Transsulfuration pathway

The transsulfuration pathway is the major route for the metabolism of the sulfur-containing amino adds 674 Homocystinuria is the result of the congenital absence of cystathionine synthase, a key enzyme of the transsulfuration pathway 676 Homocystinuria can be treated in some cases by the administration of pyridoxine (vitamin B6), which is a cofactor for the cystathionine synthase reaction 676... 

The transsulfuration pathway is the major route for the metabolism of the sulfur-containing amino acids. 

The transsulfuration pathway (Fig. 40-4) entails the transfer of the sulfur atom of methionine to serine to yield cysteine. The first step is activation of methionine, which reacts with ATP to form S-adenosylmethionine (Fig. 40-4 reaction 1). This compound is a key methyl donor and plays a prominent role in the synthesis of several... 

Hydrolysis of SAM After donation of the methyl group, S-adenosylhomocysteine is hydrolyzed to homocysteine aid adenosine. Homocysteine has two fates. If there is a deficiency of methionine, homocysteine may be remethylated to methionine (see Figure 20.8). If methionine stores are adequate, homocysteine rmty enter the transsulfuration pathway, where it is converted to cysteine. 

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... 

Cysteine is formed in plants and in bacteria from sulfide and serine after the latter has been acetylated by transfer of an acetyl group from acetyl-CoA (Fig. 24-25, step f). This standard PLP-dependent (3 replacement (Chapter 14) is catalyzed by cysteine synthase (O-acetylserine sulfhydrase).446 447 A similar enzyme is used by some cells to introduce sulfide ion directly into homocysteine, via either O-succinyl homoserine or O-acetyl homoserine (Fig. 24-13). In E. coli cysteine can be converted to methionine, as outlined in Eq. lb-22 and as indicated on the right side of Fig. 24-13 by the green arrows. In animals the converse process, the conversion of methionine to cysteine (gray arrows in Fig. 24-13, also Fig. 24-16), is important. Animals are unable to incorporate sulfide directly into cysteine, and this amino acid must be either provided in the diet or formed from dietary methionine. The latter process is limited, and cysteine is an essential dietary constituent for infants. The formation of cysteine from methionine occurs via the same transsulfuration pathway as in methionine synthesis in autotrophic organisms. However, the latter use cystathionine y-synthase and P-lyase while cysteine synthesis in animals uses cystathionine P-synthase and y-lyase. 

The transsulfuration pathway involves conversion of homocysteine to cysteine by the sequential action of two pyridoxal phosphate (vitamin B6)-dependent enzymes, cystathionine- 5-synthase (CBS) and cystathionine y-lyase (Fig. 21-2). Transsulfuration of homocysteine occurs predominantly in the liver, kidney, and gastrointestinal tract. Deficiency of CBS, first described by Carson and Neill in 1962, is inherited in an autosomal recessive pattern. It causes homocystinuria accompanied by severe elevations in blood homocysteine (>100 (iM) and methionine (>60 (iM). Homocystinuria due to deficiency of CBS occurs at a frequency of about 1 in 300,000 worldwide but is more common in some populations such as Ireland, where the frequency is 1 in 65,000. Clinical features include blood clots, heart disease, skeletal deformities, mental retardation, abnormalities of the ocular lens, and fatty infiltration of the fiver. Several different genetic defects in the CBS gene have been found to account for loss of CBS activity. 

Cysteine is considered a nonessential nutrient because it can be synthesized from methionine via the transsulfuration pathway (Figs. 21-1 and 21-2). Production of cysteine is metabolically important because it serves as a source of sulfur for incorporation into proteins and detoxification reactions. A lack of cysteine needed for incorporation into the structural protein collagen may be responsible for the musculoskeletal abnormalities seen in patients with CBS deficiency. A major metabolic use of cysteine is in the production of glutathionine (y-glutamylcysteinylglycine), an important antioxidant. Another important pathway for cysteine metabolism is its oxidation to cysteinesulfinate, which serves as a precursor for taurine, an amino acid that stabilizes cell membranes in the brain. 

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). 

Pyridoxine (vitamin B6) Transsulfuration pathway cofactor for cystathionine-(3-synthase and cystathionine "/-lyase Folate cycle methylation of tetrahydrofolate cofactor for serine hydroxymethyltransferase... 

Banerjee R. 2006. A functional transsulfuration pathway in the brain links to glutathione homeostasis. J Biol Chem... 

Methylation of homocysteine by 5-methyltetrahydrofolate-homocysteine methyl reductase depends on an adequate supply of 5-methyltetrahydrofoIate. The unmethylated folate is recycled in a cobalamin-dependent pathway, by remethylation to 5,10-methylene-tetrahydrofolate, and subsequent reduction to 5-methyltetrahydrofolate. The transferase enzyme, also named 5,10-methyltretrahydrofolate reductase catalyzes the whole cycle [3,91]. S-adenosylmethionine and 5-methyltetrahydrofolate are the most important methyl unit donors in biological system. S-adenosylmethionine is reported to regulate methylation and transsulfuration pathways in the homocysteine metabolism [3,91]. 

Homocysteine is metabolized in the liver, kidney, small intestine and pancreas also by the transsulfuration pathway [1,3,89]. It is condensed with serine to form cystathione in an irreversible reaction catalyzed by a vitamin B6-dependent enzyme, cystathionine-synthase. Cystathione is hydrolyzed to cysteine that can be incorporated into glutathione or further metabolized to sulfate and taurine [1,3,89]. The transsulfuration pathway enzymes are pyridoxal-5-phosphate dependent [3,91]. This co-enzyme is the active form of pyridoxine. So, either folates, cobalamin, and pyridoxine are essential to keep normal homocysteine metabolism. The former two are coenzymes for the methylation pathway, the last one is coenzyme for the transsulfuration pathway [ 1,3,89,91 ]. 

Horowitz JH, Rypins EB, Henderson JM, Heymsfield SB, Moffitt SD, Bain RP, Chawla RK (1981) Evidence for impairment of transsulfuration pathway in cirrhosis. Gastroenterology 81 668-67530... 

Selenomethionine metabolism to selenide and the incorporation into selenium-specific proteins may occur by two pathways metabolism to methane selenol and selenide or via selenocysteine. Evidence that the incorporation of selenium from selenomethionine into protein is by the transsulfuration pathway (methionine to cysteine) comes from studies of selenomethionine metabolism in lymphoblast cell lines deficient in cystathionine lyase and cystathionine synthetase, enzymes of the transsulfuration pathway (Beilstein and Whanger 1992). Deficiency in these enzymes greatly reduces the incorporation of selenomethionine into glutathione peroxidase. 

CGS catalyzes the 7-replacement reaction of an activated form of L-homoserine with L-cysteine, leading to cystathionine. 0-Succinyl-L-homoserine (l-OSHS), 0-acetyl-L-homoserine (OAHS), and 0-phospho-L-homoserine (OPHS) are substrates for CGS ftom bacteria, fungi, and plants, respectively. The plant enzyme is also able to convert the microbial substrates, albeit at much higher values. This reaction is the first step in the transsulfuration pathway that converts L-Cys into L-homocysteine, the immediate precursor of L-methionine. The 0-activated L-homoserine substrate is situated at a metabolic branch point between L-Met and L-Thr biosynthesis, and which substrate is used by CGS depends on the species. In analogy with TS, CGS is tightly regulated by SAM concentration in plants. ... 

Autotrophic organisms synthesize methionine from asparfafe as shovm in the lower right side of Fig. 24-13. This involves fransfer of a sulfur atom from cysfeine info homocysfeine, using the carbon skeleton of homoserine, the intermediate cystathionine, and two PLP-dependent enzymes, cystathionine y-synthase and cystathionine p-lyase. This transsulfuration sequence (Fig. 24-13, Eq. 14-33) is essentially irreversible because of the cleavage to pyruvate and NH4+ by the P-lyase. Nevertheless, this transsulfuration pathway operates in reverse in the animal body, which uses two different PLP enzymes, cystathionine P s3mthase (which also contains a bound heme) and cystathionine y-lyase (Figs. 24-13,24-16, steps h and i), in a pathway that metabolizes excess methionine. 

Methionine is an essential amino acid with a unique role in the initiation of protein synthesis, hi addition, by conversion to 5 -adenosyhnethionine, it serves as the major methyl group donor involved in the formation of creatinine and choline, in the methylation of bases in RNA, and as the source of the aminopropyl group in the formation of polyamines. Finally, in relationship to classical homocystinuria, it is converted by way of homocysteine and cystathionine in a series of reactions termed as the transsulfuration pathway (Fig. 20.3). 

Homocysteine metabolism involves three key enzymes methionine synthase, betaine homocysteine methyl transferase (BHMT) and cystathione p-synthase. Both vitamin B12 and folate are required in the methylation of homocysteine to methionine via metheonine synthase after donation of a methyl group from SAM during the methylation process. Homocysteine is also methylated by betaine in a reaction catalysed by BHMT and does not involve vitamin B12 and folate. The other metabolic fate for homocysteine is the transsulfuration pathway which degrades homocysteine to cysteine and taurine, and is catalysed by cystathione p-synthase with vitamin Bg as coenzyme. 

Hyperhomocysteinemia has long been identified as a risk factor for dementia including Alzheimer s disease (AD) and vascular dementia (VaD) (Morris 2003). The relationship of homocysteine metabolism (methylation and transsulfuration pathways) to deficiencies of the vitamin B complex suggests that hypervitaminosis (Bg, B12 and folate) could contribute to hyperhomocysteinemia (Gonzalez-Gross et al. 2001). 

Homocysteine is an intermediate metabolic product at the junction of two metabolic pathways, transsulfuration (requiring vitamin Bg as a coenzyme)and remethylation (requiring vitamin B12 as a coenzyme). When vitamin B12 and vitamin Bg are viewed in terms of homocysteine metabolism, both vitamins may be linked with each other at the degradation of homocysteine. The reduced remethylation in patients with CKD may stimulate sulfur transfer. We consider that the linkage between vitamin B12 and vitamin Bg may be mediated by SAM, since it has been demonstrated that accumulated SAM accelerates the transfer of sulfur (Purohit et al. 2007). Based on the fact as observed in patients with CKD that the transsulfuration pathway did not deteriorate and that the... 

Transsulfuration pathway. Homocysteine is either remethylated to methionine via methionine synthase) or is transsulfurated to cysteine via cystathionine beta synthase). Transsulfuration requires vitamin as a cofactor. 

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