Methionine synthase homocysteine metabolism

The remethylation cycle allows the conversion of homocysteine back to methionine by two pathways. The first and major pathway is catalyzed by the enzyme, methionine synthase, and links the folate cycle with homocysteine metabolism. Methionine synthase requires the cofactor, meth-ylcobalamin. The second pathway utilizes the enzyme, betaine-homocysteine methyltransfer-ase [8]. This pathway remethylates homocysteine using a methyl group derived from betaine, formed via oxidation of choline, and is presumably responsible for up to 50 % of homocysteine remethylation [10]. Both methionine and homocysteine play important roles in protein synthesis, folding, and function. 

In mammals and in the majority of bacteria, cobalamin regulates DNA synthesis indirectly through its effect on a step in folate metabolism, catalyzing the synthesis of methionine from homocysteine and 5-methyltetrahydrofolate via two methyl transfer reactions. This cytoplasmic reaction is catalyzed by methionine synthase (5-methyltetrahydrofolate-homocysteine methyl-transferase), which requires methyl cobalamin (MeCbl) (253), one of the two known coenzyme forms of the complex, as its cofactor. 5 -Deoxyadenosyl cobalamin (AdoCbl) (254), the other coenzyme form of cobalamin, occurs within mitochondria. This compound is a cofactor for the enzyme methylmalonyl-CoA mutase, which is responsible for the conversion of T-methylmalonyl CoA to succinyl CoA. This reaction is involved in the metabolism of odd chain fatty acids via propionic acid, as well as amino acids isoleucine, methionine, threonine, and valine. 

Fig. 14.10 Folate metabolism and role of MTHFR. Genetically reduced MTHFR activity affects the distribution between folate species required for protein and DNA synthesis. Higher availabil ity of 5,10-methylenetetrahydrofolate (CH2THF) potentiates the TS inhibition by 5-FdUMP, the active metabolite of 5-FU. Hey, homocysteine Met, methionine CH3HF, 5-methyltetrahydrofolate TS, thymidylate synthase 5-FdUMP, fluorodeoxyuridine monophosphate.

A simple observation led to the identification of homocysteine as a risk factor for coronary heart disease. Homocysteine is an intermediate in metabolism of the amino acid methionine. Indeed, the first reaction in the catabolism of methionine involves the formation of homocysteine but it can be converted back to methionine in a reaction that is catalysed by methionine synthase (see Figure 22.7). 

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-...

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... 

Figure 21-1. Structural and metabolic relationships between methionine, homocysteine, and cysteine. CBS, cystathionine b-synthase CTH, cystathionine y-lyase MAT, methionine adenosyltransferase MS, methionine synthase 5-MTHF, 5-methyltetrahydrofoIate MTs, methyl transferases PLR pyridoxal phosphate SAH, S-adenosylhomocysteine SAHH, SAH hydrolase THF, tetrahydrofolate.

Vitamin B12 deficiency results in impairment in the activities of the B -requiring enzymes. This impairment prevents synthesis of the enzyme s products and forces the accumulation of reactants in the cell. Inhibition of methionine synthase prevents the synthesis of methionine and the regeneration of tetrahydrofolate. This inhibition results in interruption of the methylation cycle, which involves S-ade-nosylmethionine. The inhibition also results in an impairment of folate-mediated metabolism, because of the failure to regenerate H4folate from 5-methyl-H4folate. The major effect of 6 2 deficiency is an impairment of growth, particularly of rapidly growing cells such as immature red blood cells. B12 deficiency also results in the buildup of homocysteine in the cell and bloodstream. 

An increased plasma level of homocysteine is regarded as a risk factor for cardiovascular disease and the development of arteriosclerosis. Homocysteine concentrations in plasma are reduced by remethylation and transsulfuration (Komarnisky et al. 2003). The remethylation is catalyzed by methionine synthase, which in turn is influenced by vitamin B12 and folate. The transsulfura-tions depend on cystathionine 3-synthase. A dietary deficiency of vitamins B, B12 and folate, accompanied by a high protein intake, can cause hyperhomocystinemia in humans (Jacobsen 1998). Furthermore, a genetic disorder of enzymes involved in the metabolism of homocysteine leads to hypercystinuria (Mudd et al. 1989). 

Methionine synthase (MetH) of E. coli represents the most thoroughly studied B12-dependent methyl transferase and is one of the essential roles of B12 in mammalian metabolism [125,153,154]. It is a modular enzyme containing separate binding domains for homocysteine, N -methyltetrahydrofolate, S-adenosyl-methionine (SAM) and the Bi2-cofactor [125,153-155]. The B12-binding domain in its different oxidation states must interact punctually and specifically with each of the other three domains The Co(I) form with the N -methyltetrahydrofolate binding domain, the Co(II) form with the SAM binding domain, and the CH3 - Co (III) form with the homocysteine binding domain [153,155]. 

Figure 29.6 Pathways for the metabolism of homocysteine. Normal transsulfuration requires cystathionine P-synthase with vitamin Bg as cofactor. Reme-thylation requires 5,10-methylenetetrahydrofolate reductase and methionine synthase. The latter requires folate as cosubstrate and vitamin Bi2 (cobalamin) as cofactor. An alternative remethylation pathway also exists using the cobalamin independent betaine-homocysteine methyltransferase (Robinson 2000).

Figure 44.1 Folate-mediated one carbon metabolism network. Enzymes and transport proteins are enclosed in rectangular boxes. AHCY S-adenosyDiomocys-teine hydrolase AICART 5-aminoimidazole carboxamide ribonucleotide transferase BHMT betaine homocysteine methyltransferase CBS cystathionine beta-synthase DHFR dihydrofolate reductase FR folate receptor FTCD formimidoyltransferase cyclodeaminase GART glycinamide ribonucleotide transformylase MATs (MATI/MATIII) adenosylmethionine transferase enzyme I/III MS methionine synthase MSR methionine synthase reductase MT methyltransferase MTHFD methylenetetrahydrofolate dehydrogenase MTHFR 5,10-methylenete-trahydrofolate reductase MTHFS 5,10-methylenetetrahydrofolate synthase. RFC reduced folate AdoMet 5-adenosylmethionine AdoHcy S-adenosylhomocysteine Hey homocysteine SHMT serine hydroxymethyltransferase TS thymidylate synthase.

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. 

Vitamin B12 is an essential coenzyme for the methylation cycle by activating THF. An activated folate is not only a coenzyme for methionine synthase but also plays a pivotal role in one-carbon metabolism it promotes the generation of methionine from homocysteine, which is a cytotoxic sulfur-containing amino acid that can induce DNA strand breakage, oxidative stress and apoptosis. The methylation cycle is very important in the brain and depends on the SAM concentration. 

In vitamin B12 deficiency, methionine synthase is inhibited causing increased levels of homocysteine and SAH. SAH in turn inhibits SAM mediated methylation, thereby leading to toxic levels of homocysteine causing direct damage to the vascular endothelium and inhibition of iV-methyl-o-aspartate receptors (NMDA) (Moretti et al. 2008). Homocysteine is produced entirely from the methylation cycle, as it is totally absent from any dietary source (Pietrzik and Bronstrup 1997). Hence, an elevated plasma homocysteine concentration is a sensitive marker for vitamin B12 and folate deficiency (Pametti et al. 1997). In addition, it can be due to increased frequency of impaired genetic capacity to metabolize homocysteine (Nilsson et al. 1996). 

Fig. 10.1. Defects of transmethylation (methioninehomocysteine), transsulfuration (methionine sulfate), and remethylation (homocysteine - methionine) enzymes of sulfur amino acid metabolism 10.1, methionine adenosyltransferase 10.2, cystathionine ) -synthase 10.3, y-cystathionase 10.4, sulfite oxidase 10.5, molybdenum cofactor 10.6, methylenetetrahydrofolate reductase 10.7 and 10.8, methionine synthase.

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

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