Homocysteine oxidation

Specifically, the quick, accurate determination of homocysteine is critical, because its concentration indicates the risk of heart attrack. Chailapkul et al.[l2] have studied the electrochemical oxidation of homocysteine both at as deposited and anodized (oxidized) BDD thin film electrodes with cyclic voltammetry, flow injection analysis and high-pressure liquid chromatography with amperometric detection. It was found that the anodized BDD electrodes provided highly reproducible, well-defined cyclic voltammograms for homocysteine oxidation in acidic media, while as-deposited diamond did not provide a detectable signal. In alkaline media, however, the oxidation response was obtained, both at as-deposited and anodized diamond electrodes, as shown in the Fig. 15.5. 

Mechanistic aspects of the action of folate-requiring enzymes involve one-carbon unit transfer at the oxidation level of formaldehyde, formate and methyl (78ACR314, 8OMI2I6OO) and are exemplified in pyrimidine and purine biosynthesis. A more complex mechanism has to be suggested for the methyl transfer from 5-methyl-THF (322) to homocysteine, since this transmethylation reaction is cobalamine-dependent to form methionine in E. coli. 

Immobilized dihydrolipoamide (thioctic acid) (Gorecki and Patchornick, 1973 Gorecki and Patchornick, 1975) and immobilized N-acetyl-homocysteine thiolactone (Eldjarn and Jellum, 1963 Jellum, 1964) are the two most commonly used immobilized disulfide reductants. In addition, immobilized TCEP provides a reducing matrix that is free of thiols (Thermo Fisher). Such immobilized reductants successfully can be used to reduce many types of biological disulfides, including small molecules like oxidized glutathione and bovine insulin. They... 

High levels of homocysteine or one of its metabolites may directly affect brain function. The administration of homocysteine to rats induces grand mal convulsions, a phenomenon that is aggravated by either methionine or pyridoxine. Homocysteine-induced blockade of the y-aminobutyric acid (GABA) receptor may be involved. In addition, brain can oxidize homocysteine to homocys-teic acid, which has a glutamatergic activity. 

The response-to-injury hypothesis states that risk factors such as oxidized LDL, mechanical injury to the endothelium, excessive homocysteine, immunologic attack, or infection-induced changes in endothelial and intimal function lead to endothelial dysfunction and a series of cellular interactions that culminate in atherosclerosis. The eventual clinical outcomes may include angina, myocardial infarction, arrhythmias, stroke, peripheral arterial disease, abdominal aortic aneurysm, and sudden death. 

The best characterized B 12-dependent methyltransferases is methionine synthase (Figure 15.11) from E. coli, which catalyses the transfer of a methyl group from methyltetrahydrofolate to homocysteine to form methionine and tetrahydrofolate. During the catalytic cycle, B12 cycles between CH3-Co(in) and Co(I). However, from time to time, Co(I) undergoes oxidative inactivation to Co(II), which requires reductive activation. During this process, the methyl donor is S-adenosylmethionine (AdoMet) and the electron donor is flavodoxin (Fid) in E. coli, or methionine synthase reductase (MSR) in humans. Methionine synthase... 

S-Nitroso derivatives of the biological thiols—glutathione, cysteine (115) and homocysteine—have been considered as bioactive intermediates in the metabolism of organic nitrates and the endothelium-derived relaxing factor with properties of nitric oxide. A simple, rapid and reproducible method for separating these thiols from their... 

Of considerable biochemical interest, several factors are associated with Alzheimer s disease but their significance is not known. An elevated plasma level of homocysteine is associated with the disease and it is considered as a risk factor for development of the disease. The damage may be caused by a degradation product of homocysteine a thio-lactone which causes oxidative damage to cells (Chapter 22 see Figure 22.7). 

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

There are two reports describing the preparation of derivatives of 1,2-thiazetidine-1,1-dioxide. The sulfur atom in L-cystine diethyl ester was oxidized and the corresponding sulfonyl chloride was cyclized with ammonia (Scheme 3) (60CB784). A similar transformation used protected )3-homocysteine as starting material (94LA251). 

Vitamin Bjj (8.50, cobalamin) is an extremely complex molecule consisting of a corrin ring system similar to heme. The central metal atom is cobalt, coordinated with a ribofuranosyl-dimethylbenzimidazole. Vitamin Bjj occurs in liver, but is also produced by many bacteria and is therefore obtained commercially by fermentation. The vitamin is a catalyst for the rearrangement of methylmalonyl-CoA to the succinyl derivative in the degradation of some amino acids and the oxidation of fatty acids with an odd number of carbon atoms. It is also necessary for the methylation of homocysteine to methionine. 

When present in excess methionine is toxic and must be removed. Transamination to the corresponding 2-oxoacid (Fig. 24-16, step c) occurs in both animals and plants. Oxidative decarboxylation of this oxoacid initiates a major catabolic pathway,305 which probably involves (3 oxidation of the resulting acyl-CoA. In bacteria another catabolic reaction of methionine is y-elimination of methanethiol and deamination to 2-oxobutyrate (reaction d, Fig. 24-16 Fig. 14-7).306 Conversion to homocysteine, via the transmethylation pathway, is also a major catabolic route which is especially important because of the toxicity of excess homocysteine. A hereditary deficiency of cystathionine (3-synthase is associated with greatly elevated homocysteine concentrations in blood and urine and often disastrous early cardiovascular disease.299,307 309b About 5-7% of the general population has an increased level of homocysteine and is also at increased risk of artery disease. An adequate intake of vitamin B6 and especially of folic acid, which is needed for recycling of homocysteine to methionine, is helpful. However, if methionine is in excess it must be removed via the previously discussed transsulfuration pathway (Fig. 24-16, steps h and z ).310 The products are cysteine and 2-oxobutyrate. The latter can be oxidatively decarboxylated to propionyl-CoA and further metabolized, or it can be converted into leucine (Fig. 24-17) and cysteine may be converted to glutathione.2993... 

Other neurotransmitters. The abundant glutamate, GABA, and glycine are major neurotransmitters. Do other amino acids also function in the brain Roles for L-aspartate and D-serine (p. 1785) have been identified, but it is very difficult either to discover or to disprove a neurotransmitter function for other amino acids. It is even more difficult for small amounts of various amines and small peptides that are present in the brain. Taurine (Fig. 24-25) is one of the most abundant free amino acids in animals and meets several criteria for consideration as both an inhibitory and an excitatory transmitter.797 798 However, its function is still uncertain (see Chapter 24). Homocysteic acid, formed by oxidation of homocysteine, is a powerful neuroexcitatory substance, but its concentration in the brain is very low.149 d-Aspartate is also present... 

Paran, E. and Engelhard, Y. 2001. Effect of Lyc-O-Mato, standardized tomato extract on blood pressure, serum lipoproteins, plasma homocysteine and oxidative stress markers in grade 1 hypertensive patients. In Proceedings of the 16th Annual Scientific Meeting of the Society of Hypertension , San Francisco, USA. 

---