Methionine synthesis, regulation

Cysteine inhibited sugar beet and radish threonine synthases. It was, therefore, proposed that O-phosphohomoserine would be diverted toward methionine synthesis as cysteine inhibited the enzyme (Madison and Thompson, 1976). Effective regulation could be achieved by the opposing effects of the methionine precursor, cysteine, and the methionine derivative, 5-adenosylmethionine. However, this can not be considered a universal regulatory pattern for plant threonine synthases since the barley enzyme was not inhibited by cysteine (Aarnes, 1978) and the effects of cysteine on the activity of the pea enzyme were questionable (Thoen et al., 1978b). 

A hypothesis has been proposed to explain all known causes of hyperho-mocysteinemia by a single, biochemical principle (Selhub and Miller 1992). The hypothesis emphasizes the existence of coordinate regulation by AdoMet of the partitioning of homocysteine between methionine synthesis and catabolism through cystathionine synthesis Elevated homocysteine levels in blood can be caused by a number of factors, including folate and B vitamin (B12, Bg) deficiency and pre-existing diseases such as atherosclerotic disease, diabetes and by various drugs. 

These data indicate that methionine, or a derivative thereof, controls vivo assimilation of sulfate into cystathionine and its products, and therefore that the regulatory locus is at cystathionine synthesis. Furthermore, since regulation at this step did not cause an accumulation of cysteine and its products, regulation of sulfate assimilation into cysteine is also indicated. It has not yet been firmly established whether methionine also controls novo synthesis of the carbon moieties of methionine. Such regulation of the 4-carbon moiety would be expected if exogenous methionine regulates the cystathionine synthesis step, since it is at this step that both the sulfur and 4-carbon moieties become committed to methionine. 

Fig. 5. Regulation of the enzymes of methionine biosynthesis and related pathways. Enzymes catalyzing the synthesis of methionine and 5 -adenosylmethionine (SAM) from cysteine are (1) cystathionine y-synthase, (2) j9-cystathionase, (3) methionine synthase, and (4) SAM synthetase. Enzymes associated with the synthesis and metabolism of phospbohomoserine which are relevant to the regulation of methionine synthesis are (5) aspartate kinase, (6) homoserine kinase, and (7)...

Phosphohomoserine is a substrate for both threonine synthase and cystathionine y-synthase. Thus, although threonine synthase is not involved in the synthesis of either methionine or phosphohomoserine the properties of this enzyme are relevant to methionine synthesis as it competes with cystathionine y-synthase for the same substrate. Moreover, as discussed in the ensuing section, the activity of threonine synthase and the synthesis of phosphohomoserine are regulated by products of the methionine biosynthetic pathway. 5-Aden-osylmethionine is an extremely potent positive effector of threonine synthase, virtually serving as an absolute requirement for enzyme activity (Aames, 1978 Giovanelli et a/., 1984 Madison and Thompson, 1976 Thoen eta/., 1978). In the presence of SAM, Giovanelli et al. (1984) found that threonine synthase had an extremely high affinity for phosphohomoserine (A = 2.2-6.9 nM). 

The regulation of methionine synthesis is intricately enmeshed with the pathways involved in the formation of the other amino acids derived from... 

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. 

ACS activity may be reversibly regulated by various substances associated with the methionine-recycling pathway, SAM metabolism, and polyamine synthesis, and by natural and chemical analogues of SAM or inhibitors of PLP-dependent enzymes. 

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. 

Fig. 1. Ethylene biosynthesis. The numbered enzymes are (1) methionine adenosyltransferase, (2) ACC (l-aminocyclopropane-l-carboxylic acid) synthase, (3) ethylene forming enzyme (EFE), (4) 5 -methylthio-adenosine nucleosidase, (5) 5 -methylthioribose kinase. Regulation of the synthesis of ACC synthase and EFE are important steps in the control of ethylene production. ACC synthase requires pyridoxal phosphate and is inhibited by aminoethoxy vinyl glycine EFE requires 02 and is inhibited under anaerobic conditions. Synthesis of both ACC synthase and EFE is stimulated during ripening, senescence, abscission, following mechanical wounding, and treatment with auxins.

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