Homocysteine synthesis

This evidence is consistent with, but does not provide definitive proof for OAS being the physiologically important precursor of cysteine. Only a limited number of O-esters of serine have been tested for activity with cysteine synthase (Section II,B,2), and no systematic studies have been made to determine whether serine O-esters other than OAS are synthesized by plants, or to identify the physiologically important a-aminopropionyl donor for cysteine synthesis. Experiments analogous to those used to identify the a-aminobutyryl donor for cystathionine and homocysteine synthesis (Section III,A,3) and the physiological carrier in sulfate reduction in Chlorella (Section IV,D,3) should be informative in this respect. 

Phosphohomoserine is used as a substrate for synthesis of cystathionine [Reaction (4)J and homocysteine [Reaction (5)J by extracts of all plants examined (Datko et al., 1974, 1977), but not by any microorganism tested (See Giovanelli et al., in press). Plants are therefore unique among the organisms studied in using 0-phosphohomoserine for cystathionine or homocysteine synthesis. 

Quantitative analysis of these data (Giovanelli et al., 1978) showed that transsulfuration accounts for at least 97% of homocysteine synthesis by Chlorella under the conditions specified. 

A further factor to consider with respect to the localization of homocysteine synthesis in chloroplasts is whether the intermediates of the pathways involved are present at concentrations which sustain homocysteine synthesis at rates commensurate with the rate of production of methionine by the whole cell or organism. In this regard Giovanelli et al. (1986) reported that cystathionine... 

The antiviral activity of (5)-DHPA in vivo was assessed in mice inoculated intranasaHy with vesicular stomatitis vims ( 5)-DHPA significantly increased survival from the infection. (5)-DHPA did not significantly reduce DNA, RNA, or protein synthesis and is not a substrate for adenosine deaminase of either bacterial or mammalian origin. However, (5)-DHPA strongly inhibits deamination of adenosine and ara-A by adenosine deaminase. Its mode of action may be inhibition of Vadenosyl-L-homocysteine hydrolase (61). Inhibition of SAH hydrolase results in the accumulation of SAH, which is a product inhibitor of Vadenosylmethionine-dependent methylation reactions. Such methylations are required for the maturation of vital mRNA, and hence inhibitors of SAH hydrolase may be expected to block vims repHcation by interference with viral mRNA methylation. 

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. 

Fig. 14.10 Folate metabolism and role of MTHFR. Genetically reduced MTHFR activity affects the distribution between folate species required for protein and DNA synthesis. Higher availabil ity of 5,10-methylenetetrahydrofolate (CH2THF) potentiates the TS inhibition by 5-FdUMP, the active metabolite of 5-FU. Hey, homocysteine Met, methionine CH3HF, 5-methyltetrahydrofolate TS, thymidylate synthase 5-FdUMP, fluorodeoxyuridine monophosphate.

A newer therapeutic approach is the administration of betaine (6-12 g daily), which lowers homocysteine levels by favoring remethylation [33], A theoretical hazard of betaine treatment is increasing the blood methionine, sometimes to an extravagant degree ( 1 mmol/1). Experience to date indicates that betaine administration is safe, with no major side effects except for a fishy odor to the urine. Other therapeutic approaches have included the administration of salicylate to ameliorate the thromboembolic diathesis. Patients also have been treated with dietary supplements of L-cystine, since the block of the transsulfura-tion pathway in theory could diminish the synthesis of this amino acid. 

SMM synthesis is mediated by the enzyme methionine S-methyltransferase (MMT) through the essentially irreversible, AdoMet-mediated methylation of methionine.48"5 Both MMT and SMM are unique to plants 48,50 The opposite reaction, in which SMM is used to methylate homocysteine to yield two molecules of methionine, is catalyzed by the enzyme homocysteine S-methyltransferase (HMT).48 Unlike MMT, HMTs also occur in bacteria, yeast, and mammals, enabling them to catabolize SMM of plant origin, and providing an alternative to the methionine synthase reaction as a means to methylate homocysteine. Plant MMT and HMT reactions, together with those catalyzed by AdoMet synthetase and AdoHcy hydrolase, constitute the SMM cycle (Fig. 2.4).4... 

Important pathways requiring SAM include synthesis of epinephrine and of the 7-methylgua-nine cap on eukaryotic mRNA, Synthesis of SAM from methionine is shown in Figure T17-3. After donating the methyl group, SAM is converted to homocysteine and remethylated in a reaction catalyzed by N-methyl THF-homocysteine methyltransferase requirii both vitamin Bj2 and N-meth d-THF. The methionine produced is once again used to make SAM. 

Small methyl groups are important in the stractnre of some small compounds, nucleotides, some bases in DNA mole-cnles and in postranslational modification of amino acids in proteins. The transfer of a single carbon atom is important in the synthesis of purine nncleotides. The componnds involved in the whole process of methyl gronp transfer, and are carbon metolism, are methionine, homocysteine, serine and the vitamins, folic acid and B12. 

In methylcobalamin, X is a methyl group. This compound functions as a coenzyme for several methyltransferases, and among other things is involved in the synthesis of methionine from homocysteine (see p. 418). However, in human metabolism, in which methionine is an essential amino acid, this reaction does not occur. 

Kinetics of O-Methylaiion. The steady state kinetic analysis of these enzymes (41,42) was consistent with a sequential ordered reaction mechanism, in which 5-adenosyl-L-methionine and 5-adenosyl-L-homocysteine were leading reaction partners and included an abortive EQB complex. Furthermore, all the methyltransferases studied exhibited competitive patterns between 5-adenosyl-L-methionine and its product, whereas the other patterns were either noncompetitive or uncompetitive. Whereas the 6-methylating enzyme was severely inhibited by its respective flavonoid substrate at concentrations close to Km, the other enzymes were less affected. The low inhibition constants of 5-adenosyl-L-homocysteine (Table I) suggests that earlier enzymes of the pathway may regulate the rate of synthesis of the final products. 

Cobalamin compounds Tight Cobalamin (B12) Transfer of methyl group to homocysteine during synthesis of methionine metabolism of methylmalonyl coenzyme A... 

Difluorocysteine, like 3,3-difluoroserine, is unstable. However, a protected derivative has been described. Conversely, 3,3-difluoro-L-homocysteine and 3, 3-difluoro-L-methionine are much more stable. They are prepared from difluoro-homoserine. This latter is prepared through a multistep synthesis starting from isoascorbic acid (Figure 5.24). ... 

Figure 5.24 Synthesis of difluoro-L-homocysteine and difluoro-L-methionine. ...

Scheme 58 Synthesis of S-p-n-Galactosylated Cysteine and Homocysteine Building Blocksl1651...

Convergent Synthesis of Neoglycopeptides by Coupling of 2-Bromoethyl Glycosides to Cysteine (or Homocysteine)... 

Cyanocobalamin A cofactor required for essential enzymatic reactions that form tetrahydrofolate, convert homocysteine to methionine, and metabolize l-methylmalonyl-CoA Adequate supplies are required for amino acid and fatty acid metabolism, and DNA synthesis Treatment of vitamin B12 deficiency, which manifests as megaloblastic anemia and is the basis of pernicious anemia Parenteral vitamin B12 is required for pernicious anemia and other malabsorption syndromes Toxicity No toxicity associated with excess vitamin B12... 

Homocysteine (Hey) metabolism is closely linked to that of the essential amino acid methionine and thus plays a central role in several vital biological processes. Methionine itself is needed for protein synthesis and donates methyl groups for the synthesis of a broad range of vital methylated compounds. It is also a main source of sulphur and acts as the precursor for several other sulphur-containing amino acids such as cystathionine, cysteine and taurine. In addition, it donates the carbon skeleton for polyamine synthesis [1,2]. Hey is also important in the metabolism of folate and in the breakdown of choline. Hey levels are determined by its synthesis from methionine, which involves several enzymes, its remethylation to methionine and its breakdown by trans-sulphuration. 

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