Methionine metabolism deficiency

Although clinical deficiency disease is rare, there is evidence that a significant proportion of the population have marginal vitamin Bg status. Moderate deficiency results in abnormalities of tryptophan and methionine metabolism. Increased sensitivity to steroid hormone action may be important in the development of hormone-dependent cancer of the breast, uterus, and prostate, and vitamin Bg status may affect the prognosis. 

Measurement of blood tHcy is usually performed for one of three reasons (1) to screen for inborn errors of methionine metabolism (2) as an adjunctive test for cobalamin deficiency (3) to aid in the prediction of cardiovascular risk. Hyperhomocysteinemia, defined as an elevated level of tHcy in blood, can be caused by dietary factors such as a deficiency of B vitamins, genetic abnormalities of enzymes involved in homocysteine metabolism, or kidney disease. All of the major metabolic pathways involved in homocysteine metabolism (the methionine cycle, the transsulfuration pathway, and the folate cycle) are active in the kidney. It is not known, however, whether elevation of plasma tHcy in patients with kidney disease is caused by decreased elimination of homocysteine in the kidneys or by an effect of kidney disease on homocysteine metabolism in other tissues. Additional factors that also influence plasma levels of tHcy include diabetes, age, sex, lifestyle, and thyroid disease (Table 21-1). 

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. ... 

Several inherited disorders of methionine metabolism (Chapter 17) give rise to exeessive production of homocysteine, HS-CH2-CH2CH(NH3 )COO , and its excretion in urine. The most common form of homocystinuria is due to a deficiency of cystathionine synthase (Chapter 17). A major clinical manifestation of homocystinuria is connective tissue abnormalities that are probably due to the accumulation of homocysteine, which either inactivates the reactive aldehyde groups or impedes the formation of polyfunctional cross-links. 

Methionine metabolism is very dependent on both FH4 and vitamin B12. Homocysteine is derived from methionine metabolism and can be converted back into methionine by using both methyl-FH4 and vitamin B12. This is the only reaction in which methyl-FH4 can donate the methyl group. If the enzyme that catalyzes this reaction is defective, or if vitamin B12 or FH4 levels are insufficient, homocysteine will accumulate. Elevated homocysteine levels have been linked to cardiovascular and neurologic disease. A vitamin B12 deficiency can be brought about by the lack of intrinsic factor, a gastric protein required for the absorption of dietary B12. A consequence of vitamin B12 deficiency is the accumulation of methyl-FH4 and a decrease in other folate derivatives. This is known as the... 

Cirrhosis of the liver in man is often found in chronic alcoholism and is probably due to dietary deficiency. In active fatty alcoholic cirrhosis, choline administration has been shown to lead to a decrease in liver fat. An increase in the rate of phospholipid turnover, following administration of 10 g. of choline or methionine, has been demonstrated in patients with cirrhosis who had evidence of fatty infiltration of the liver as shown by biopsy. In animals, vitamin B12 and folic acid are intimately related to choline and methionine metabolism and are important in the prevention of fatty livers under certain conditions. Whether these vitamins are related to accumulation of fat in the liver and cirrhosis in man remains to be ascertained. The value of high protein diets in the prevention and treatment of experimental dietary cirrhosis in animals is well established there is much evidence that such is also true in man (see also p. 521). 

Most studies of vitamin B requirements have followed the development of abnormalities of tryptophan and methionine metabolism during depletion and normalization during repletion with graded intakes of the vitamin. Adults maintained on vitamin B -deficient diets develop abnormalities of tryptophan and methionine metabolism faster, and their blood vitamin B falls more rapidly, when their protein... 

Homocysteine is markedly elevated in different inborn errors of homocysteine metabolism such as cystathionine p-synthase, methionine synthase deficiencies,... 

Although some 80% of the total body pool of vitamin Bg is associated with muscle glycogen phos-phorylase, this pool turns over relatively slowly. The major metabolic role of the remaining 20% of total body vitamin Bg, which turns over considerably more rapidly, is in amino acid metabolism. Therefore, a priori, it seems likely that protein intake will affect vitamin Bg requirements. People maintained on (experimental) vitamin Bg-deficient diets develop abnormalities of tryptophan and methionine metabolism faster, and their blood vitamin Bg falls more rapidly, when their protein intake is high. Similarly, dming repletion of deficient subjects, tryptophan and methionine metabolism and blood vitamin Bg are normalized faster at low than at high levels of protein intake. 

A high intracerebral level of S-adenosylhomocysteine may inhibit methylation reactions involving S-adenosyl-methionine. The metabolic repercussions would be extensive, including deficient methylation of proteins and of phos-phatidylethanolamine as well as an inhibition of catechol-O-methyltransferase and histamine-N-methyltransferase. 

Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12. In the absence of normal B12 activation, homocystinuria results from a failure of normal vitamin B12 metabolism. Complementation analysis classifies defects in vitamin B12 metabolism into three groups cblC (most common), cblD and cblF. Most individuals become ill in the first few months or weeks of life with hypotonia, lethargy and growth failure. Optic atrophy and retinal changes can occur. Methylmalonate excretion is excessive, but less than in methylmalonyl-CoA mutase deficiency, and without ketoaciduria or metabolic acidosis. 

B37. Brown, D. D., Silva, O. L., Gardiner, R. C., and Silverman, M., Metabolism of formiminoglutamic acid by vitamin B12 and folic acid deficient rats fed excess methionine. J. Biol. Chem. 235, 2058-2062 (1960). 

It is the role of jV5-methyl THF which is key to understanding the involvement of cobalamin in megaloblastic anaemia. The metabolic requirement for N-methyl THF is to maintain a supply of the amino acid methionine, the precursor of S-adenosyl methionine (SAM), which is required for a number of methylation reactions. The transfer of the methyl group from jV5-methyl THF to homocysteine is cobalamin-dependent, so in B12 deficiency states, the production of SAM is reduced. Furthermore, the reaction which brings about the formation of Ns-methyl THF from N5,N10-methylene THF is irreversible and controlled by feedback inhibition by SAM. Thus, if B12 is unavailable, SAM concentration falls and Ah -methyl THF accumulates and THF cannot be re-formed. The accumulation of AT-methyl THF is sometimes referred to as the methyl trap because a functional deficiency of folate is created. 

Valine, methionine, isoleucine, and threonine are all metabolized through the propionic acid pathway (also used for odd-carbon fatty acids). Defidency of either enzyme results in neonatal ketoacidosis from failure to metabolize ketoacids produced from these four amino adds. The defidendes may be distinguished based on whether meth)dmalonic adduria is present. A diet low in protein or a semisynthetic diet with low amounts of valine, methionine, isoleudne, and threonine is used to treat both deficiencies. 

Cyanocobalamin A cofactor required for essential enzymatic reactions that form tetrahydrofolate, convert homocysteine to methionine, and metabolize l-methylmalonyl-CoA Adequate supplies are required for amino acid and fatty acid metabolism, and DNA synthesis Treatment of vitamin B12 deficiency, which manifests as megaloblastic anemia and is the basis of pernicious anemia Parenteral vitamin B12 is required for pernicious anemia and other malabsorption syndromes Toxicity No toxicity associated with excess vitamin B12... 

Fig. 2.2.1 Outline of homocysteine metabolism in man. BMT Betaine methyltransferase, cblC cobalamin defect type C, cblD cobalamin defect type D, GNMT def glycine N-methyltransferase deficiency, MAT methionine adenosyl transferase, MeCbl methylcobalamin, Met Synth methionine synthase, MTHFR methylenetetrahydrofolate reductase, SAH Hyd dc/S-adenosylhomocys-...

A large elevation of Hey in body fluids and tissues is found in several genetic enzyme deficiencies, the homocystinurias. These include cystathionine /3-synlhase deficiency [9], the remethylation defects due to deficiency of MTHF reductase [10], methionine synthase and methionine synthase reductase deficiencies, as well as defects of intracellular cobalamin metabolism [11], namely the cblF, cblC and cblD defects. It is noteworthy that low levels of total Hey (tHcy) have been described in sulphite oxidase deficiency [12]. 

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. 

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... 

Label cellular proteins metabolically by incubating cultures for 4-24 h with 35S-methionine, 3H-lysine, or l4C-amino acids in medium deficient in the relevant amino acid. 

Sulfur. Sulfur is present in every cell in the body, primarily in proteins containing the amino acids methionine, cystine, and cysteine. Inorganic sulfates and sulfides occur in small amounts relative to total body sulfur, but the compounds Lhat contain them are important to metabolism. Sulfur intake is thought to be adequate if protein intake is adequate anil sulfur deficiency has not been reported. 

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