Pyrimidine Biosynthesis

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:

Regulation of Pyrimidine Biosynthesis

The regulation of pyrimidine biosynthesis in mammals is outlined below:

Degradation of Nucleotides

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.

Metabolic Integration

Begin with a review of the Stages of Catabolism. Recall the major branch point at pyruvate and the decision point when making acetyl-CoA which is now committed to energy production or lipid biosynthesis. Note also the entry of glucose by facilitated diffusion, which is then committed to the cell by phosphorylation by Hexokinase - the net effect is an active transport, since G-6-P cannot escape the cell.

Fat Biosynthesis

Biosynthesis of fatty acids from glucose requires the integration of a number of pathways. Glucose can ultimately provide carbons, energy equivalents, and reducing equivalents:

• Glycolysis provides carbons (as AcCoA in mitosol), ATP and, indirectly, reducing equivalents as NADH (must be converted to NADPH).
• Pentose Phosphate Shunt provides reducing equivalents as NADPH.
• Pyruvate-Malate Cycle transfers AcCoA from mitosol to cytosol (costs 1 ATP) and enables tranformation of NADH_cyto to NADPH.
• Fatty acid biosynthesis combines eight AcCoA_cyto to make fatty-acyl CoA. Requires ATP and NADPH.

"Carbohydrate Stress" and Fasting

As an exercise in the integration of metabolic systems we can look at how the body responds to "carbohydrate stress," the situation occurring when blood glucose levels fall below the normal homeostatic level of about 5 mM. This commonly occurs during a fasting state.

Before following the development of a fasting state and its metabolic consequences, let's set some baselines by noting the potential available fuel in humans as represented by a 'typical' male, as shown in Table 1, below:

Next let's look at the normal and fasting fuel usage of various tissues in Table 2:

Pathway Diagrams

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Lecture Notes

Last modified 23 February 2008