|Lecture Notes: 20 February||
Serine turns out to be one of the most metabolically active amino acids. It has a very high turn-over rate: it is a major source of carbons in the one-carbon pool, and it is used in the synthesis of glycine. One of the various pathways for serine synthesis from glucose is shown below:
Serine can now be used to provide a methylene group to H4-folate. (Note that Serine hydoxymethyl transferase uses PLP to catalyze a C-C bond cleavage in this reaction.)
The glycine produced in the transferase reaction can now be used to provide a second methylene group via Glycine synthase. So how many of glucose's 6 carbons can be incorporated by this pathway? (Get two serines/glucose; one carbon + glycine from each serine, then a second carbon from glycine with the remaining carbon lost as carbon dioxide. Therefore 4/6 glucose carbons can go into the one-carbon pool.)
As can be seen in the Main Folate Metabolic Pathways diagram, H4-folate can carry carbon in the various oxidation states required in a variety of metabolic reactions:
Methionine is essential for protein biosynthesis. It is also used as a source for carbons, and as a carrier for activated carbons in the one-carbon pool. In addition it serves as the source of Sulfur in cysteine biosynthesis. The latter three all involve methyl group transfers. The terminal methyl group on met is activated via reaction with ATP to give S-Adenosylmethionine, phosphate and pyrophosphate (= 2.5 ATP equiv. at a cost of 3 ATP's). This gives the high-energy sulphonium group:
S-Adenosylmethionine can now donate its activated methyl group.
We've been looking at the sources and carriers for carbon in the one-carbon pool, we can now look at some main uses for these carbons.
S-Adenosylmethionine can donate its activated methyl group. For example creatine is synthesized as shown below, starting with glycine:
Note that arginine provides "most of a urea" just as it does in the Urea Cycle, but here it is transferred to glycine instead of to water. This is a fairly active synthesis since P-creatine spontaneously and irreversibly cyclizes to creatinine, which is then excreted as waste.
Choline is synthesized by methylating ethanolamine on Phosphatidyl ethanolamine three times using S-Adenosylmethionine as the source of methyl groups:
The phosphatidyl choline can then be used as a membrane lipid, or choline can be hydrolyzed off to give the free molecule for acetyl choline synthesis. The phosphatidyl ethanolamine is derived from phosphatidyl serine (via a PLP catalyzed decarboxylation). Since serine can be synthesized from glucose, choline can be biosynthesized de novo.
S-Adenosylmethionine is obviously an important source of carbon groups in biosynthesis. There are two main pathways for regenerating it from S-Adenosylhomocysteine. First it may be regenerated by homocysteine methyltransferase (coenzyme B12-dependent) using 5-methyl H4-folate as a methyl group source. In this case glucose may thus serve as the ultimate source of the methyl group:
Alternatively it can be regenerated using choline as the source of the methyl group:
The N,N-dimethyl glycine can be oxidized further to give two formaldehydes and glycine.
S-Adenosyl homocysteine may also be irreversibly degraded. Adenosine is first hydrolyzed off. The thiol group of the resulting homocysteine then attacks the -methyl carbon of serine displacing the hydroxyl group to give water and cystathionine (catalyzed by cystathionine -synthase, requires PLP). Hydrolysis by cystathionine gamma-lyase (PLP requiring) continues the process.
Last modified 16 February 2009