Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 432

Biochemistry

Spring 2009

Lecture Notes: 23 February

© R. Paselk 2006
 
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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:

    Structural diagram of the reactions for the synthesis of Dihydroorotate from glutamine and bicarbonate
  2. Dihydroorotate dehydrogenase is localized in the mitochondria (on the outer surface of the inner membrane).
    Structural diagram of the reaction catalysed by dihydroorotate DH
  3. Orotate phosphorybosyl transferase and OMP decarboxylase are in a second cytosolic complex.
    Structural diagram of the reactions of Orotate phosphorybosyl transferase and OMP decarboxylase

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:

Structural diagram of the reaction onverting UTP to CTP

 

Regulation of Pyrimidine Biosynthesis

The regulation of pyrimidine biosynthesis in mammals is outlined below:

Flow diagram for pyrimidine biosynthesis with feedback control loops for mammals

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.

Structural diagram of the reactions of teh Purine Nucleotide Cycle

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:

"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:

Table 1: Average Fuel Storage in a "Normal" 65 kg Man*
Tissue Total amount of fuel Estimated duration of fuel reserve hours (days)
  g kJ Starvation walking running (long distance)
 Liver glycogen 90 1500

3.6

(0.15)

1.2

(0.05)

0.31

(0.013)

 Extracellular glucose 20 320

0.72

(0.03)

0.24

(0.01)

0.07

(0.003)

 Adipose fat 9,000 337,000

816

(34)

259

(10.8)

67

(2.79)

 Protein 8,800 150,000

288

(15)

115

(4.8)

31

(1.3)

Muscle glycogen 350 6,000

14.4

(0.6)

4.8

(0.20)

1.2

(0.05)

* Assuming 12% of body weight is fat for normal men (normal women are about 26%)

Data from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY. p 337.

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

Table 2: Tissue Fuel Usage in Fed and Fasting States in Humans

 Tissue

Fed 

Fasting
 used released used released
Liver Glucose (stored as glycogen), Amino acids, Fatty acids Fats, Glucose Amino acids, Lactate, Fatty acids, Glycerol Glucose, Ketone bodies
 Kidney  Glucose   Amino acids, Lactate, Fatty acids, Glycerol   Glucose
 Intestine  Glucose, Aspartate & Glutamate, Asparagine & Glutamine Fatty acids, Amino acids other than asx & glx, Carbohydrates     
 Adipose  Glucose     Fatty acids, glycerol 
 Muscle  Glucose (some stored as glycogen), Branched chain amino acids  Lactate, Alanine & Glutamine  Fatty acids, Ketone bodies, Branched chain amino acids  Amino acids other than branched chain, Lactate
 Brain  Glucose  -  Glucose & Ketone bodies  -

Pathway Diagrams

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Last modified 23 February 2008