Sulphur amino acid metabolism

The sulphur amino acids are methionine and cysteine. Their metabolism is interlinked. As a result of this metabolism, the sulphur moiety is incorporated into a number of end-products, three of which, glutathione, taurine and proteins, have important roles in immune function. Methionine is a nutritionally essential amino acid, due to the inability of mammals to synthesize its carbon skeleton. Cysteine is considered to be semi-essential, in that it is synthesized from methionine provided that the dietary supply of the latter is sufficient. The methyl group of methionine can be removed from and reattached to the carbon skeleton of the amino acid by a cyclical process referred to as the transmethylation pathway (Fig. 7.1). The formation of homocysteine, part way along the transmethylation pathway, is an important branch point in the metabolism of methionine. Homocysteine can be remethylated to form methionine or can be metabolized by the transulphuration pathway to form cysteine (Fig. 7.1). Both the remethylation of homocysteine and the formation of cysteine utilize serine. This latter amino acid forms the carbon skeleton of cysteine and acts as a methyl-group donor to tetrahydrofolic acid, once the methyl version of the latter compound has donated its methyl group to homocysteine during the formation of methionine.

Methionine is intimately involved in the synthesis of the polyamines sper-mine and spermidine, in which the carbon chain of methionine is donated to a third polyamine, putrescine, which is derived from ornithine (Fig. 7.2). The polyamines are present in high concentrations in rapidly dividing cells, such as those of an activated immune system. Their role is poorly defined but appears to be important. Polyamines have been likened to 'molecular grease', in that they are permissive metabolites, ensuring the fidelity of DNA transcription and RNA translation (Grimble and Grimble, 1998). In in vitro studies, cells depleted

© CAB International 2002. Nutrition and Immune Function (eds P.C. Calder, C.J. Field and H.S. Gill)

Protein

Serine Glycine

5-methylene THFA

THFA

5-methyl THFA

THFA

Betaine

Methionine r

Dimethyl glycine

S-AM

Betaine x-ch3

Choline

S-AH

Serine

Homocysteine

Vit. B6 Cystathionine

Sulphate Taurine

Cysteine sulphinate

1° J 9 Glutathione

Fig. 7.1. Outline of sulphur amino acid metabolism. Enzymes: 1, methionine adenosyl transferase; 2, methyl transferase; 3, adenosyl homocysteinase; 4, betaine methyltransferase; 5, S-methyltetrahydrofolate methyl transferase; 6, cystathionine p-synthase; 7, cystathionine 7-lyase; 8, l-cysteinyl-tRNA synthetase; 9, 7-glutamyl cysteine synthase; 10, cysteine dioxygenase. S-AH, S-adenosyl homocysteine; S-AM, S-adenosyl methionine; THFA, tetrahydrofolic acid.

Ornithine

Spermidine

Fig. 7.2. Polyamine biosynthesis.

of polyamines exhibit increased error rates in both processes. The first enzyme in the step from ornithine to putrescine is highly induced in rapidly dividing cells.

Methionine also acts as a methyl donor in the synthesis of creatine (Fig. 7.3), which is essential for muscle energy generation through its phosphorylation to creatine phosphate. Creatine phosphate can transfer its phosphate to ADP to restore cellular ATP supplies during periods of high metabolic activity.

In addition to incorporation into proteins, cysteine can be incorporared into the key antioxidant glutathione (GSH), or converted to taurine and inorganic sulphate. The possession of an SH group by cysteine and GSH allows the formation of an S-S bridge between two molecules of cysteine or of GSH to form cystine and oxidized glutathione (GSSG), respectively. Taurine has many roles, including formation of the bile salt taurocholic acid, and is a puta-

Arginine + Glycine

Guanidoacetic acid + Ornithine

S-adenosyl methionine

Creatine

Fig. 7.3. Creatine biosynthesis.

Methionine

S-adenosyl homocysteine tive antioxidant and cell membrane stabilizer. Taurine is the predominant nitrogenous compound in immune cells.

The synthesis of glutathione from its three constituent amino acids is mainly limited to the liver. Two consecutive steps are required to synthesize glutathione, each step consuming one ATP molecule (Fig. 7.4). The rate-limiting enzyme in the pathway is 7-glutamyl cysteine synthetase (step 1 of Fig. 7.4). Under normal physiological conditions, there is feedback on the activity of this enzyme by GSH. Thus, conversion of cysteine to GSH is strongly influenced by the rate of utilization/transport of GSH within and between the cells of the body. In other words, synthesis is a 'demand-led' process, provided that cysteine is available.

Glutathione is transferred to the blood and transported around the body in both plasma and cells mainly in its reduced form (GSH).

Thus, apart from protein synthesis, sulphur amino acids are involved as direct and indirect participants in pathways involved in cell replication and stabilization, antioxidant defence, assimilation of lipids and energy metabolism. As the immune response involves major changes in cell replication, oxidant stress and lipid and energy metabolism, it is not surprising that the availability of sulphur amino acids has a major impact on immune function.

Amino acid

Cysteine I 1 Glutamate

5-oxoproline ^^

Fig. 7.4. Formation of glutathione and its role in the 7-glutamyl cycle. Enzymes: 1, 7-glutamyl cysteine synthase; 2, glutathione synthase.

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