and choline (73) and recently was shown to take part in the enzymatic synthesis of citric acid. This concept may be illustrated as follows ... 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

Miquel, K., Pradines, A., Terce, F., Sehni, S., and Favre, G., 1998, Compehhve inhibition of choline phosphotransferase by geranylgeraniol and famesol inhibits phosphatidylchohne synthesis and induces apoptosis in human lung adenocarcinoma A549 ceUs. JBiol Chem. 273 26179-26186... 

Glycerophospholipids are used for membrane synthesis and for producing a hydrophilic surface layer on lipoproteins such as VLDL. In cell membranes, they also serve as a reservoir of second messengers such as diacylglycerol, inositol 1,4,5-triphosphate, and arachidonic acid. Their structure is similar to triglycerides, except that the last fatty acid is replaced by phosphate and a water-soluble group such as choline (phosphatidylcholine, lecithin) or inositol (phosphatidyl-inositol). 

Synthesis and characterization of the 12-ring zeolites UZM-4 (BPH) and UZM-22 (MEI) via the charge density mismatch approach in the Choline-Li20-Sr0-Al203-Si02 system. Stud. Surf. Sd. Catal., vol 170A, Elsevier, Amsterdam, pp. 347-354. 

Hypersensitivity to salicylates or nonsteroidal anti-inflammatory drugs (NSAIDs). Use extreme caution in patients with history of adverse reactions to salicylates. Cross-sensitivity may exist between aspirin and other NSAIDs that inhibit prostaglandin synthesis, and aspirin, and tartrazine. Aspirin cross-sensitivity does not appear to occur with sodium salicylate, salicylamide, or choline salicylate. Aspirin hypersensitivity is more prevalent in those with asthma, nasal polyposis, chronic urticaria. 

T.R. DeGrado, R.E. Coleman, S. Wang, S.W. Baldwin, M.D. Orr, C.N. Robertson, T.J. Polascik, D.T. Price, Synthesis and evaluation of F-labeled choline as an oncologic tracer for positron emission tomography Initial findings in prostate cancer. Cancer Res. 61 (2001) 110-117. 

Cholinesterase inhibitors cross the blood-brain barrier and decrease enzymatic hydrolysis of acetylcholine in the synaptic cleft, thereby increasing acetylcholine availability for neurotransmission. The rationale for using cholinergic agents to treat Alzheimer s disease stems from evidence of decreased cerebral choline acetyltrans-ferase (the enzyme responsible for acetylcholine synthesis) and cholinergic neuron loss in the nucleus basalis of Meynert, which correlate with plaque formation and cognitive impairment (Arendt et al. 1985 Davies and Maloney 1976 Etienne et al. 1986 Perry et al. 1978b). 

Diethanolamine has been shown to inhibit choline uptake into cultured Syrian hamster embryo (SHE) and Chinese hamster ovary cells and to inhibit the synthesis of phosphatidylcholine in in-vitro systems in a concentration-dependent, competitive and reversible manner (Lehman-McKeeman Gamsky, 1999, 2000). Diethanolamine treatment caused a marked reduction in hepatic choline metabolite concentrations in mice following two weeks of dermal dosing. The most pronounced reduction was in the hepatic concentration of phosphocholine, the intracellular storage form of choline (Stott et al, 2000). Moreover, the pattern by which choline metabolites were altered was similar to the pattern of change that has been observed following dietary choline deprivation in rodents (Pomfret et al, 1990). Excess choline also prevented diethanolamine-induced inhibition of phosphatidylcholine synthesis and incorporation of diethanolamine into SHE cell phospholipids (Lehman-McKeeman Gamsky, 2000). 

Lehman-McKeeman, L.D. Gamsky, E.A. (1999) Diethanolamine inhibits choline uptake and phosphatidylcholine synthesis in Chinese hamster ovary cells. Biochem. biophys. Res. Comm., 262, 600-604... 

Homocysteine (Hey) metabolism is closely linked to that of the essential amino acid methionine and thus plays a central role in several vital biological processes. Methionine itself is needed for protein synthesis and donates methyl groups for the synthesis of a broad range of vital methylated compounds. It is also a main source of sulphur and acts as the precursor for several other sulphur-containing amino acids such as cystathionine, cysteine and taurine. In addition, it donates the carbon skeleton for polyamine synthesis [1,2]. Hey is also important in the metabolism of folate and in the breakdown of choline. Hey levels are determined by its synthesis from methionine, which involves several enzymes, its remethylation to methionine and its breakdown by trans-sulphuration. 

It is postulated that inhibition of PtdCho synthesis and the release of choline are key steps associated with excitotoxicity and are common to NMDA and AMPA receptor stimulation. The mechanism of inhibition of PtdCho is not fully understood. Metabolic labeling experiments in cortical cultures demonstrate that NMDA receptor over activation does not modify the activity of phosphochohne or phospho-ethanolamine cytidylyltransferases but strongly inhibits choline and ethanolamine phosphotransferase activities. This effect is observed well before any significant membrane damage and cell death. Moreover, cholinephosphotransferase activity is lower in microsomes from NMDA-treated cells. These results show that membrane... 

Gasull T., DeGregorio-Rocasolano N., Zapata A., and Trullas R. (2000). Choline release and inhibition of phosphatidylcholine synthesis precede excitotoxic neuronal death but not neurotoxicity induced by serum deprivation. J. Biol. Chem. 275 18350-18357. 

Leslie, G.M. and Buckley, G.T. (1976). Phospholipid composition of goldfish (Carassius auratus) liver and brain and temperature-dependence of phosphatidyl choline synthesis. Comparative Biochemistry and Physiology 53B, 335-337. 

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