5-Adenosylmethionine, from structure

Adenosine triphosphate, coupled reactions and. 1128-1129 function of, 157, 1127-1128 reaction with glucose, 1129 structure of, 157, 1044 S-Adenosylmethionine, from methionine, 669 function of, 382-383 stereochemistry of, 315 structure of, 1045 Adipic acid, structure of, 753 ADP, sec Adenosine diphosphate Adrenaline, biosynthesis of, 382-383 molecular model of, 323 slructure of, 24... 

The transmethylation hypothesis depended on the psychosis of mescaline as an example of how methylated compounds similar in structure to the monoamine neurotransmitters could be psychotogenic, and demonstrated how methionine, the precursor of the methyl donor S-adenosylmethionine, could exacerbate the psychotic symptoms of schizophrenia in patients. This theory was fed by studies of the now notorious pink spot, an amine found in paper chromatography of urine extracts from schizophrenics and thought to be 3,4-dimethoxyphenylethylamine (i.e., O-methylated dopamine). Subsequent studies eventually identified this as another compound or compounds, primarily of dietary origin. Another methylated derivative erroneously proposed to be found in higher quantities in schizophrenia was dimethyltryptamine. This compound is similar in structure to LSD, the hallucinogenic nature of which was the key to the serotonin deficiency hypothesis, which proposed that the known antagonism of serotonin (5-HT) by LSD indicated that psychotic disorders such as schizophrenia may result from a hypofunction of 5-HT. 

Homologous components of the bacteriohopane-tetrol mixture from A. rancens and A. xylinium have been identified as 3-methylhopane derivatives.The structure (163) of the product of the periodate-borohydride reaction sequence was confirmed by reduction to (22i )-3-methyl-29-ethylhopane (164) identical with a synthetic sample. The 3-methylhopanes can arise either by direct cyclization of squalene initiated by 5-adenosylmethionine or by formation of 3-methylsqualene and subsequent cyclization by the cyclase enzyme. Rohmer and Ourisson favour the latter course in view of the low substrate specificity of the cyclase enzyme of A. rancens (see p. 131). 

Fig. 3 Structural features of methionine synthase. Methionine synthase is comprised of five domains, which bind homocysteine (HCY), methylfolate (5-methyl THF), cobalamin, and S-adenosylmethionine (SAM). The Cap domain restricts oxidation of cobalamin in its vulnerable Cbl(I) state. Strucmres from E.coli (Bandarian et al., 2002 Dixon et al. 1996) and T.maritima (Evans et al. 2004) (PDB codes 1Q8J, 1K98 and IMSK, respectively) were used to construct this composite model. An uncharacteiized linker segment between the folate and cap domains is absent...

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... 

The enzymatic methylation of calmodulin in rat brain cytosolic preparations has recently been investigated (28). Methyl group transfer from S-adenosylmethionine occurred principally into -trimethyllysine residues and was inhibited by EGTA. Methylation was stimulated by divalent cations, with Mn + providing the highest rate. It is unclear, however, whether the effect of the cation was enzyme or substrate directed. While the trimethyllysine residue of calmodulin has received considerable attention because of its rarity in protein structures, the residue is not apparently required for calmodulin to activate enzymes (29). 

Polyamine metabolism by parasites differs in several significant ways from the mammalian host these include, but are not limited to, enzyme half-life, turnover, substrate specificity, types and quantities of polyamines produced. The production of the novel bis glutathionyl spermidine adduct by trypanosomatids, its role as an antioxidant and the protein structure of trypanothione reductase is discussed with respect to the more conventional glutathione reductase system. The role of S-adenosylmethionine and decarboxylated S-adenosylmethionine as critical precursors in the biosynthesis of the higher polyamines is explored with respect to differences in the function and control of the pathway by various parasites. Polyamine biosynthesis in parasites is sufficiently different from that of the host to afford multiple opportunities for drug development, these may be aimed directly at circumventing polyamine biosynthesis or at inhibiting precursors necessary for polyamine synthesis. 

Fig. 31.30 Reaction mechanism of 0-methylation of catechols catalysed by catechol 0-methyltransferase. The structure of S-adenosylmethionine (SAM) is shown in the insert (from Mannisto and Kaakkola, with permission). ...

C42H5 ClN4NiO,7, Mr 1006.04, uv, (pentamethyl ester, F 430 M in HjO) 431,418,296,274 nm. F. belongs to the structural class of the hydroporphyrins. Occurrence F. (coenzyme F 430), is the prosthetic group of methyl-coenzyme M reductase, which catalyzes the last step of methane formation in methano-genic bacteria. The mechanism of formation of methane from methyl-coenzyme M (H3C-S-CH2-CH2-SOJ) is still unknown. However, the central nickel atom in F. most certainly participates in the reduction. Biosynthesis F. is formed from 5-amino-4-oxova-leric acid via the normal biosynthetic route for porphi-noid compounds. The 2- and 7-methyl groups originate from 5-adenosylmethionine. 

DL-Met is prepared on the industrial scale (more than 100,000 tons annually) by a Strecker synthesis, using P-methylmercaptopropionaldehyde prepared from acrolein and methylmercaptan. nt-Met is used to supplement poltry feed. Both d- and L-forms are effective, so that no prior separation of enantiomers is necessary. [F.Takusagawa et al. Crystal Structure of S-Adenosylmethionine Synthetase / BioL Chem. 271 (1996) 136-147]... 

The structural resemblance between saxitoxin and purines of primary metabolism confounded efforts to determine the biosynthetic pathway for saxitoxin. Isotope-labeled precursor feeding studies revealed that saxitoxin is produced from arginine, acetate, and 5-adenosylmethionine (SAM) by a unique pathway [149, 150, 223]. 

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