Control of sulphur amino acid metabolism

The Km values for the homocysteine transferase enzymes (steps 4 and 5 of Fig. 7.1) (which lead to the recycling of methionine) are two orders of magnitude lower than those for cystathionine synthase (step 6 of Fig. 7.1) and cystathionine 7-lyase (step 7 of Fig. 7.1) (which process methionine towards catabolism via the transulphura-tion pathway). Thus, at low intracellular concentrations of methionine, remethyla-tion will be favoured over transulphuration and methionine will be conserved. When these two pathways were examined in vivo in rats fed diets containing 3, 15 and 30 g L-methionine kg-1 of diet, the percentage of methionine metabolized by the two competing pathways changed (Finkelstein and Martin, 1984, 1986). With increasing dietary methionine intake, substrate flux through the transmethylation pathway fell and flux through the transulphuration pathway increased.

Examination of the Km values for rate-limiting enzymes processing the major cysteine metabolites provides a further insight into how sulphur amino acid metabolism is influenced by alteration in the supply of cysteine. The Km for L-cys-teinyl-tRNA synthetase (step 8 of Fig. 7.1) (essential for incorporation of cysteine into protein) is less than one-tenth of that for 7-glutamyl cysteine synthetase (step 9 of Fig. 7.1) (the rate-limiting enzyme for GSH synthesis) or cysteine dioxyge-nase (step 10 of Fig. 7.1) (forming cysteine sulphinate, the precursor for sulphate and taurine). Thus, under conditions of low cysteine availability, protein synthesis will be maintained and sythesis of sulphate, taurine and GSH curtailed.

From the kinetics of the key enzymes in sulphur amino acid metabolism reported above, it can be seen that, when the diet is low in sulphur amino acids, cellular methionine is highly conserved. Flux down the transulphuration pathway, which ultimately leads to methionine catabolism, increases only as dietary methionine intake increases. It can also be seen that, at low flux rates of substrate down the transulphuration pathway, conversion of cysteine into its main metabolites will be affected, so that protein synthesis will be relatively maintained while sulphate and GSH synthesis rates will fall. Synthesis of GSH and sulphate will increase in concert as increasing levels of substrate flow through the pathway. In a study in rats, seven molecules of cysteine were incorporated into GSH for every ten incorporated into protein in liver at adequate sulphur amino acid intake (Grimble and Grimble, 1998). At inadequate sulphur amino acid intake, the ratio fell to < 3: 10. This response to a low intake of sulphur amino acids will not necessarily be advantageous since GSH is an important component of antioxidant defence. Thus, at low sulphur amino acid intakes, antioxi-dant defences will become weakened. The immune response makes large demands on these defences and sulphur amino acid metabolism in particular.

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