Homocysteine and Methionine

Homocystinuria can be treated in some cases by the administration of pyridoxine (vitamin Bs), which is a cofactor for the cystathionine synthase reaction. Some patients respond to the administration of pharmacological doses of pyridoxine (25-100 mg daily) with a reduction of plasma homocysteine and methionine. Pyridoxine responsiveness appears to be hereditary, with sibs tending to show a concordant pattern and a milder clinical syndrome. Pyridoxine sensitivity can be documented by enzyme assay in skin fibroblasts. The precise biochemical mechanism of the pyridoxine effect is not well understood but it may not reflect a mutation resulting in diminished affinity of the enzyme for cofactor, because even high concentrations of pyridoxal phosphate do not restore mutant enzyme activity to a control level. 

This pyridoxal-phosphate-dependent enzyme [EC 4.2.99.9], also known as cystathionine y-synthase, catalyzes the reaction of O-succinyl-L-homoserine with L-cysteine to produce cystathionine and succinate. The enzyme can also use hydrogen sulfide and methanethiol as substrates, producing homocysteine and methionine, respectively. In the absence of a thiol, the enzyme can also catalyze a /3,y-elimination reaction to form 2-oxobu-tanoate, succinate, and ammonia. 

Loehrer FMT, Schwab R, Angst CP, Haefeli WE, Fowler (1997) Influence of oral S-adeno-sylmethionine on plasma 5-methyltetrahydrofolate, S-adenosylhomocysteine, homocysteine and methionine in healthy humans. J Pharmacol Exp Therapeut 282 845-850... 

The homocystinurias are a group of disorders involving defects in the metabolism of homocysteine. The diseases are inherited as autosomal recessive illnesses, characterized by high plasma and urinary levels of homocysteine and methionine and low levels of cysteine. The most common cause of homocystinuria is a defect in the enzyme cystathionine /3-synthase, which converts homocysteine to cystathionine (Figure 20.21). Individuals who are homozygous for cystathionine [3-synthase deficiency exhibit ectopia lentis (displace ment of the lens of the eye), skeletal abnormalities, premature arte rial disease, osteoporosis, and mental retardation. Patients can be responsive or non-responsive to oral administration of pyridoxine (vitamin B6)—a cofactor of cystathionine [3-synthase. Bg-responsive patients usually have a milder and later onset of clinical symptoms compared with B6-non-responsive patients. Treatment includes restriction of methionine intake and supplementation with vitamins Bg, B, and folate. 

Legume nodules and cyanobacterial heterocysts 1388 4. Metabolism of Homocysteine and Methionine... 

The latter can be converted in one pathway to lysine and in another to homoserine. Homoserine can yield either homocysteine and methionine or threonine. Although threonine is one of the end products and a constituent of proteins, it can also be converted further to 2-oxobutyrate, a precursor of isoleucine. 

Apeland T, Mansoor MA, Strandjord RE, Vefring H, Kristensen O. Folate, homocysteine and methionine loading in patients on carbamazepine. Acta Neurol Scand 2001 103(5) 294-9. 

S-Adenosyl methionine is the major methyl donor in biological reactions. It is regenerated via the intermediates S-adenosyl homocysteine, homocysteine and methionine in the activated methyl cycle. 

How does a diet deficient in folate affect homocysteine and methionine metabolism ... 

A large number of disorders are associated with cobalamin deficiency in infancy or childhood. Of these, the most commonly encountered is the Imerslund-Graesbeck syndrome, a condition that is characterized by inability to absorb vitamin B,2, with or without IF, and proteinuria. It appears to be due to an inability of intestinal mucosa to absorb the vitamin B,2 IF complex. The second most common of these is congenital deficiency of gastric secretion of IF. Very rarely, congenital deficiency of vitamin B12 in a breast-fed infant is due to deficiency of vitamin B12 in maternal breast milk as a result of unrecognized pernicious anemia in the mother. This is rare because most women with undiagnosed and untreated pernicious anemia are infertile. Additionally, there are some rare methylmalonic acidemias (acidurias) caused by inborn errors in homocysteine and methionine metabolism that are responsible for disorders in vitamin B status. ... 

The role of folic acid in the metabolism of homocysteine has received increased interest recently. Elevations of plasma homocysteine concentrations have been shown to be independent risk factors for coronary artery disease and probably cerebrovascular disease (see Chapter 26). The involvement of folate in its coenzyme forms with homocysteine and methionine metabolism is summarized in Figure 30-22. Folate is the principal micronutrient determinant of homocysteine status, and supplementation with folate has been used as a treatment modality to reduce circulating homocysteine concentrations. Primary (fasting) homo-cystinemia can be treated with 0.5 to 5.0mg/day of folic... 

Treatment is directed toward early reduction of the elevated levels of homocysteine and methionine in the blood. In addition to a diet low in methionine, very high oral doses of pyridoxine (vitamin B6) have significantly decreased the plasma levels of homocysteine and methionine in some patients with cystathionine 3-synthase deficiency. (Genetically determined responders to pyridoxine treatment make up approximately 50% of type I homocystinurics.) PLP serves as a cofactor for cystathionine (3-synthase however, the molecular properties of the defective enzyme that confer the responsiveness to B6 therapy are not known. 

Animal experiments suggest that increased concentrations of homocysteine and methionine in the brain may trap adenosine as S-adenosylhomocysteine, diminishing adenosine levels. Because adenosine normally acts as a central nervous system depressant, its deficiency may be associated with a lowering of the seizure threshold as well as a reduction in cognitive function. 

In the nonprotein fraction reduced glutathione, GSH, is ubiquitous, and is commonly a mqjor constituent (Table I). The soluble fraction of plants also includes a variety of other sulfur-containing compounds that are normally present in relatively small amounts (a) Intermediates on the route to protein cysteine and protein methionine, such as cysteine, cystathionine, homocysteine, and methionine, (b) Compounds involved in methyl transfer reactions and polyamine synthesis AdoMet.t AdoHcy, and, presumably, 5 -methyl-thioadenosine. The biochemistry of the compounds in both groups (a) and (b) will be discussed here, (c) Compounds clearly related metabolically to cysteine or methionine, such as 5-methylcysteine and 5-methylmethionine. Because in certain plants these derivatives comprise a major portion of the nonprotein sulfur amino acids, they will be discussed here, (d) A number of compounds of uncertain function, the biochemistry of which has often not been clarified. Discussion of such compounds (Richmond, 1973 Fowden, 1964) is beyond the scope of this chapter. 

Homocystinuria is caused by a deficiency in the enzyme, cystathionine-P-synthase (CBS), and results in the accumulation of homocysteine and methionine. 

Homocyslinuiia is an autosomal recessive condition caused by a deficiency of the enzyme, cystalhionine-p-synthase (CBS), which results in the accumulation of homocysteine and methionine and a deficiency of cystathionine and cysteine. There are other disorders to consider when an elevated homocysteine concentration is identified. These disorders include vitanun Bn uptake or activation defects, which may or may not have associated elevated methylmalonic acid, severe 5,10-methylenetetrahydrofolate reductase deficiency, and 5-methyl-THF-homocysteine meth-yltransferase deficiency. The latter two are typically associated with an elevated homocysteine, but low methionine concentrations, so it is relatively easy to disaiminate these conditions from homocystinuria. It is also important to consider that nongenetic causes of hyperhomocyste-inemia exist, such as dietary deficiencies, end-stage renal disease, and administration of several drugs [6]. 

Figure 17.2 Proposed pathways of bioproduction of volatile sulphur compounds from cysteine, homocysteine and methionine by yeasts. Modified after Vermeulen et al. (2006) and Tan et al. (2012).

Cystathionine fisynthase (EC 4.2.1.22). Failure to form cystathionine from homocysteine and serine. Elevated homocysteine and methionine in serum. Urine contains homocystine and homocysteine-cysteine disulfide. Cystathionine virtually absent from brain, where it is normally present in significant quantities. Mental retardation. Lens detachment. Skeletal abnormalities (tall stature, arachnodactyly). Arterial and venous thrombosis. 

Integrated pulsed amperometry has also been applied for the simultaneous analysis of homocysteine and methionine in plasma [590]. Homocysteine has been established as an independent risk factor for cardiovascular disease [591]. 

Sulphuration of 0-acetylhomoserine to homocysteine is catalysed by enzymes in spinach. The product is further transformed into S-adeno yl-homocysteine and methionine. The main pathway of sulphur to methionine. 

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. 

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