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.
FYI - For your curiosity and entertainment:
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)
Nucleotide Metabolism
Nucleoside = nitrogenous base + ribose
Nucleotide = nitrogenous base + ribose + phosphate
We have already seen how important the nucleotides etc. are to life as the monomer residues in nucleic acids (DNA & RNA), energy transfer cofactors, components of essential cofactors (e.g. NADH, CoA), and secondary messengers (e.g. cAMP) etc.
Today we want to look at their anabolism and catabolism.
Recall the basic structures:
Purines are synthesized via IMP:
Pyrimidines are synthesized via UMP:
the other nucleotides are then obtained by modification of IMP and UMP.
The two initial nucleotides are biosynthesized by two quite different strategies:
AMP. The diagram below shows the origins of the various atoms in the nitrogenous base:
The strategies also differ for subsequent modification. Thus for the purines the monophosphate is modified and then phosphorylated:
while for the pyrimidines the monophophate is first phosphorylated, and then modified:
OMP CO2 + UMP UDP UTP
dTMP is derived from dUMP which in turn is modified from dUTP.
Purines are synthesized in a multi-step process outlined in the Purine Biosynthesis Pathway in your packet.
Note the strategy: Start with PRPP (phosphoribosyl pyrophosphate synthesized from ribose-5-P, then add atoms one at a time to build ring system with the exception of a three atom group from glycine.
Recall the origins of the purine ring system:
Regulation of Purine Biosynthesis
Regulation in E. coli is more complex, reflecting the primacy of this synthesis in growth and replication:
In addition GTP is required as a co-substrate for the synthesis of adenylosuccinate from IMP, while ATP is a required co-substrate for synthesizing GMP from XMP. This cross-over between the two pathways tends to keep the [ATP] = [GTP] as needed in nucleic acid synthesis for cell replication.
FYI — A couple of enzyme regulatory mechanisms are in play: AMP and GMP are competitive inhibitors in their own biosynthesis from IMP, while the first commited step of IMP biosynthesis from PRPP is regulated by two allosteric sites, one binding the adenylates and the other the guadenylates. These sites operate independently but synergistically to regulate IMP production.
Unlike purine biosynthesis, where all of the enzymes are in the cytosol, in pyrimidine synthesis the enzyme localization is split, and the enzymes are mostly in complexes.
1. Carbamoyl phosphate synthetase II (which synthesizes carbamoyl P using glutamine instead of ammonia as a nitrogen source - carbamoyl phosphate synthetase I is the mitochondrial enzyme used in Urea biosynthesis from ammonia), Aspartate transcarbamoylase (ATCase) and Dihydrooratase are in a single cytosolic complex. The reactions are outlined below:
2. Dihydroorotate dehydrogenase is localized in the mitochondria (on the outer surface of the inner membrane).
3. Orotate phosphorybosyl transferase and OMP decarboxylase are in a second cytosolic complex.
UMP is then phosphorylated twice using ATP (catalyzed by nucleoside mono- and diphophate kinases. respectively) to give UTP. CTP is then synthesized from UTP as below:
The regulation of pyrimidine biosynthesis in mammals is outlined below:
In muscle tissue the Purine Nucleotide Cycle (or AMP cycle) is important to fill the TCA cycle in muscle, since muscle is lacking most anapleurotic enzymes for the TCA cycle. In effect it deaminates aspartate to fumerate which can then be used as a TCA intermediate, allowing higher TCA activity.
The Purines themselves are catabolized to a variety of products. depending on the organism. Thus most mammals degrade the purine to allantoin, a soluble product, which is excreted in the urine. On the other hand, primates excrete uric acid, a sparingly soluble molecule, as do birds and reptiles. The over all pathway of purine degradation is given in the handout.
 Pathway Diagrams |
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© R. A. Paselk 2010;
Last modified 3 May 2013
