In this article we will discuss about the metabolism of sulphur-containing amino acids.
There are 3 sulphur-containing amino acids, methionine, cysteine and cystine, but since the last two are very easily interconvertible by oxidation-reduction, they may be taken as one. Methionine is an essential amino acid — for rat as well as man – while cysteine is not. However, when cysteine is supplied, methionine requirements decrease, which suggests that a part of methionine is utilized for forming cysteine; this was confirmed by studies carried out with the help of radioactive isotopes.
Formation of Cysteine from Methionine:
In animals and man, the mechanism of this transformation, called transulphuration, implies two enzymes containing pyridoxal phosphate: the first, cystathionine synthetase (E1) catalyzes the formation of an intermediate compound, cystathionine, from serine and homocysteine (higher homologue of cysteine, formed by the demethylation of methionine).
Cystathionine synthetase first catalyzes a dehydration of serine (first substrate) according to the mechanism described in fig. 7-2, and then, on the double bond thus formed between α and β carbons, the addition of the homocysteine molecule (second substrate).
This cystathionine is then split by cystathionase (E2) giving on the one hand cysteine, formed from carbon and nitrogen atoms of serine and the sulphur of methionine, and on the other hand, homoserine which is not released from this second enzyme and undergoes a deamination (α-γ elimination reaction whose mechanism is close to the one described for serine in fig. 7-2) which converts it into α-ketobutyric acid (see fig. 7-17).
a) Fate of the Homoserine Formed:
In bacteria, homoserine is a precursor of threonine and isoleucine as we will see while studying the amino acids deriving from aspartate. First a migration of the alcoholic hydroxyl leads from homoserine (or more exactly from its derivative phosphoryiated on the alcohol group) to threonine, then a deamination gives α- acetobutyric acid.
There are now two possibilities: either the formation of isoleucine, or the decarboxylation of α-ketobutyric acid to propionic acid (see fig. 7-17). But we have seer, (see fig. 5-13) that propionyl-coA can be transformed into succinyl-coA; the carbon atoms of propionic acid can then follow this pathway and be present for example in glucose after neoglucogenesis.
b) Reversibility of Trans-Sulphuration:
In animals and man, trans-sulphuration is not reversible, but it is so in various organisms which can therefore form cystathionine from homoserine and cysteine under the action of a cystathionine synthetase (E1’) and split this cystathionine by a cystathionase (E2’) into homocysteine, pyruvate and ammonia (see fig. 7-22); in other words these organisms can (by this process) form homocysteine from cysteine and are thus capable of synthesizing methionine.
Methylation of Homocysteine into Methionine:
If the methyl groups of choline or betain are labeled, radioactivity is observed in CH3 of methionine. Methylation is therefore possible (it takes place thanks to N5-methyl-FH4 which brings the one-carbon unit); it is possible even in animals. Therefore, it is homocysteine rather than methionine, which is essential, and if it is fed to the animal it is methylated into methionine.
Metabolism of Methionine:
In addition to its role of amino acid constitutive of proteins and its part in the initiation of protein biosynthesis, methionine is mostly a supplier of methyl groups. It must be first activated by ATP to give S-adenosyl- methionine which is the real agent participating in the transmethylation process.
It can then yield its methyl group to very diverse compounds and be converted into S-adenosyl-homocysteine, as shown by figure 7-18; this is the mechanism involved for example in the biosynthesis of choline, creatine, adrenaline, in the methylation of some bases (called abnormal or rare) of tRNAs, etc.
Metabolism of Cysteine:
Let us first recall that cysteine is a constituent of glutathione (see fig. 1-12) whose mode of formation we discussed while studying the metabolism of glycine.
Moreover, one must remember the reversible oxidation cysteine ←→ cystine (thiol ←→ disulphide, i.e. 2R —SH ←→ R —S —S —R) which can take place in the free amino acid, in glutathione or in proteins. As for the decarboxylation of cysteine, it leads to mercaptoethylamine or cysteamine (H2N —CH2-CH2—SH) which is a constituent of coenzyme A (see fig. 2-18).
a) Transformation of Cysteine into Pyruvic Acid:
Two pathways are possible:
1. The first, which we already studied (see fig. 7-2), consists of a deamination catalyzed by cysteine desulphydrase;
2. The second consists of an oxidation of cysteine to cysteine-sulphinic acid which loses its amino group by transamination and gives sulphinyl-pyruvic acid. The latter gives pyruvic acid by liberating sulphur which is found in the form of sulphite and then sulphate.
This sulphate is activated in the form of adenosine 3′-phosphate-5′-phos- pho-sulphate which can react with diverse compounds like phenols or steroids which are then eliminated in urine in the form of sulpho-conjugated derivatives (detoxication).
b) Formation of Taurine:
Cysteine-sulphinic acid whose formation by oxidation of cysteine we mentioned above can — instead of being transaminated — be decarboxylated to hypotaurine, which is then oxidized to taurine (there can also be, first oxidation to cysteic acid, then decarboxylation to taurine) as shown by figure 7-19. Taurine can — like glycine — be conjugated with the bile acids (see fig. 5-7).
Figure 7-20 presents a recaptulative diagram of reactions of the metabolism of sulphur-containing amino acids.