In this article we will discuss about the metabolism of glycine and serine.
They are two non-essential amino acids; as we shall see in the following they are inter-convertible, so that for a long time, one did not know which one was formed first and gave rise to the other. It is now known that it is not the simpler of the two (glycine), but serine which is synthesized first and we will therefore study it in the first place.
Synthesis of Serine:
Serine is formed from 3-phosphoglyc.eric acid (a compound of the intermediate metabolism which appears during glycolysis) by a series of 3 reactions represented in figure 7-8.
Metabolism of Serine:
Under the action of serine dehydratase, serine is deaminated to pyruvic acid. We shall see in a later section that the metabolism of serine is linked with that of sulphur-containing amino acids (see fig. 7-17). The decarboxylation of serine gives ethanolamine which will be referred to in connection with glycine (see fig. 7-10).
Serine-Glycine Interconversion:
This interconversion is catalyzed by a specific enzyme (its name, serine transhydroxymethylase, is a misnomer, because it is not a hydroxymethyl but a formyl which is transferred) and requires two coenzymes: on the one hand, pyridoxal phosphate which forms intermediately a Schiff base with the amino acid, as already seen, and on-the other hand a tetrahydrofolic derivative (FH4).
In fig. 2-19, FH4 is one of the two carriers of one-carbon units (the other carrier is S-adenosyl-methionine). Some authors suggested that a hydroxymethylated derivative of FH4 is formed (on N5 or N10), but in fact it rather appears that it is N5-N10-methylene FH4 which is formed by the removal of a molecule of water as shown by figure 7-9.
Metabolism of Glycine:
a) Formation of Glycine from Ethanolamine:
To begin with, ethanolamine must be transformed into choline through 3 successive methylations at the cost of S-adenosylmethionine: this takes place while ethanolamine is linked to a phosphatidic acid; in fact, there is therefore conversion of phosphatidyl-ethanolamine into phosphatidyl-choline (see structures in figure 5-3).
The liberated choline can be oxidized to betain and then lose successively its 3 methyl groups to give glycine (see fig. 7-10). FH4 picks up these methyl groups.
b) Deamination and Transamination of Glycine:
Glycine is transformed into glyoxylic acid by oxidative deamination (under the influence of a specific glycine oxidase) or by reversible transamination. This compound undergoes an oxidative decarboxylation to CO2 + formiate which is not liberated in the mixture but picked up by FH4 to form Ns-formyl FH4 or N10-formyl FH4 (see fig. 7-11).
Glycine can also be formed by transamination — as the process is reversible — from glyoxylic acid. The latter, as we have seen, can arise from isocitric acid (see fig. 5-26) and the glyoxyiic acid cycle also represents a contact point of carbohydrate and lipid metabolism (see fig. 5-27).
It is of interest to note that during the 3 processes we have just studied (serine-glycine interconversion, transformation of betain into glycine, catabolism of glycine), one-carbon atom units are detached and taken over by FH4; they join the pool of one-carbon units which can be used in various reactions like de novo biosynthesis of purine nucleotides (see fig. 6-19), methylation of dUMP to dTMP etc.
c) Formation of Hippuric Acid and Conjugated Bile Acids:
Glycine permits the elimination of some compounds which are toxic for the organism, e.g. benzoic acid; the latter is first activated and then bound to the amino group of glycine to form hippuric acid (thus called because it was discovered in horse urine) as shown in fig. 7-12.
By a similar mechanism, cholic and deoxycholic acids are first activated and then conjugated with glycine to form glycocholic and glycodeoxycholic acids (see fig. 5-7).
d) Synthesis of Glutathione:
The synthesis of glutathione (see fig. 1-12) takes place in 2 steps:
Glutamic acid + cysteine + ATP → γ-glutamyl-cysteine + ADP + Pi
γ-glutamyl-cysteine + glycine + ATP → glutathione + ADP + Pi
e) Synthesis of Creatine:
This synthesis begins with a transfer of the guanidic group from arginine to glycine; the product formed is then methylated to creatine by S-adenosyl-methionine (see fig. 7-13).
It is observed that the carbon atoms of creatine originate from 3 different amino acids. the importance of creatine: when ATP concentration is high, creatine is converted in the muscle into creatine-phosphate which can once again decompose with formation of ATP when the muscle needs it (see fig. 7-13); creatine-phosphate thus constitutes an immediately usable energy reserve, supplying the ATP required for muscular contraction, until the glycolysis stimulation brings about an increased formation of ATP.
f) Shemin Cycle:
This cycle is a derivation of the Krebs cycle at the succinyl-coA level. Its 3 steps are shown in fig. 7-14.
i. Succinyl-coA condenses with glycine to give δ-aminolevulinic acid, in presence of δ-aminolevulinate synthetase, an enzyme containing pyridoxal phosphate;
ii. The latter can condense on itself, leading to porphyrins, will be seen in the next paragraph. But in the Shemin cycle it undergoes a transamination, which causes the loss of its NH2 and the creation of an aldehyde group (not a ketone group because NH2 was at the end of the chain);
a. The α-ketoglutaraldehyde thus obtained returns to the Krebs cycle, either by a simple oxidation to α-ketoglutaric acid (path 1), or by detachment of a one-carbon atom unit (taken over by FH4) which gives rise to succinic acid (path 2).
g) Synthesis of Porphyrins:
The precursor of porphyrins is δ-amino- levulinic acid; its mode of formation was explained in the preceding paragraph. As shown by figure 7-15, the condensation of 2 molecules of this compound leads to porphobilinogen.
We will not study here the series of reactions leading to porphyrins, particularly type III protoporphyrin found in the prosthetic group of hemoglobin (see fig. 1-29), but it is clear that 4 molecules of porphobilinogen are needed for the formation of the tetrapyrrolic ring; as for the substituents of pyrrole rings, it may be seen that the 4 methyl groups can be formed by decarboxylation of the 4 acetic radicals, and that, of the 4 propanoic radicals present, two will remain while the other two will be decarboxylated and then dehydrogenated into vinyl groups.
The reactions we have just studied concerning glycine and serine are recapitulated in a general diagram (fig. 7-16) which gives an overall view of the metabolism of these two amino acids. It will be noted that a number of reactions yield fragments in C1; this is why glycine and serine are often counted among amino acids yielding one-carbon units.
