Adenosylmethionine modifications

Posttranslational modification of preformed polynucleotides can generate additional bases such as pseudouridine, in which D-ribose is linked to C-5 of uracil by a carbon-to-carbon bond rather than by a P-N-glycosidic bond. The nucleotide pseudouridylic acid T arises by rearrangement of UMP of a preformed tRNA. Similarly, methylation by S-adenosylmethionine of a UMP of preformed tRNA forms TMP (thymidine monophosphate), which contains ribose rather than de-oxyribose. 

Icmt catalyzes the methyl esterification of the prenylated cysteine residue after Reel has proteolyzed the -CaaX-containing proteins. The first step in identification of the minimal substrate for Icmt was through identification of AFC (Figure 9.2) as described above. Interestingly, farnesylcys-teine (FC), which is devoid of the acetyl substitution, was not a substrate but did possess some activity as an inhibitor [51], suggesting that the free amine of FC requires modification for catalytic turnover. Alterations in the stereochemistry about the FC backbone also appeared to be detrimental to substrate activity. The stereoisomer, d-AFC, was not a substrate for Icmt but was a modest mixed-type inhibitor of the enzyme. AFC-methyl ester (AFC-Me) was also reported to be a mixed-type inhibitor with respect to both l-AFC and -adenosylmethionine (SAM), the methyl donor, with Ki values of 41 and 73 pM, respectively [52,53] The farnesyl homocysteine homolog of AFC is not a substrate for the enzyme however, the racemic DL-homocysteine farnesyl derivative is in fact a weak inhibitor [40]. Similar to the results with racemic prenylcysteine, these data demonstrate that the linker between the carboxylate and thioether moieties is critical for substrate activity. 

Methylases specific for each of the four bases of sRNA (97) and for adenine and cytosine of DNA (98) are available. Selective modification of a nucleic acid or its oligonucleotide fragments before digestion with a specific nuclease gives additional dimensions for selective degradation. Use of C-methyl labelled S-adenosylmethionine permits selective isotopic labelling by these enzymes. 

Atta, M., Mulliez, E., Arragain, S., Forouhar, F, Hunt, J. R, Fontecave, M. (2010). S-Adenosylmethionine-dependent radical-based modification of biological macromolecules. Current Opinion in Structural Biology, 20, 684—692. 

Many intracellular proteins can be modified after their biosynthesis by the enzymatic addition of a methyl group from S-adenosylmethionine. These posttransla-tional reactions can permanently or temporarily modify the structure and function of the target proteins. Importantly, these modifications can expand the repertoire of the cellular chemistry performed by proteins. Unmodified proteins must function with only the 20 amino acid residues incorporated in ribosomal protein synthesis, while methylation reactions can create a variety of new types of residues for specialized cellular roles. At this point, we understand best the processes that reversibly form methyl esters at carboxylic acid residues. One such reaction in bacteria methylates glutamate residues on several membrane-bound chemorecep-tors whose signaling properties are modulated by the degree of modification at multiple methylation sites. Another methylation system in higher cells leads to C-terminal methyl ester formation on a variety of proteins such as the small and... 

Pyruvoyl cofactor is derived from the posttranslational modification of an internal amino acid residue, and it does not equilibrate with exogenous pyruvate. Enzymes that possess this cofactor play an important role in the metabolism of biologically important amines from bacterial and eukaryotic sources. These enzymes include aspartate decarboxylase, arginine decarboxylase," phosphatidylserine decarboxylase, . S-adenosylmethionine decarboxylase, histidine decarboxylase, glycine reductase, and proline reductase. ... 

Methylation underlies several important biological processes, including restriction and modification, mismatch error correction (a DNA repair process), and the control of eukaryotic gene expression. S-Adenosylmethionine (AdoMet) is the substrate for methylation of both RNA and DNA. Methylation occurs at the polynucleotide level, with transfer of a methyl group from AdoMet to a nucleotide residue. 

See also Cathepsins, Calpains, Protein Turnover (from Chapter 20), S-Adenosylmethionine and Biological Methylation, Covalent Modification of Proteins... 

The bases are modified at the same time the endonucleolytic cleavage reactions are occurring (see Fig. 14.20, circle 3). Three modifications occur in most tRNAs (1) Uracil is methylated by S-adenosylmethionine (SAM) to form thymine (2) one of the double bonds of uracil is reduced to form dihydrouracil , and (3) a uracil residue (attached to ribose by an A-glycosidic bond) is rotated to form pseudouridine, which contains uracil linked to ribose by a carbon-carbon bond, (see Fig. 14.17). Other, less common but more complex, modifications also occur and involve bases other than uracil. Of particular note is the deamination of adenosine to form the base inosine. 

Hi) N -Methyllysines. Monomethyllysine was first observed in the flagellum protein of S. typhimurium by Ambler and Rees (1959). Since then, mono-, di-, and trimethyl derivatives of lysine have been found in a wide variety of proteins (see Paik and Kim, 1975). The methyl groups, as in other such derivatives, arise from S-adenosylmethionine, but the functional importance of the modifications remains obscure. Numerous procedures have been developed for their identification and quantification (Glazer et a/., 1975 Paik and Kim, 1975). 

Selected DNA modifications caused by enzymatic (5-methyl and 5-hydroxymethylcytosine) and chemical (i.e. damaging) methylation (1-meA, 1-meG, 3-meT, 3-meC). Enzymes capable of catalysing deme-thylation of 5-meC have not yet been discovered. DNMT = DNA methyltransferase SAM = S -adenosylmethionine. 

Although the list of transmethylation reactions in which S-adenosylmethionine can function as the methyl donor could now undoubtedly be greatly expanded, the more recently added reactions, with the exception of the carbon methylations discussed below (Section II,C,6), appear from the chemical point of view to be further examples of types of reactions which were already known. Therefore, no complete compilation will be attempted. From the physiological standpoint, on the other hand, some of the reactions recently studied may be of great interest. For example, systems have now been reported for the enzymic methylation of RNA (Srinavasan and Borek, 1964 Rodeh et al, 1967), DNA (Oda and Marmur, 1966 Kalousek and Morris, 1969), pectin (Kauss and Hassid, 1967), and protein (Comb et al, 1966 Paik and Kim, 1968 Liss et al, 1969). The specific modifications of the properties of these biopolymers consequent to methylation may, of course, be important in... 

In the case of macromolecules, both the informational and the non-inf ormational ones, S-adenosylmethionine contributes to some of their post-synthetic modifications, thus allowing the attainment of their native configuration, which displays the specific biological function. 

The specificity of human 5 -methylthioadenosine phosphorylase is rather strict if compared with that of the enzyme purified from E. coli The replacement of the sulfur atom of 5 -methylthioade-nosine by selenium and the replacement of the methyl group by an ethyl one are the only substrate modifications compatible with enzymic activity. The rate of breakdown of 5 -methylselenoadenosine equals that of 5 -methylthioadenosine (see Fig. 8). This finding agrees with the generally accepted view that the enzyme systems that normally utilize sulfur metabolites also convert their selenium analogues, i.e. the interchangeability of methionine and selenomethionine has been demonstrated in protein synthesisas well as that of S-adenosylmethionine and Se-adenosylselenomethionine in polyamine biosynthesis. 

Host-control modification and restriction enzymes of Escherichia coli B and the role of adenosylmethionine, in The Biochemistry of Adenosylmethionine", F. Salvatore, E. Borek,... 

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