Lexicon #1 - Adenosine Tri-Phosphate

Bioenergetics and ATP

Symbols used in this article:
Orthophosphate group -> Pi
Pyrophosphate group -> PPi
An organic group -> R (or) R'
A fatty acid or amino acid -> J
A high energy bond -> ~

The structure of ATP

Adenosine triphosphate (ATP) is a high energy compound. This means on hydrolysis it releases a large amount of free energy (highly exergonic). For an introduction to ATP coupled reactions refer to the last portion of this blog post.

ATP is a nucleotide that consists of three phosphate groups. Throughout this article (~) symbol will be used to denote high energy bonds. The phosphoanhydride bonds are the bonds that release a large amount free energy when hydrolyzed. On the other hand, hydrolysis of the phosphoester bond does not release large amounts of free energy.

Phosphoanhydride bonds are high energy bonds. Phosphoester bonds are not high energy.

The difference between these two types of bonds cannot be overstated. Note that a high energy bond has nothing to do with bond energy.It simply refers to the energy liberated on hydrolysis of the bond.

What makes some bonds liberate more energy than others on hydrolysis?

If the products formed on hydrolysis are more stable than the reactants, then a large amount of energy is liberated during the reaction. The phosphoanhydride bond, due to its structure and chemical nature is unstable.

Firstly, the repulsion of negative charges on the oxygen atoms of two adjacent phosphorus atoms destabilize the structure. Secondly, both the oxygen atoms compete for the lone pairs of electrons on the oxygen atom in between them. These factors of instability are absent in a phosphoester bond. Lastly, in an aqueous environment, the products of hydrolysis: ADP and $P_i$ are solvated more effectively than their reactant ATP.

Though thermodynamically unstable, ATP is kinetically stable. Due to the high activation energy required for ATP hydrolysis, this reaction cannot take place arbitrarily in the body. Thus, it makes for the perfect energy currency molecule.

The bioenergetic utility of phosphoryl ($PO^{2-}_3$)-transfer reactions stems from their kinetic stability to hydrolysis combined with their capacity to transmit relatively large amounts of
free energy. - Donald Voet and Judith G Voet

Group Transfer Potential

The magnitude of energy released when a compound transfers its phosphoryl group ($PO^{2-}_3$) to water is known as its group transfer potential.

Say compound A has a group transfer potential of 60 kJ. This means that A, when transferring its phosphoryl group to water will release 60kJ of free energy and become that much more stable. (Lower the energy of a compound, the higher its stability).
A compound with a higher group transfer potential will spontaneously transfer its phosphoryl group to a compound with a lower group transfer potential. This like the activity series of metals! A metal higher in the activity series transfers electrons to (or reduces) the ones lower in the series.

Compound	kJ mol$^{-1}$
Phosphoenolpyruvate	-61.9
1,3-Bisphosphoglycerate (to 3-phosphoglycerate)	-49.3
Creatine phosphate	-43.1
ATP $\rarr$ AMP + PP$_i$	-32.2
ATP $\rarr$ ADP + P$_i$	-30.5
Glucose-1-phosphate	-20.9
PP$_i$	-19.2
Fructose-6-phosphate	-15.9
Glucose-6-phosphate	-13.8
Glycerol-3-phophate	-9.2

The “-” sign shows that the change in Gibbs free energy is negative. The magnitude of energy tells us the group transfer potential.

Note that 1,3-Bisphosphoglycerate, is a mixed anhydride. Here, the middle oxygen atom is flanked by a phosphorus attached to an oxygen and a carbonyl oxygen. It is probably the instability caused by the repulsion of negative charges on these oxygen atoms that gives this compound such a high group transfer potential. For phosphoenolpyruvate, most of its free energy is liberated post hydrolysis when the compound, enol pyruvate spontaneously converts into its more stable keto form.

High energy Vs Low energy phosphates

As a general rule the compounds that lie above ATP in the above table are considered biologically high energy compounds while those below ATP are considered biologically low energy. From the table it is evident that glucose-1- phosphate, fructose-6-phosphate, glucose-6-phosphate etc. are low energy individuals.

Phosphates that transfer their phosphoryl moiety to ATP spontaneously are high energy phosphates. The molecules that ATP spontaneously transfers its phosphoryl group to are low energy phosphates.

Reactions of ATP

Formation of ATP

Formation of ATP takes place in the body by three major reactions:

• Substrate level phosphorylation: When compounds with higher group transfer potential react with ADP, they form ATP.
• Oxidative phosphorylation: Most of the ATP is produced in this manner. A detailed account of oxidative phosphorylation can be found here.
• Adenylyl kinase reaction (Violet colored in the figure): The group transfer potential of ADP is used to produce ATP. Two ADP molecules react to produce ATP and AMP.

Consumption of ATP

Low energy biomolecules
The exergonic hydrolysis of ATP to ADP may be enzymatically coupled to an endergonic phosphorylation reaction to form “low energy” phosphate compounds such as glucose to glucose 6 phosphate.

Synthesis of other nucleotides
Nucleoside diphosphate (NDP) kinases are non-specific enzymes that convert nucleoside diphosphate to nucleoside triphosphates with the consumption of an ATP molecule. Nucleoside monophosphate (NMP) kinases non-specifically convert nucleoside monophosphates to nucleoside diphosphate. NMP kinases also utilize one ATP molecule per conversion.

The acyl and carbamoyl phosphates
When a fatty acid or an amino acid, both compounds with an acyl group (represented by ‘J’ in the figure below) react with ATP, the reaction tends to be highly reversible.

This is probably because of their relative concentrations in the body and the similar chemical nature of the reactant and product molecules (grey box region; inclusive of the oxygen atom in between). Thus, these reactions do not proceed to completion.

To work around this problem, instead of breaking the first high energy bond (plum colored), the second high energy bond (yellow colored) is broken. This results in the formation of pyrophosphate ($PP_i$) instead of orthophosphate ($P_i$). $PP_i$ is rapidly hydrolyzed into two $P_i$ molecules with the help of the enzyme inorganic pyrophosphatase. Thus, the reaction becomes irreversible and proceeds to completion.

Break down of $ATP$ to $AMP$ and $PP_i$ is seen during the acylation of fatty acids and the aminoacylation of t-RNA (above figure).

ATP storage

Phosphagens(“phosphate” + “gen”[producer]) are chemical compounds that act as reservoirs of free energy. The role of ATP is transient and is restricted to reactions. When high concentrations of ATP is available in the cell, creatine (a phosphagen) reacts with ATP to form phosphocreatine (or creatine phosphate). Phosphocreatine as seen from the group transfer potential table, is higher than ATP. Thus, in vitro, this reaction endergonic. However, at physiological conditions, concentrations are maintained such that the reaction is at equilibrium. In times of exertion, there is rapid consumption of ATP, this causes the reaction to proceed in the reverse direction, giving rise to large amounts of ATP.

ATP + creatine $\leftrightarrow$ phosphocreatine + ADP
$\Delta$ G= +12.6 kJ mol $^{-1}$

Thus, creatine phosphate acts as a store house of free energy in vertebrate muscle tissue. Another example of a phosphagen that is found in invertebrates is arginine phosphate.

Read More

Why did nature choose phosphates?

• Stack Exchange answer
• Article by FH Westheimer
• Articleby Kamerlin et al., 2013

Sources

• Thumbnail: ATP is the energy currency fueling the body.
• Harper’s Illustrated Biochemistry 31st Edition
• Biochemistry by Donald Voet and Judith G. Voet