Humboldt State University ® Department of Chemistry

Richard A. Paselk

Chem 438

Introductory Biochemistry

Spring 2007

Lecture Notes: 2 May

© R. Paselk 2006
 
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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

1.44

(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  -

For humans the brain uses about 20% of resting energy, regardless of whether its user is "vegging out" or studying like crazy. In the fed state the brain uses about 4 g/hr of glucose while the anaerobic tissues (e.g. red blood cells) use about 1.5 g/hr. This is a particular problem because the brain is quite restricted in what fuels it can use, while the anaerobic tissues are restricted to glucose alone.

Now we can look at what occurs in fasting. (overhead P 23.5) In Table 3, below, is some data on the varying concentrations of key fuels and insulin, the major metabolic regulatory hormone. Notice that glucose concentrations fall for a few days, but then stabilize at about 3.5 mM. Given that an average liver has about 100 g of glycogen, and that glucose usage in the fed state is about 9-10 g/hr an average man would run out of glucose in only ten hours if some other fuel source did not become available after feeding. In fact liver glycogen lasts for about 24 hours. So what's going on?

Table 3: Concentrations of Major Fuels During Starvation in Man
Substance 

Serum or plasma concentration (mM) 

 Days

Fed 1 2 3 4 5 6 7  28-42
Glucose 5.5 4.7 4.1 3.8 3.6 3.6 3.5 3.5  3.6
 Fatty acids 0.30 0.42 0.82 1.04 1.15 1.27 1.18 1.88  1.44
 Ketone bodies 0.01 0.03 0.55 2.15 2.89 3.64 3.98 5.34  7.32
Insulin* >40 15.2 9.2 8.0 7.7 8.6 7.7 8.3  6

 *Insulin concentration is expressed in mU/mL

Data from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY. pp 338 & 539.

Looking at fasting from 24 hours to 24 days or so, we see

So how are these changes initiated and controlled? (overhead P 23.2, Fuel Use of Tissues)

Glucose/Fatty acid control cycle (muscle): During carbohydrate stress (liver glycogen stores are depleted, so serum [glucose] falls) the utilization of glucose by muscle falls as fatty acids are metabolized. (overhead P 23.12)

Glucose/Ketone body/Fatty acid control cycle (peripheral tissues, i.e. brain, kidney, intestine): When at rest the non-muscle peripheral tissues generally consume more glucose than muscle. So how do they respond to carbohydrate stress? (overhead P 23.17)

Metabolism in Exercise

(This discussion is based largely on material from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY. and R.W. McGilvery (1979) Biochemistry: A Functional Approach. W. B. Saunders Company, Philadelphia)

Heavy exercise may also result in carbohydrate stress. There are two extreme situations:

First, if we look at athletes (human or animal) at these two extremes, there are significant difference in muscle types, thus for humans,

Let's look at the performance of world class runners as a function of distance (time). If we look at the figure below it appears that there are three processes (as shown by the three different best fit lines), indicating three different metabolic regimes corresponding to:

  1. The initial 20 seconds.
  2. The time from 20 to 200 seconds.
  3. Times exceeding 200 seconds.

Redrawn from R.W. McGilvery (1979) Biochemistry: A Functional Approach. W. B. Saunders Company, Philadelphia: p 704

Fuel Utilization in Prolonged Exercise

 

Fuel O2 utilization

 

Fuel Concentrations in Blood (mM)

  Blood-delivered Fuels
Exercise Time (min) Muscle Glycogen Glucose Fatty Acid Glucose Lactate Fatty Acid Glycerol
0       4.5 1.1 0.66 0.04
40 36% 27% 37% 4.6 1.3 0.78 0.19
90 22% 41% 37%        
180 14% 36% 50% 3.5 1.4 1.57 0.39
240 8% 30% 62% 3.1 1.8 1.83 0.48
Data from E. A. Newsholme & A. R. Leach (1983) Biochemistry for the Medical Sciences, John Wiley, NY. pp 370-372.


Pathway Diagrams

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Last modified 2 May 2007