Methionine metabolism

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. 

One day prior to the isolation of polysomes, approximately 5 million HeLa cells are plated into 10-cm dishes. The following day, the media is replaced with fresh DMEM and compound is added to a concentration previously determined to inhibit translation in vivo by 35S-methionine metabolic labeling (see previously). 

In order to estimate the flux through the SMM cycle and to explore its function, a computer model of methionine metabolism in mature Arabidopsis rosette leaves was developed based on data from radiotracer experiments and on metabolite contents. This model suggested that the cycle serves to stop accumulation of AdoMet, rather than to prevent depletion of free methionine, as proposed by Mudd and Datko.54 Because plants lack the AdoMet feedbacks on MTHFR and AdoMet synthetase that regulate AdoMet pool size in other eucaryotes, the SMM cycle may be the main mechanism whereby plants achieve short-term control of AdoMet level. MMT knockouts of maize and Arabidopsis recently became available, and these can now be used to further investigate the role of the SMM cycle, and to test the predictions of the model. 

Methionine metabolism Cysteine metabolism Valine, leucine, and isoleucine degradation... 

Cobalamin compounds Tight Cobalamin (B12) Transfer of methyl group to homocysteine during synthesis of methionine metabolism of methylmalonyl coenzyme A... 

The metabolic control of methionine metabolism is complex and involves, for example, changes of enzyme levels in particular tissues, mechanisms linked to the kinetic properties of the various enzymes and their interaction with metabolic effectors [6, 7]. A particularly important metabolic effector is AdoMet. This inhibits the low Km isoenzymes of MAT, and MTHF reductase, inactivates betaine methyltransferase, but activates MAT III (the high-Km isoenzyme) and cystathionine /1-synthase. Therefore, high methionine intake and thus higher AdoMet levels favour trans-sulphuration, and when levels are low methionine is conserved. AdoHcy potently inhibits AdoMet-dependent methyltransferases and both Hey remethylating enzymes. Another important control mechanism is the export of Hey from cells into the extracellular space and plasma, which occurs as soon as intracellular levels increase [8]. 

Several drugs, such as the antifolate compound methotrexate or the anaesthetic gas nitrous oxide, may interfere with methionine metabolism and lead to mild increases of Hey [2]. Abnormal renal function has been shown to lead to increased plasma Hey, for example, in end-stage renal disease patients [15]. 

Finkelstein JD (1990) Methionine metabolism in mammals. J Nutr Biochem 1 228-237... 

Arsenic. Arsenic is under consideration for inclusion as an essential element. No clear role has been established, but arsenic, long thought to be a poison, may be involved in meihyluliort of mucromoleculcs and as an el lector ol methionine metabolism. 

Production and Inhibition of Ethylene. Now I would like to illustrate how knowledge about a plant hormone can be used to control and regulate its action. Methionine is the precursor of ethylene in plant tissues (30). Therefore, any compound which blocks methionine metabolism might be expected to inhibit ethylene biosynthesis. Rhizobitoxine was recognized as an inhibitor of methionine biosynthesis (31) as were its analogues shown in Figure 6 (32). 9... 

Mild hyperhomocysteinemia is defined as a plasma tHcy concentration of 10-30 (tmol/L moderate hyperhomocysteinemia is classified as 30-100 tmol/L. A very severe form of hyperhomocysteinemia, which produces plasma tHcy concentrations greater than 100 tmol/L, can be caused by one of several inborn errors of methionine metabolism. Patients with these disorders also have high levels of tHcy in their urine, a condition known as homocystinuria. 

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 ... 

The first really molecular study of phytotoxins was done at the Rockefeller Institute, starting in the late 1940 s by a physiologist-biochemist team, Braun and Woolley, who worked with Pseudomonas syringae pv. tabaci. This bacterium produces the so called wildfire toxin, the name coming from the rapidity with which chlorosis is induced by the pathogen producing toxin in the leaves of the natural host, tobacco. They proposed a structure for this toxin, and because of its presumed structural and physiological resemblances to methionine sulfoximine, a recently discovered compound that interfered with methionine metabolism, they hypothesized that wildfire toxin acted in a similar, if not identical, manner. 

Rather that interfering with methionine metabolism, T-3-L is a specific, site-directed inhibitor of glutamine synthetase (GS), a critical enzyme for nitrogen assimilation (12). The widespread... 

Early studies of vitamin Be requirements used the development of abnormalities of tryptophan or methionine metabolism during depletion, and normalization during repletion with graded intakes of the vitamin. Although tryptophan and methionine load tests are unreliable as indices of vitamin Be status in epidemiological studies (Section 9.5.4 and Section 9.5.5), under the controlled conditions of depletion/repletion studies they do give a useful indication of the state of vitamin Be nutrition. More recent studies have used more sensitive indices of status, including the plasma concentration of pyridoxal phosphate, urinary excretion of 4-pyridoxic acid, and erythrocyte transaminase activation coefficient. 

The identification of hyperhomocysteinemia as an independent risk factor in atherosclerosis and coronary heart disease (Section 10.3.4.2) has led to suggestions that intakes of vitamin Be higher than are currently considered adequate to meet requirements may be desirable. Homocysteine is an intermediate in methionine metabolism and may undergo one of two metabolic fates, as shown in Figure 9.5 remethylation to methionine (a reaction that is dependent on vitamin B12 and folic acid) or onward metabolism leading to the synthesis of cysteine (trans-sulfuration). Therefore, intakes of folate, vitamin B12, and/or vitamin Be may affect homocysteine metabolism. 

Krebs HA, Hems R, and Tyler B (1976) The regnlation of folate and methionine metabolism. Biochemical Journal 158,341-53. 

Rodionov DA, Vitreschak AG, Mironov AA, Gelfand MS. Comparative genomics of the methionine metabolism in Grampositive bacteria a variety of regulatory systems. Nucleic Acids 62. Res. 2004 32(11) 3340-3353. 

Figure 23.27. Methionine Metabolism. The pathway for the conversion of methionine into succinyl CoA. S-Adenosylmethionine, formed along this pathway, is an important molecule for transferring methyl groups.

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... 

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. 

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