Methyl transferases

Dopamine. Dopamine (DA) (2) is an intermediate in the synthesis of NE and Epi from tyrosine. DA is localized to the basal ganglia of the brain and is involved in the regulation of motor activity and pituitary hormone release. The actions of DA are terminated by conversion to dihydroxyphenylacetic acid (DOPAC) by monoamine oxidase-A and -B (MAO-A and -B) in the neuron following reuptake, or conversion to homovanillic acid (HVA) through the sequential actions of catechol-0-methyl transferase (COMT) and MAO-A and -B in the synaptic cleft. 

Uroporphyrinogen I (16c), a constitutional isomer of uroporphyrinogen III, also plays no direct role in porphyrin and corrin biosynthesis, but this unnatural substrate is methylated to give 17c10c f in the presence of SAM by the methyl transferase of some bacteria. A constitutional type I dihydroisobacteriochlorin can be obtained by methylation of uroporphyrinogen I with methylase Ml. Methyltransferase M1 is able to methylate the unnatural precorrin once more to give the trimethylpyrrocorphin type I.IOc 1... 

Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase Pharmacological aspects and physiological role. Pharmacol Rev 27 135-206... 

Mannisto PT, Kaakkola S (1999) Catechol-O-methyl-transferase (COMT). Biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51 593-628... 

The principal mechanism for terminating dopamine signaling is reuptake by the presynaptic neuron via the dopamine transporter (DAT). Dopamine that is not taken up is metabolized by the enzymes monoamine oxidase (MAO) and catechol-O-methyl transferase... 

Histamine is synthesized from the amino acid histidine via the action of the specific enzyme histidine decarboxylase and can be metabolized by histamine-TV-methyl transferase or diamine oxidase. Interesting, in its role as a neurotransmitter the actions of histamine are terminated by metabolism rather than re-uptake into the pre-synaptic nerve terminals. 

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... 

N5-Methyltetrahydrofolate homocysteine methyl-transferase (= methionine synthase). This reaction is essential to restore tetrahydrofolate from N5-methyltetrahydrofolate (Fig. 2). 

Just as the synthesis of DA and NA is similar so is their metabolism. They are both substrates for monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). In the brain MAO is found in, or attached to, the membrane of the intraneuronal mitochondria. Thus it is only able to deaminate DA which has been taken up into nerve endings and blockade of DA uptake leads to a marked reduction in the level of its deaminated metabolites and in particular DOPAC. The final metabolite, homovanillic... 

After reuptake into the cytosol, some noradrenaline may be taken up into the storage vesicles by the vesicular transporter and stored in the vesicles for subsequent release (see above). However, it is thought that the majority is broken down within the cytosol of the nerve terminal by monoamine oxidase (MAO ECl.4.3.4). A second degradative enzyme, catechol-O-methyl transferase (COMT EC2.1.1.6), is found mostly in nonneuronal tissues, such as smooth muscle, endothelial cells or glia. The metabolic pathway for noradrenaline follows a complex sequence of alternatives because the metabolic product of each of these enzymes can act as a substrate for the other (Fig 8.8). This could enable one of these enzymes to compensate for a deficiency in the other to some extent. 

Histamine is synthesised by decarboxylation of histidine, its amino-acid precursor, by the specific enzyme histidine decarboxylase, which like glutaminic acid decarboxylase requires pyridoxal phosphate as co-factor. Histidine is a poor substrate for the L-amino-acid decarboxylase responsible for DA and NA synthesis. The synthesis of histamine in the brain can be increased by the administration of histidine, so its decarboxylase is presumably not saturated normally, but it can be inhibited by a fluoromethylhistidine. No high-affinity neuronal uptake has been demonstrated for histamine although after initial metabolism by histamine A-methyl transferase to 3-methylhistamine, it is deaminated by intraneuronal MAOb to 3-methylimidazole acetic acid (Fig. 13.4). A Ca +-dependent KCl-induced release of histamine has been demonstrated by microdialysis in the rat hypothalamus (Russell et al. 1990) but its overflow in some areas, such as the striatum, is neither increased by KCl nor reduced by tetradotoxin and probably comes from mast cells. 

The enzyme /i-phenylethanolamine-A-methyl transferase, which is required to convert noradrenaline (NA) to adrenaline (Ad), is present in the CNS and there is histofluoro-metric evidence (positive staining with antibodies to that enzyme and to tyrosine hydroxylase and dopamine /i-hydroxylase as well) for adrenergic cell bodies in two groups (nuclei) alongside NA neurons of the locus coeruleus (EC) but ventral and lateral (Ci) and dorsal and medial (C2) to it. Projections go to the hypothalamus and in... 

The deamination of DA to DOPAC can be prevented by MAOb inhibitors such as selegiline while COMT inhibitors stop its further o-methylation to HVA and the conversion of dopa to OMD. COMT inhibitors can act just peripherally (entacapone) or in the CNS as well (tolcapone). DD — dopa decarboxylase MAO—monoamine oxidase COMT—catechol-o-methyl transferase... 

Ralph, J. Lapierre, C. Lu, F. Marita, J. M. Pilate, G. Van Doorsselaere, J. Boerjan, W. Jouanin, L. NMR evidence for benzodioxane structures resulting from incorporation of 5-hydroxyconiferyl alcohol into lignins of O-methyl-transferase-deficient poplars. j. Agric. Food Chem. 2001, 49, 86-91. 

Hu P, Zhang Y (2006) Catalytic mechanism and product specificity of the histone lysine methyl-transferase set7/9 An ab initio QM/MM-FE study with multiple initial structures. J Am Chem Soc... 

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. 

Champier, J., Claustrat, B., Besancon, R. el al. (1997). Evidence for tryptophan hydroxylase and hydroxy-indol-O-methyl-transferase mRNAs in human blood platelets. Life Sci 60, 2191-7. 

Methyl transferases are responsible for methylation of a nucleophile, typically using SAM as the carbon donor. They are known to accept a wide range of nucleophiles such as halides (eq. 1 in Figure 13.22) [64], amines (eq. 2 in Figure 13.22) [65], hydroxyls, and enolates. As expected, the reactivity of methyl transfer to halides follows the order of iodide, bromide, and chloride, with chloride being the poorest acceptor. Methylation of amines in nucleotides and proteins plays important roles in biological activities. 

Weinig, S., Hecht, H.-J., Mahmud, T. and Muller, R. (2003) Melithiazol biosynthesis further insights into myxobacterial PKS/NRPS systems and evidence for a new subclass of methyl transferases. Chemistry Biology, 10, 939-952. 

Lee EJD, Kalow W. Thiopurine S-methyl-transferase activity in a Chinese population. Clin Pharmacol Ther 1993 54 28-33. 

Hon YY, Fessing MY, Pui CH, Reeling MV, Krynetski EY, Evans WE. Polymorphism of the thiopurine S-methyl-transferase (TPMT) gene in African Americans. Hum Mol Genet 1999 8 371-376. 

McLeod HL, Syvanen A-C, Githang a J, Indalo A, Ismai D, Dewar K et al. Ethnic differences in catechol O-methyl-transferase pharmacogenetics frequency of the codon 108/158 low activity allele is lower in Kenyan than Caucasian or South-west Asian individuals. Pharmacogenetics 1998 8 195-199. 

Deficiency of thiopurine S-methyl transferase (TPMT) is another phenotype that exhibits inter-ethnic differences in frequency. TPMT is an enzyme that catalyzes methylation of therapeutic agents used in the treatment of acute lymphoblastic leukemia, rheumatoid arthritis, and autoimmune/inflammatory diseases, as well as in organ transplantation. Patients who have TPMT deficiency experience less efficient methylation and are at greater risk of fatal toxicity when treated with standard doses of fhiopurines. TPMT phenotype is defined by erythrocyte 6-mercapto-purine methylation. African American populations exhibit a 20% lower erythrocyte TPMT than Caucasian Americans, and persons of Chinese descent tend to exhibit greater activity than either of these other American subpopulations. 

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