Homocystine metabolism

The biosynthesis of adenosine is theoretically controlled by several processes namely (1) the biosynthesis of adenosine from AMP by 5 -nucleotidase [EC 3.1.3.5], (2) from S-adenosyl homocysteine by S-adenosyl homocystine hydrolase [EC 3.3.1.1], (3) the metabolism of adenosine to AMP by adenosine kinase [EC 2.7.1.20], and (4) to inosine by adenosine deaminase (ADA) [EC 3.5.4.2], Interestingly, both 5 -nucleotidase and ADA activities were found to be highest in the leptomeninges of rat brain in contrast, the adenosine kinase activity was widely distributed throughout the brain parenchyma, which has negligible ADA activity... 

Correct answer = B. Alkaptonuria is a rare metabolic disease involving a deficiency in homogentisic acid oxidase, and the subsequent accumulation of homogentisic acid in the urine, which turns dark upon standing. The elevation of methylmalonate (due to methylmalonyl CoA mutase deficiency), phenylpyruvate (due to phenylalanine hydroxlyase deficiency), a-ketoisovalerate (due to branched-chain a-ketoacid dehydrogenase deficiency), and homocystine (due to cystathionine synthase deficiency) are inconsistent with a healthy child with darkening of the urine. 

The most effective activator of liver FDPase is homocystine, which is known to be the major catabolic product in the metabolism by methio-... 

Transmethylation yields 1 mole of adenosine for every mole of methylated product. Patients are known with inborn errors that lead to incomplete metabolism of the homocysteine released after transmethylation. Homocysteinurics release about 3 mg of homocysteine per kilogram on unsupplemented diets, more on supplemented (G3, LI). This is minimal, owing to other fates of homocysteine and possible incompleteness of the block (L2). Cystathioninurics have been reported to excrete over a gram of cystathionine per day and up to 0.6 g per gram of creatinine (F6, H3, K9). Since the latter probably have some cystadiioninase, and some remethylation of homocystine may occur, the reported values are also minimal. Nevertheless, the moles of homocysteine and its products are of the same order as the amount of hypoxanthine formed per day. 

A similar separation of 50 physiological amino adds can be obtained with the highly efficient 3 pm cation exchanger from Hitachi (Tokyo, Japan) in about 2 h. The Hitachi column is characterized by an extremely low back pressure of 370-800 psi over the course of the run. In addition to key amino adds related to certain metabolic errors, less common amino acids such as homocysteine, homocitrulline, //o-isoleucine, argininosuccinic acid, cysteine-homocysteine mixed disulfides, homocystine, and argininosuccinic acid anhydride can also be separated under similar chromatographic conditions. 

Investigations into urine and plasma samples must consider that certain compounds such as antibiotics are not metabolized after its administration. Antibiotics pass through the body without changing their structure and, finally, get into the urine or plasma and interfere with the amino acid analysis via reaction with ninhydrin. Perry et al. [52] reported this problem for the first time. In urine samples oxidized with hydrogen peroxide, they detected a signal in the retention range of cysteic acid and homocystine, which they attributed to o-penicillamine-sulfonic acid. This compound was formed by oxidation of the antibiotic D-peni-cillamine, which was administered to the patient whose urine was investigated. 

An inborn error of metabolism in which homocystine is excreted in the urine due to a deficiency of cystathionine synthase, the enzyme which catalyses the formation of cystathionine from homocysteine and serine. Homocysteine is a sulphur containing amino acid and can be detected in the urine by tests for this type of amino acid. Among the symptoms of the condition are minor congenital abnormalities, mental retardation and dislocated lenses. 

When administered to subjects of the metabolic disease cystinuria, cysteine, homocysteine and methionine are excreted largely as additional cystine whereas administered cystine, homocystine and glutathione are almost completely oxidised. From these observations it is concluded that cystine can be metabolised without previous reduction to cysteine, and that glutathione can be meta-bobsed without previous hydrolysis, indicating that the metabolic history of an amino acid may depend on whether it is free or combined. Methionine, previous to its conversion into cysteine is demethylated to form homocysteine, which may undergo condensation to homocystine or degradation to simpler products. 

Reaction 4 is catalysed by cystathionine synthase (EC 4.2.1.13), an enzyme widely distributed in the tissues. In homocystinuria, cystathionine synthase is virtually completely absent or inactive in all tissues examined liver, brain and fibroblasts grown in tissue culture [33]. In some cases 1 to 2% of the normal enzymic activity can be demonstrated, in others no enzymic activity has been found [34]. As a result of the metabolic block, homocysteine accumulates and is partly converted to homocystine, partly to homocysteine-cysteine mixed disulphide and partly S-methylated to methionine by reactions 6 and 7 with, respectively, N -methyltetrahydrofolic acid and betaine as methyl donors. In infancy methionine and homocysteine are present in high concentrations in the plasma while homocystine and homocysteine-cysteine mixed disulphide are excreted in the urine later the concentration of methionine in the plasma drops. Cystathionine is normally present in highest concentration in the cells of the brain, though traces are found elsewhere and in the urine in homocystinuria no cystathionine can usually be demonstrated in the brain or urine [35]. The body s cysteine and cystine are also largely biosynthesized from methionine, though some is obtained from cysteine and cystine in dietary proteins in homocystinuria, cysteine/cystine becomes an essential amino acid. 

In analogy with what is known about the oxidation of cysteine to cystine, one can admit the possibility of the oxidation of homocysteine to homocystine, imder certain conditions, although no exact study of such an oxidation by a biological path seems to have been carried out as yet. It is of interest to compare homocysteine metabolism with that of homocystine. In comparing these two, one notes very distinct differences in the metabolism. The work of Virtue and Doster-Virtue (134) shows that the sulfur of homocystine ingested by dogs is excreted mainly in the form of... 

A number of inborn errors of metabolism are due to an enzyme deficiency which leads to the accumulation of the precursor of that particular pathway. This type of clinical expression was among the first to be described, since simple clinical screening tests often uncovered the increased excretion in the urine, or accumulation in the blood, of early metabolites of the pathway which had been blocked. An important example of such a defect is homocystinuria, where both methionine and homocystine accumulate as the result of the deficiency of activity of cystathionine synthase (Mudd and Levy, 1978). A variant of the foregoing occurs when both the precursor of the main pathway and metab-... 

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