Creatine Case Study

Case Study

History

Learning Goals /
Concept Map

Creatine and Related Compounds

Structure

Amino Acids

Creatine in the Body

Equilibrium

Creatine-Creatinine Equilibrium

Creatinine Test for Kidney Function

Detection

Regulation and Ethics

Amine & Nitrile Chemistry

Laboratory Synthesis

Chemical Analysis

Creatine-Phosphocreatine Equilibrium

Uses & Side Effects



Creatine, Phosphocreatine, and ATP

Creatine, whether synthesized naturally in the body or supplemented by dietary sources, is important for energy production in the human body.  The initial energy needed for muscle contraction is provided by the molecule ATP, or adenosine triphosphate[1,2].  ATP is normally produced through the metabolism of glucose and fatty acids and is the only direct source of energy that can be used by cells[3,4].  A molecule of ATP consists of adenosine bonded to three phosphate groups. 

ATP releases energy by breaking one of its high-energy phosphate bonds to liberate a phosphate group and form a new molecule known as ADP (adenosine diphosphate). 

ATP can only supply enough energy for a few seconds of muscle movement, so in order for sustained muscle contraction to occur, ATP must be regenerated[1,5].  This is where creatine comes in.  In skeletal muscle, creatine exists in equilibrium with its phosphorylated form, which is called creatine phosphate or phosphocreatine.  One third of the creatine in skeletal muscle is free creatine, and the remaining two thirds is phosphorylated[2,3,6]. 

Phosphocreatine can give up its phosphate group to the ADP molecule, resulting in the regeneration of ATP[1-3,5]. 

According to Le Châtelier’s Principle, as the concentration of ATP is depleted in the first few seconds of intense exercise, the phosphocreatine-creatine equilibrium shifts to favor the formation of ATP.  ATP can then be used again to power muscle contraction for up to 10 seconds of extremely intense activity, such as a 100-meter sprint[1-5,7]. 


Sources of ATP during exercise.  In the first few seconds of exercise, energy is provided by ATP and creatine phosphate.  After those initial sources of ATP are consumed, ATP must be regenerated from metabolic pathways.  Adapted from Figure 5.17.[4]

The supply of phosphocreatine in muscle is limited, however, and can only be regenerated by the rephosphorylation of accumulated creatine when the muscles are at rest.  In principle, if more creatine is available, then more phosphocreatine can be formed in the body and more ATP can be generated, thereby allowing muscle movement to be sustained for a few additional seconds[1,3,8].  For this reason, creatine is a popular supplement among sprinters and other athletes who rely on short bursts of energy, but not among endurance athletes.
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Michael Johnson at the Atlanta Olympic Games. (Source: AP)[9]

Phosphocreatine as an Energy Source
How much energy does the hydrolysis of ATP to form ADP provide?  What about the hydrolysis of phosphocreatine to give creatine? 

Standard Free Energies of Hydrolysis of Some Phosphorylated Compounds[4]

Compound

kJ mol-1

kcal mol-1

Phosphoenolpyruvate

-61.9

-14.8

1,3-Bisphosphoglycerate

-49.4

-11.8

Phosphocreatine

-43.1

-10.3

ATP (to ADP)

-30.5

-7.3

Glucose 1-phosphate

-20.9

-5.0

Pyrophosphate

-19.3

-4.6

Glucose 6-phosphate

-13.8

-3.3

Glycerol 3-phosphate

-9.2

-2.2

From the above table we learn how much energy is released when the high energy phosphate bond in a phosphorylated compound such as phosphocreatine is hydrolyzed to produce creatine and a phosphate group (Pi):

We also learn how much energy is released when ATP undergoes hydrolysis to produce ADP and a phosphate group:

In the same way that we invoke Hess’s Law to combine enthalpy changes for a series of reactions, we can combine the free energy changes of these reactions to find out how much energy is released when a phosphate group is transferred from phosphocreatine to ADP when an athlete is sprinting:

 


Equilibrium Constant Calculations
Now that we have calculated the standard free energy change, DG°, for the phosphorylation of ADP by phosphocreatine,

we can use the standard free energy change to find the equilibrium constant, K:

The gas constant, R, is equal to 8.31451 J K-1 mol-1.  The temperature, T, is 25 °C.  Dimensional analysis shows us that we must convert the temperature units into Kelvin, so the units will cancel when we multiply R by T.  Because 0 °C = 273 K,

(temp in K) = (temp in °C) + 273
(temp in K) = 25 + 273
(temp in K) = 298 K

Furthermore, we must convert kJ into J: 

-12.6 kJ/mol x 1000 J/kJ = -12,600 J/mol

Therefore, the equilibrium constant, K, for the phosphorylation of ADP by phosphocreatine is


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[1] Graham, Angie S.; Hatton, Randy C.  “Creatine Studies.” Journal of the American Pharmaceutical Association. 1999, 39(6), 803-810.
[2] Feldman, Elaine B. Creatine: A dietary supplement and ergogenic aid. Nutrition Reviews 1999, 57(2), 45-50.
[3] Athletic Supplements: Creatine.  <http://www.geocities.com/HotSprings/Spa/9971/creatine.html> (accessed April 2009).
[4] Berg, Jeremy M.; Tymoczko, John L.; Stryer, Lubert. Biochemistry, 6th ed.; Freeman: New York, 2007, pp 416-417.
[5] Wyss, Markus; Kaddurah-Daouk, Rima. “Creatine and Creatinine Metabolism.” Physiological Reviews. 2000, 80, 1107-1213. <http://physrev.physiology.org/cgi/content/full/80/3/1107> (accessed April 2009).
[6] Balsom, Paul D; Soderlund, Karin; Ekblom, Bjorn.  “Creatine in Humans with Special Reference to Creatine Supplementation.”  Sports Medicine. 1994, 18, 268-280.
[7] Whitney, Ellie; Rolfes, Sharon Rady. Understanding Nutrition, 11th ed.; Thomson Wadsworth: Belmont, CA, 2008, pp 484-485.
[8] Garrett, Reginald H.; Grisham, Charles M. Biochemistry, Updated Third Edition; Thomson Brooks/Cole: Belmont, CA, 2007, p 888.
[9] Michael Johnson at the Atlanta Olympic Games. (Source: AP) <http://www.factmonster.com/spot/summer-olympics-michael-johnson.html> (accessed April 2009).