Methyltransferases cofactors

S-adenosyl-L-methionine (AdoMet, SAM) is a cofactor and the most important donor of the methyl (CH3-) group for methyltransferases, including COMT. When the methyl-group has been transferred, the remaining demethylated compound is called S-adenosyl-L-homo-cysteine. 

The enzyme mediating remethylation, 5-methyltetrahy-drofolate-betaine methyltransferase (Fig. 40-4 reaction 4), utilizes methylcobalamin as a cofactor. The kinetics of the reaction favor remethylation. Faulty remethylation can occur secondary to (1) dietary factors, e.g. vitamin B12 deficiency (2) a congenital absence of the apoenzyme (3) a congenital inability to convert folate or B12 to the methylated, metabolically active form (see below) or (4) the presence of a metabolic inhibitor, e.g. an antifolate agent that is used in an antineoplastic regimen. 

The methyltransferases represent a relatively large number of enzymes that utilize the cofactor, S-adenosyl-L-methionine, in which the methyl group is bound to a positively charged sulfur, to transfer a methyl group to an oxygen, sulfur, or nitrogen atom in an appropriate substrate as shown in Figure 7.9 (8). 

Figure 2.16. Pathways for the synthesis and metabolism of the catecholamines. A=phenylalanine hydroxylase+pteridine cofactor+Oj B tyrosine hydroxylase+ tetrahydropteridme+Fe+ +Oj C=dopa decarboxylase+pyridoxal phosphate D= dopamine beta-oxidase+ascorbate phosphate+Cu+ +Oj E=phenylethanolamine N-methyltransferase+S-adenosylmethionine l=monoamine oxidase and aldehyde dehydrogenase 2=catechol-0-methyltransferase+S-adenosylmethionine.

In multicellular eukaryotes, DNA methylation is associated with transcriptional silencing [3]. In these organisms, DNA methylation has been observed exclusively on the C5 position of the cytosine ring and is frequently found in CpG-rich regions. This process is attributed to the action of DNA methyltransferases (DNMTs), which utilize the cofactor, S-adenosyl-L-methionine. Approximately half of all human genes have CpG islands in their promoter regions but these stretches of DNA are typically... 

Reversible histone methylation is a highly specific process that is catalyzed by the action of histone methyltransferases (HMTs) and histone demethylases on lysine and arginine residues. Like DNMTs, HMTs employ a SAM cofactor. Lysine can be... 

During the past several years, a variety of crystal structures of histone lysine and arginine methyltransferase in complex with the cofactor analog SAH and/or in complex with peptide substrates have been reported [92]. However, no 3D structure of a complex between a histone methyltransferase (HMT) and an inhibitor has been reported so far. Due to the lack of experimental structures, a variety of molecular modeling and docking studies has been carried out for H MTs in order to understand the structural requirements for inhibitor binding. 

Islam K, Zheng W, Yu H et al (2011) Expanding cofactor repertoire of protein lysine methyltransferase for substrate labeling. ACS Chem Biol 6(7) 679-684... 

Xu 2001), glutathione (glutathione S-transferases, Raney et al. 1992 Slone 1995), acetyl-coenzyme A (N-acetyltransferases) or S-adenosylmethionine (methyltransferases). NADPH as a cofactor has to be added if cytosolic reductases are the aim of interest (Inaba 1989). 

The enzyme catechol-O-methyltransferase (COMT) is involved in pain regulation and regulation of neurotransmitters. COMT acts to catalyze the transfer of a methyl group from the cofactor S-adenosyl-L-methionine (SAM, 5) to the 0 of catecholate 4 (Reaction 9.5). The catechol structure is found in neurotransmitters such as dopamine, noradrenahne, and adrenaline. A related set of enzymes are the DNA methyltransferases that appear to have similar structure, especially in their active sites, to the structure of COMT. ... 

Figure 3 Repair of O methyiguanine by methyiguanine DNA methyltransferase. Methyiguanine DNA methyl transferase has no cofactors and recognizes DNA cooperativeiy. It flips the O methylguanine into its active site and transfers the methyl group to a nucleophilic cysteine in an 2 reaction.

A swap of the methyl carbon with nitrogen in aza-AdoMet leads to sinefungin (see Fig. 2g)—a natural nucleoside antibiotic found in Streptomyces griseolus. Such reverse chemistry additionally enhances the chemical stability of cofactor. Because of the positive charge of the protonated amine and correct chirahty at the carbon center, sinefungin has an extremely high inhibitory potential for AdoMet-dependent methyltransferases. 

Figure 3 Methyltransferase-directed coupling of extended groups to biomolecules using analogs of AdoMet. (a) Covalent coupling of N-aziridine and N-mustard cofactor mimics (b) transfer of an extended aliphatic chain from a double-activated cofactor, S-adenosyl-L-propenthionine (c) covalent coupling of an 5-vinyl-analog of AdoMet.

Dalhoff C, Lukinavicius G, Klimasauskas S, Weinhold E. Direct transfer of extended groups from synthetic cofactors by DNA methyltransferases. Nat. Chem. Biol. 2006 2 31-32. 

Goedecke K, Pignot M, Goody RS, Scheidig AJ, Weinhold E. Structure of the N6-adenine DNA methyltransferase M.Taql in complex with DNA and a cofactor analog. Nat. Struct. Biol. 2001 8 121-125. 

The first evidence for cobalamin involvement in the conversion of methanol to methane was provided by Blaylock and Stadtman [196,216-218] with extracts of methanol-grown M. barkeri they demonstrated enzymatic formation of methylcobalamin from methanol, and subsequent reduction of methylcobalamin to methane. Later Blaylock [196] showed that conversion of methanol to methylcobalamin requires a heat-stable cofactor and at least three proteins, a 100-200 kDa Bi2-enzyme (methyltransferase), a ferredoxin, and an unidentified protein. Blaylock speculated that the role of hydrogen and ferredoxin in the conversion of methanol to methylcobalamin was in the reduction of the Bi2-protein. This work led to the proposal that methylcobalamin was the direct precursor of methane in methanogenesis from various substrates [196,218]. 

---