Methionine activated form

Detoxifica.tlon. Detoxification systems in the human body often involve reactions that utilize sulfur-containing compounds. For example, reactions in which sulfate esters of potentially toxic compounds are formed, rendering these less toxic or nontoxic, are common as are acetylation reactions involving acetyl—SCoA (45). Another important compound is. Vadenosylmethionine [29908-03-0] (SAM), the active form of methionine. SAM acts as a methylating agent, eg, in detoxification reactions such as the methylation of pyridine derivatives, and in the formation of choline (qv), creatine [60-27-5] carnitine [461-06-3] and epinephrine [329-65-7] (50). 

Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria 677 Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12 677 Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration 678... 

Cobalamin-c disease remethylation of homocysteine to methionine also requires an activated form of vitamin B12. In the absence of normal B12 activation, homocystinuria results from a failure of normal vitamin B12 metabolism. Complementation analysis classifies defects in vitamin B12 metabolism into three groups cblC (most common), cblD and cblF. Most individuals become ill in the first few months or weeks of life with hypotonia, lethargy and growth failure. Optic atrophy and retinal changes can occur. Methylmalonate excretion is excessive, but less than in methylmalonyl-CoA mutase deficiency, and without ketoaciduria or metabolic acidosis. 

The coenzyme tetrahydrofolate (THF) is the main agent by which Ci fragments are transferred in the metabolism. THF can bind this type of group in various oxidation states and pass it on (see p. 108). In addition, there is activated methyl, in the form of S-adenosyl methionine (SAM). SAM is involved in many methylation reactions—e. g., in creatine synthesis (see p. 336), the conversion of norepinephrine into epinephrine (see p. 352), the inactivation of norepinephrine by methylation of a phenolic OH group (see p. 316), and in the formation of the active form of the cytostatic drug 6-mercaptopurine (see p. 402). 

Vitamin B12 (cobalamin) has as its active forms, methylcobalamin and deoxyadenosyl cobalamin. It serves as a cofactor for the conversion of homocysteine to methionine, and methylmalonyl CoA to succinyl CoA. A deficiency of cobalamin results in pernicious (megaloblastic) anemia, dementia, and spinal degeneration. The anemia is treated with IM or high oral doses of vitamin B12. There is no known toxicity for this vitamin. 

Other kinds of modifications may be necessary to convert a newly synthesized protein to its biologically active form. The N-formyl group of the initiating methionine in prokaryotes is removed by a deformylase. A methionine amino-peptidase removes the initiating residue in many eukaryotic proteins. Other posttranslational modifications may include acetylation, amidation, hydroxy lation, methylation, phosphorylation, and sulfation of specific amino acid resi-... 

Much interest has been shown in the biosynthesis of insect juvenile hormones (62 R1, R2 = Me or Et). In adult male moths, [l-14C]propionate was specifically incorporated into juvenile hormone I [JH-1, (62 R1 = R2 = Et)], and tracer was only found at, and equally distributed between, C-7 and C-ll.90 Application of [2-14C]-and [3-14C]-propionate led to extensive randomization of label, which suggests that C-2 and C-3 formed in propionate catabolism can be re-used as smaller fragments, whilst C-l is either removed from propionate in a metabolically active form or is highly diluted. Ternary complexes of brain, corpora cardiaca, and corpora allata from the tobacco budworm Heliothis virescens produced labelled JH-I and JH-II (62 R1 = Et, R2 = Me) when incubated with L-[Me-14C]methionine or sodium [l-l4C]propionate.91 Partial degradation of the juvenile hormones showed that in JH-I portions a and /3 (62) had incorporated one atom of tracer from each propionate, whereas fraction y was unlabelled, and in JH-II only fraction a was... 

The widespread co-occurrence of noradrenaline and adrenaline in itself suggests that noradrenaline is the immediate adrenaline precursor. This had been considered probable even before the natural occurrence of noradrenaline was known (70, 71), and the methylation of noradrenaline has since been shown both in vitro in adrenal preparations (110) and in vivo on perfusing the surviving adrenal (111). The methyl group can arise from methionine, probably formed from choline, in which the adrenal is extremely rich. A large proportion of the activity of administered (methyl-C ) methionine appears in the adrenal (460, 569). 

Methylation is the addition of a carbon atom to a molecule, usually causing a change in the function of the methylated molecule. For example, methylation of the neurotransmitter dopamine by catechol-O-methyltransferase renders it inactive. With only two exceptions, 5-adenosylmethionine (SAM), an activated form of the essential amino acid methionine, is the methyl donor for each of the more than 150 methylation reactions, which regulate a large number of cellular functions. One exception is methylation of homocysteine (HCY) to methionine by the cobalamin (vitamin Bi2)-dependent enzyme methionine synthase, which utilizes 5-methyltetrahydrofolate (methylfolate) as the methyl donor, serving to complete the methionine cycle of methylation, as illustrated in Fig. 1 (lower right). Notably, HCY formation from S-adenosylhomocysteine (SAH) is reversible and, as a result, any decrease in methionine synthase activity will be reflected as an increase in both HCY and SAH. This is significant because SAH interferes with SAM-dependent methylation reactions, and a decrease in methionine synthase activity will decrease all of these reactions. Clearly methionine synthase exerts a powerful influence over cell function via its control over methylation. 

Folate (foUc acid) is an essential vitamin which, in its active form of tetrahydrofolate (THF, Figure 4-1), transfers 1-carbon groups to intermediates in metaboUsm. Folate plays an important role in DNA synthesis. It is required for the de novo synthesis of purines and for the conversion of deoxyuridine 5-monophosphate (dUMP) to deoxythymidine 5 -monophosphate (dTMP). Additionally, folate derivatives participate in the biosynthesis of choline, serine, glycine, and methionine. However, in situations of folate deficiency, symptoms are not observed from the lack of these products as adequate levels of chohne and amino acids are obtained from the diet. (See also Case 3.)... 

Proteolysis makes the length of the amino acid chain in proteins shorter. In all proteins, the N-terminal amino acid methionine occurring as the initiation amino acid is removed as soon as or even before the synthesis of a protein is over. In addition, many proteins are originally synthesized as a longer chain but later are shortened by proteolytic cleavage to a much shorter active form of the protein or enzyme. The common examples of this class of proteins are insulin and zymogen. These proteins are synthesized as pre-pro-proteins and undergo proteolysis first to yield as pro-proteins and then to proteins, which are the active form of these pre-pro-proteins. 

CGS catalyzes the 7-replacement reaction of an activated form of L-homoserine with L-cysteine, leading to cystathionine. 0-Succinyl-L-homoserine (l-OSHS), 0-acetyl-L-homoserine (OAHS), and 0-phospho-L-homoserine (OPHS) are substrates for CGS ftom bacteria, fungi, and plants, respectively. The plant enzyme is also able to convert the microbial substrates, albeit at much higher values. This reaction is the first step in the transsulfuration pathway that converts L-Cys into L-homocysteine, the immediate precursor of L-methionine. The 0-activated L-homoserine substrate is situated at a metabolic branch point between L-Met and L-Thr biosynthesis, and which substrate is used by CGS depends on the species. In analogy with TS, CGS is tightly regulated by SAM concentration in plants. ... 

S-adenosylmethionine (AdoMet) is a metabolically activated form of methionine involved in donating methyl groups. Transfer of a methyl group from AdoMet to a target molecule converts AdoMet to S-Adenosylhomocysteine (AdoHcy) (see here). 

S-Adenosylmethionine (AdoMet) is a metabolically activated form of methionine capable of donating a methyl group. AdoMet is formed in the reaction shown here. Transfer of a methyl group from AdoMet to a target molecule converts AdoMet to S-Adenosylhomocysteine (AdoHcy) (see here). Table 21.1 lists some important AdoMet-dependent transmethylations. Substrates range from small metabolites, such as norepinephrine, to polymers, such as DNA (see here), RNA, or proteins. 

We have now from single turnover experiments direct evidence for an electron transfer from the reduced cluster to AdoMet as an elementary process involved in glycyl radical formation [40]. The pi protein could be reduced to the EPR-active form containing the [4Fe-4S]+ center by deazaflavin and then reacted with AdoMet in the dark, i.e. in the absence of a continuous electron flow. Oxidation of the cluster could be monitored by EPR spectroscopy and an assay for methionine served to measure the one-electron reduction of AdoMet. It appeared clear that one equivalent of methionine was formed at the expense of one equivalent of the reduced... 

After proteins emerge from the ribosome, they may undergo posttranslafional modifications. The initial methionine is removed by specific proteases methionine is not the N-terminal amino acid of all proteins. Subsequently, other specific cleavages also may occur that convert proteins to more active forms (e.g., the conversion of proinsulin to insulin). In addition, amino acid residues within the peptide chain can be enzymatically modified to alter the activity or stability of the proteins, direct it to a subcellular compartment, or prepare it for secretion from the cell. 

Evidence for the [4Fe S] cluster as the active form of lysine aminomutase was obtained by Frey and co-workers, who showed by a combination of EPR spectroscopy and enzyme assays that the [4Fe-4S] -LAM generated in the presence of AdoMet was catalytically active. Unlike aRNR-AE, however, LAM catalyzes a reversible reductive cleavage of AdoMet, and thus methionine production and cluster oxidation could not be monitored as evidence of turnover. It is of interest to note that in the case of LAM, the presence of AdoMet facilitates reduction to the [4Fe-4S] state very little [4Fe-4S]" cluster is produced by the reduction of LAM with dithionite in the absence of AdoMet, while the presence of AdoMet or its analogue S-adenosylhomocysteine dramatically increases the quantity of [dFe-dS] " produced. It is not clear whether the presence of AdoMet affects the redox potential of the cluster or whether some other effect, such as accessibility of the cluster by the reductant, is at work. 

Tlirner and Shapiro (1961) first demonstrated a plant enzyme catalyzing the utilization of 5-methylmethionine as a methyl donor to homocysteine. In the reaction, Eq. (27), 2 moles of methionine are formed. The activity has been demonstrated in extracts of dry mature seeds of each plant species... 

Spermidine 4 was biosynthesized from putrescine 2 (NC4N), obtained by ornithine 1, and adenosyl-L-methionine (activated C3 unit). S -Adenosyl-L-methioninamine (decarboxylated 5-adenosyl-L-methionine) donates an aminopropyl group to putrescine 2 to form spermidine 4 in a reaction catalyzed by spermidine synthase. Homospermidine 3 is formed from two moles of putrescine 2 in an NAD" -dependent reaction catalyzed by HSS. Moreover, HSS catalyzes the NADI-dependent transfer of an aminobutyl group of spermidine 4 to putrescine 2 to form homospermidine 3. 

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