Methionine adenosyl transferase

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-...

E-S) Hypermetbioninuria (decrease in methionine adenosyl transferase) at this step. The condition is relatively benign, whereas cystathionine synthase deficiency (see above) is not benign. 

Mari, M., Colell, A., Morales, A., Pafieda, C., Varela-Nieto, I., Garcia-Ruiz, C., Fernandez-Checa JC, Acidic sphingomyelinase downregulates the liver-specific methionine adenosyl-transferase lA, contributing to tumor necrosis factor-induced lethal hepatitis, J Clin Invest, 113 (2004)895-904. 

Fig. 12. Some signaling targets and pathways affected by sphingolipid backbones that are metabolically interrelated. PKA, protein kinase A PDKl, 3-phosphoinositide-dependent kinase 1 SDKl, sphingosine-dependent kinase 1 PKC, protein kinase C PPl, protein phosphatase 1 PP2A, protein phosphatase 2A aSMase, acid sphingomyelinase PLA, phospholipase Aj SIP, sphingosine-l-phosphase MATIA, methionine adenosyl-transferase (liver specific) SFl, steroidogenic factor 1. The biophysical properties of ceramides and ceramide 1-phosphates may play important roles in membrane structure, including tendencies to form rafts, membrane curvature, and leakiness.

A second metabolic system similar to the first is shown in Figure 1, panel ii. In this schematic, the emphasis is a metabolite one or two steps proximal to the primary enzyme deficiency. For example, in normal individuals, metabolite C is converted by enzyme Y to metabolite A, which is subsequently converted by enzyme X to metabolite B. As described above, in individuals with an inherited deficiency of enzyme X, metabolite A accumulates. In this particular scenario, compounds that are converted to metabolite A, namely metabolite C, will increase as enzyme Y is inhibited by basic kinetics. An example of this enzyme system is homocystinuria. In this disorder, the metabolism of homocysteine to cystathionine by cystathionine S-synthase is blocked. An increase in homocysteine causes an accumulation of S-adenosyl homocysteine and S-adenosyl methionine. Due to an increase in these metabolites, the metabolism of methionine to S-adenosyl methionine by methionine adenosyl transferase is decreased. Hence, methionine increases in the blood of individuals with homocystinuria. Note that in this example there were two enzymatic steps before the metabolism of homocysteine. 

Amino acid metabolism A artate aminotransferase Alanine aminotransferase Cysteine aminotransferase Tyrosine aminotransferase Leucine aminotransferase Alanine-ketoacid aminotransfoase Ornithine-ketoacid aminotransferase A artate carbamoyl transferase Methionine adenosyl transferase Glutamate decarboxylase Glutamate dehydrogenase Serine hydroxymethyltransferase Aminoacyl-sRNA synthetases... 

Transmethylation Methionine adenosyl transferase Betaine-homocysteine methyltransferase iV -methyltetrahydrofolate-homocysteine 5-methyltransferase... 

In addition to the above reactions of amino acids, two others involving specific amino acids must be mentioned. The first reaction involves the conversion of methionine to 5-adenosyl methionine by methionine adenosyl transferase. In this form, methionine is an important methyl donor in animal tissue. The second reaction is that involving aspartate carbamoyl transferase which converts L-aspar-tate to Ai -carbamoyl-I aspartate. This is the begiiming of a series of reactions culminating in the synthesis of pyrimidines. An intermediate step which forms orotidine-S-phosphate is catalysed by orotidine-5-phosphate pyrophosphoxylase. The orotidine-5-phosphate formed is the immediate precursor of uridine-S-phos-phate (UMP) which occupies a central position in pyrimidine synthesis. After some degree of transformation, UMP can be converted to cytosine-5-phosphate (CMP) or thymine-5-phosphate (TMP). It might be noted here that the purine... 

Cai, J., Mao, Z., Hwang, J.J., and Lu, S.C. (1998). Differential expression of methionine adenosyl-transferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer... 

Glutamine transaminase from bovine liver, one of the enzymes involved in methionine catabolism, utilizes SeMet as well as methionine (Blazon et al., 1994). However, with some enzymes, differences in the reaction rates for SeMet and Met have been observed. For example, SeMet is a better substrate than Met for the a,7-elimination by L-methionine 7-lyase of Pseudomonas putida (Esaki et al., 1979). The adenosyltransferase from rat liver reacts with L(+)-SeMet at 51% of the rate with L(+)-Met, and with the corresponding d(—) isomers at only 13 and 10% of the rate of L-Met (Pan and Tarver, 1967). The adenosyl transferase from yeast, on the other hand, is more active with SeMet than with Met (Mudd and Cantoni, 1957). This enzyme produces the... 

Histone methylation is a common posttranslational modification fond in histones. Histone methylations have been identified on lysine and arginine residues. In case of lysines S-adenosyl-methionine (SAM) dependent methyl transferases catalyze the transfer of one, two or three methyl groups. Lysine methylation is reversible and lysine specific demethylases have been... 

The methyl transferases (MTs) catalyze the methyl conjugation of a number of small molecules, such as drugs, hormones, and neurotransmitters, but they are also responsible for the methylation of such macromolecules as proteins, RNA, and DNA. A representative reaction of this type is shown in Figure 4.1. Most of the MTs use S-adenosyl-L-methionine (SAM) as the methyl donor, and this compound is now being used as a dietary supplement for the treatment of various conditions. Methylations typically occur at oxygen, nitrogen, or sulfur atoms on a molecule. For example, catechol-O-methyltransferase (COMT) is responsible for the biotransformation of catecholamine neurotransmitters such as dopamine and norepinephrine. A-methylation is a well established pathway for the metabolism of neurotransmitters, such as conversion of norepinephrine to epinephrine and methylation of nicotinamide and histamine. Possibly the most clinically relevant example of MT activity involves 5-methylation by the enzyme thiopurine me thy Itransf erase (TPMT). Patients who are low or lacking in TPMT (i.e., are polymorphic) are at... 

An essential instrument for the suppression of transcription activity in heterochromatin, as well as for the differential regulation in euchromatin, is the methylation of DNA on the C5 atom of cytidine in the CpG sequence (Fig. 1.43). CpG sequences occur imevenly distributed in the genome. They may be concentrated in CpG islands. Higher eucaryotes possess a characteristic distribution pattern of 5-methyl cytidine (m C), which remains intact upon cell division. Mechanisms must therefore exist to ensure that the methylation pattern is precisely retained in the daughter cells following cell division. A methyl transferase that carries out hemi-methylation in the CpG sequences (Fig. 1.43) is responsible for the inheritance of the methylation pattern. The methyl group is derived from S-adenosyl methionine. The preferential substrates for the hemi-methylation are DNA sequences in which the complementary strand is already methylated. Such a hemi-methylation occurs, for example, shortly after replication of the sequence. 

There are still other important factors. Occupancy of the receptor by a ligand makes the receptor protein itself a substrate for the chemotaxis-specific methyl-transferase encoded by the cheR gene.62 70 71 This enzyme transfers methyl groups from S-adenosyl-methionine to specific glutamate side chains of the receptor to form methyl esters. In the aspartate receptor there are four such glutamate residues in a large cytoplasmic domain that includes the C terminus. 

Other enzymes capable of halogenation processes include a bacterial esterase from Pseudomonas fluorescens (2316), acid phosphatases from the bacteria Shigella flexneri and Salmonella enterica ser. typhimurium (2317), a lactonohydrolase from Acinetobacter calcoaceticus F46 (2318), and hydroperoxide halolyse from the marine diatom Stephanopyxis turris (2319). The biosynthesis of the ubiquitous methyl halides seems to involve methyl transferase enzymes, which have been isolated and purified in the plant Brassica oleracea (S -adenosyl-L-methionine ... 

A large number of both endogenous and exogenous compounds can be methylated by several N-, 0-, and S-methyl transferases. The most common methyl donor is S-adenosyl methionine (SAM), which is formed from methionine and ATP. Even though these reactions may involve a decrease in water solubility, they are generally detoxication reactions. Examples of biologic methylation reactions are seen in Figure 7.18. 

Fig. 3.1 Metabolomics of Hey. During gene and protein methylation, S-adenosyl homocysteine (SAH) is generated by methyl transferase and methionine. SAH hydrolase (SAHH) generates Hey. DZA blocks SAHH, otherwise Hey induces NOS, NADH oxidase and decreases thioredoxin in mitochondria. Hey inhibits DDAH and increases ADMA causing decrease in NO. Deficiency in MTHFR and CBS increases Hey. The decrease in kidney ability to filter increases Hey.

RUEFFER, M AMANN, M, ZENK, M.H., S-Adenosyl-L-methionine columbamine-O-methyl transferase, a compartmentalized enzyme in protoberberine biosynthesis. Plant Cell Rep., 1986,3,182-185. 

S-adenosyl-L methionine (ADO-Met) dependent DNA methyl transferase catalyzed the transfer of a methyl group from AdoMet to a specific nucleotide within the DNA helix (Cheng et al., 1993). In a concerted reaction in the enzyme active site (Fig X) with a simultaneous addition of methyl residue of AdoMet to the cytosine ring and with an elimination of the ring proton by a water molecule requires involving seven heavy nuclei (two ofCys 81, four of AdoMet and one of water. An estimation with aid of Eq. 2.44 leads to value of the reaction synchronization factor asyn 10 4, that does not rule out the concerted mechanism, if the activation energy is less than 10 kcal/mole Nevertheless, a... 

One of the hydroxyl groups of (S)-norcoclaurine is methylated by a S-adenosyl methionine-(SAM)-dependent O-methyl transferase to yield (S)-coclaurine. This enzyme has been cloned, and the heterologously expressed enzyme exhibited the expected activity (15-17). The resulting intermediate is... 

Fig. 3. Farnesylation and further processing of proteins containing a C-terminal CaaX-motif. Farnesyl transferase catalyses the transfer of a farnesyl moiety from farnesyl pyrophosphate FPP) to the cysteine residue in the CaaX-motif, where C = Cys, a = usually aliphatic amino acids, and X = Met, Ser Cys, Ala, Gin. The three C-terminal amino acids (aaX) are then cleaved off, and a methyl group is transferred from S-adenosyl methionine to the now C-terminal cysteine residue...

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