Homocystine

Cyclocondensation of D-homocystine methyl ester hydrochloride (106) and aldehyde 105 in the presence of Ph3P yielded 9-(benzyloxycarbonyla-mino)-6-oxoperhydropyrido[2,l-f ][l,3]thiazine-4-carboxylate (107) and its diastereomer (97MIP4, 98USP5710129). 

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... 

Rabenstein and Yamashita [52] determined penicillamine and its symmetrical and mixed disulfides by HPLC in biological fluids. Plasma and urine were deproteinized with trichloroacetic acid, and HPLC was performed on a column (25 cm x 4.6 mm) or Biophase ODS (5 pm) with a mobile phase comprising 0.1 M phosphate buffer (pH 3) and 0.34 mM Na octylsulfate at 1 mL/min. Detection was with a dual Hg-Au amalgam electrode versus a Ag-AgCl reference electrode. (z>)-penicillamine and homocysteine were determined at the downstream electrode at +0.15 V, and homocystine, penicillamine-homocysteine, and penicillamine disulfides were first reduced... 

Prognosis is more favorable in the pyridoxine-respon-sive patients. Patients who respond to large doses of vitamin B6 (250-500 mg/day for several weeks) have the best prognosis. Efficacy of treatment usually is reflected in a reduction of blood homocystine and methionine to normal or near-normal levels. Since supplementation with pyridoxine can cause a deficiency of folic acid, the latter should be given (2-5 mg daily) at the same time. Any patient receiving pyridoxine should be monitored carefully for any signs of hepatotoxicity and for a peripheral neuropathy (see Ch. 36). 

The reversibility of reaction (8) has not been observed as yet (H20, M3, R4) and may be attributed to other systems (M2), such as assumed by Racker (R2), the oxidation of GSH to GSSG being coupled to the reduction of homocystine under control of a transhydrogenase. 

R2. Racker, E., Glutathione-homocystine transhydrogenase. ]. Biol. Chem. 217, 867-874 (1955). 

Accumulation of homocystine in blood is associated with cardiovascular disease deep vein thrombosis, thromboembolism, and stroke dislocation of the lens (ectopic lens) and mental retardation. Homocystinemia caused by an enzyme deficiency is a rare, but severe, condition in which atherosclerosis in childhood is a prominent finding. These children often have myocardial infarctions before 20 years of age. Ail patients excrete high levels of homocystine in the urine. Treatment includes a diet low in methionine. The two major enzyme deficiencies producing homocystinemia are ... 

The title compound was synthesized from homocystine (8.06 g, 30 mmol) and fert-butyl acrylate (17.4mL, 120mmol) as described for H-Cys[(CH2)3C02tBu]-0H yield 6.75g (41%). 

Sulfur-containing amino acids such as cystine and homocystine tend to bind to plasma proteins. This binding is irreversible hence, these amino acids will be severely underestimated unless the plasma is deproteinized immediately following its separation from red cells. Blood should be left standing for as short a time as possible to avoid binding of cystine to proteins and hemolysis. 

Aminoisobutyric acid GABA ASA-anhydride 1 ASA-anhydride 2 Homocystine Ethanolamine... 

Hey is a sulphydryl amino acid of molecular weight 135.2. It oxides readily to its disulphide form homocystine, and can be converted to the thiolactone form in acid solution. In normal plasma, Hey exists in various forms the sulphydryl form (approximately 1%), bound to the cysteine residues of proteins (approximately 70%), and bound to free cysteine as cysteine-Hcy mixed disulphide (approximately 30%). When levels are elevated, the disulphide form homocystine is formed. All of these forms can be converted to Hey by chemical reduction and then measured as tHcy. 

Thiols exist in biological systems in various oxidised and reduced forms. Very little Hey in the free sulphydryl form is found in plasma and it exists mainly as cysteine-Hcy mixed disulphide, bound to cysteine residues of plasma proteins, or as its disulphide homocystine, but the latter only when levels are high. Routinely measured tHcy constitutes all of these forms together and is produced by chemical reduction. 

Internal standard D8-DL-homocystine weigh out 5.56 mg D8-DL-homocystine (ARC/CLI DLM 3619) and dissolve in 20 ml demineralised water, adding one drop of formic acid (1.007 mmol/1). A 2-ml aliquot of this solution is made up to 20 ml with water (100 pmol/1). This is then diluted 1 in 4 (25 pmol/1) with demineralised water (stable for at least 1 year at 4°C). 

Calibration standard, 25 pmol/1 homocystine accurately weigh out 33.6 mg L-ho-mocystine (Sigma H-6010) and dissolve in 50 ml demineralised water. This stock is diluted 1 in 100 with phosphate-buffered saline and stored at -20°C in 150-pl aliquots it is stable for at least 1 year. 

P. Hashemi and Z. Rahmani, A novel homocystine-agarose adsorbent for separation and preconcentration of nickel in table salt and baking soda using factorial design optimisation of the experimental conditions, Talanta, 68(5), 2006, 1677-1682. 

A green, air-stable homocystine complex, [Cr (—SCH2CH2CHNH2C02)2 2] (fleet-4.83 BM, vmax = 40 800, 39200 and 14300 cm-1), has been prepared from aqueous CrCl2 and homocystine (pH 8, NaHC03).291... 

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. 

Amino acid abnormalities, such as phenylketonuria, tyrosinemla, alkaptonuria, albinism, histidinemiu, byperprolinemia. homocystin-aria, cyslinuria, and keloaciduria. Note that these names, in general, imply the germane amino acid. 

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

On activation with homocystine the pH optimum was found to shift from 8.6 to 7.3 with Mg2+ as the activating cation and from 9.1 to 8.0 with Mn2+ as the activating cation. The specific activity of the activated enzyme with Mn2+ is the highest yet observed for mammalian FDPase under any assay conditions (Fig. 7). 

Fig. 6. Activation of purified rabbit liver FDPase by homocystine (61).

Fig. 7. Effect of activation of rabbit liver FDPase by homocystine on the pH activity curves (51). (A) Assayed with MgCL (B) assayed with MnCU.

Homocysteine is a nonprotein-building amino acid formed as a metabolite in the methionine cycle. It was first associated with disease in 1962 (1,2). Individuals with a mutation in cystathionine-(3-synthase (CBS) develop classical homocystin-uria with extremely elevated plasma tHcy (> 100 xmol/L) (3). Homocystinuria is characterized by early atherosclerosis and thromboembolism as well as mental retardation and osteoporosis and is ameliorated by vitamin supplementation aimed at reducing the blood concentration of homocysteine (4). 

Gerrrtsen T, Vaughn JG. Waisman HA. The identification of homocystine in the urine. Biochem Biophys Res Commun... 

A 6-month-old child was breast-fed exclusively by a mother who had been a strict vegetarian for at least 7 years. He was totally unresponsive to stimuli. His hemoglobin was 5.7 g/dL, and his bone marrow aspirates showed megaloblastic changes in blood cells. His serum folate and iron were normal. His urine contained increased amounts of homocystine, methylmalonic acid, and glycine. Propose a reason for this infant s illness, and discuss its biochemical etiology. Discuss other possible reasons for the same or similar symptoms in a patient. Explain the abnormal serum and urine chemistries. 

There are two pyridoxal phosphate-requiring enzymes in the homocysteine degradation pathway, which are associated with genetic diseases. In homo-cystinuria, cystathionine synthase is defective, and large amounts of homocystine are excreted in the urine. Some homocystinurics respond to the administration of large doses of vitamin B6. In cystathioninuria, cystathionase is either defective or absent. These patients excrete cystathionine in the urine. Cystathionase is often underactive in the newborns with immature livers, and cysteine and cystine become essential amino acids. Human milk protein is especially rich in cysteine, presumably to prepare the newborn for such a contingency. 

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