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ATP

The nucleotide coenzyme adenosine triphosphate (ATP) is the most important form of chemical energy in all cells. All fuel sources of Nature, all foodstuffs of living things, produce ATP, which in turn powers virtually every activity of the cell and organism.  Cleavage of ATP is strongly exergonic. The energy  provided is used to drive endergonic processes (such as biosynthesis, movement and transport processes) through energetic coupling. ATP is the “most widely distributed high-energy compound within the human body”. The other nucleoside triphosphate coenzymes (GTP, CTP, and UTP) have similar chemical properties to ATP,but they are used for different tasks in metabolism.

Structure of ATP- In ATP, a chain of three phosphate residues are linked to the 5′-OH group of the nucleoside adenosine (see  figure-1).

ATP

 Figure-1- ATP is a nucleoside triphosphate containing adenine, ribose, and three phosphate groups. In its reactions in the cell, it functions as the Mg2+ complex

These phosphate residues are termed α, β, and γ. The α phosphate is bound to ribose by a phosphoric acid ester bond. The linkages between the three phosphate residues, on the other hand, involve much more unstable phosphoric acid anhydride bonds. The active coenzyme is in fact generally a complex of ATP with an Mg2+ ion, which is coordinatively bound to the β  and γ phosphates (Mg2+ ATP4–).

One phosphate ester bond and two phosphate anhydride bonds hold the three phosphates (PO4) and the ribose together. The construction also contains a β-N glycoside bond holding the ribose and the adenine together.

Energy of hydrolysis

Energy is usually liberated from the ATP molecule to do work in the cell by a reaction that removes one of the phosphate-oxygen groups, leaving adenosine diphosphate (ADP). When the ATP converts to ADP, the ATP is said to be spent. Then the ADP is usually immediately recycled in the mitochondria where it is recharged and comes out again as ATP.
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Figure-2- showing the structure of ATP  (Adenosine tri phosphate). Adenosine attached to  two or one phosphate residues is called Adenosine di and mono phosphate respectively. The symbol ~ indicates that the group attached to the bond, on transfer to an appropriate acceptor, results in transfer of the larger quantity of free energy. For this reason, the term group transfer potential rather than “high-energy bond” is preferred . Thus, ATP contains two high-energy phosphate groups and ADP contains one, whereas the phosphate in AMP (adenosine monophosphate) is of the low-energy type, since it is a normal ester linkage.

In ATP, the oxygen atoms of all three phosphate residues have similarly strong negative charges . One of the reasons for the instability of phosphoric anhydride bonds is the repulsion between these negatively charged oxygen atoms, which is partly relieved by cleavage of a phosphate residue. In addition, the free phosphate anion formed by hydrolysis of ATP is better hydrated and more strongly resonance-stabilized than the corresponding residue in ATP. This also contributes to the strongly exergonic character of ATP hydrolysis.

Mechanisms of ATP formation -

There are two basic mechanism involved for ATP formation-

1) Substrate level phosphorylation and  2) Oxidative phosphorylation

1) Substrate level phosphorylation- involves phosphorylation of ADP to form ATP at the expense of the energy of the parent substrate molecule without involving the electron transport chain.

Substrate is a high energy compound as compared to the product, the surplus energy is used for ATP formation.

Reactions of this type take place in glycolysis  and in the tricarboxylic acid cycle.

Examples-

a) Glycolysis

i) At the level of conversion of 1,3 BPG to 3, Phosphoglycerate

The reaction is catalyzed by phosphoglycerate kinase, phosphate is transferred from 1,3-bisphosphoglycerate onto ADP, forming ATP (substrate-level phosphorylation) and 3-phosphoglycerate. Since two molecules of triose phosphate are formed per molecule of glucose undergoing glycolysis, two molecules of ATP are formed at this stage per molecule of glucose undergoing glycolysis.

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 Figure-3- Showing the conversion of 1,3 bisphosphoglycerate to 3, phosphoglycerate, and the formation of ATP by substrate level phosphorylation.

ii) At the level of conversion of phospho enol pyruvate to pyruvate

The phosphate of phosphoenolpyruvate is transferred to ADP by pyruvate kinase to form two molecules of ATP per molecule of glucose oxidized.

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Figure-4- Showing the conversion of Phosphoenol pyruvate to pyruvate and second substrate level phosphorylation in Glycolysis.

 b) TCA cyclei) At the level of conversion of Succinyl co A to succinate by the enzyme succinate thiokinase (succinyl-CoA synthetase).

This is the only example in the citric acid cycle of substrate level phosphorylation. Tissues in which gluconeogenesis occurs (the liver and kidney) contain two isoenzymes of succinate thiokinase, one specific for GDP and the other for ADP. The GTP formed is used for the decarboxylation of oxaloacetate to phosphoenolpyruvate in gluconeogenesis. Nongluconeogenic tissues have only the isoenzyme that uses ADP.
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Figure-5- Showing conversion of Succinyl co A to Succinate and formation of ATP by substrate level phosphorylation.

 c ) Another “energy-rich” phosphate compound is creatine phosphate, which is formed from ATP in muscle and can regenerate ATP as needed.

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Figure-6- Showing the conversion of Creatine phosphate to creatine and formation of ATP by substrate level phosphorylation. 

2) Oxidative phosphorylation- Most cellular ATP does not arise in the way described above (i. e., by transfer of phosphate residues from organic molecules to ADP), but rather by oxidative phosphorylation.This process takes place in mitochondria (or as light-driven phosphorylation in chloroplasts) and is energetically coupled to a proton gradient over a membrane. These H+ gradients are established by electron transport chains and are used by the enzyme ATP synthase as a source of energy for direct linking of an inorganic phosphate to ADP. In contrast to substrate level phosphorylation, oxidative phosphorylation requires the presence of oxygen (i. e., aerobic conditions).

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Figure-7- The flow of electrons guides the flow of protons across the innner mitochondrial membrane and that is coupled with release of energy which is captured for the phosphoryaltion of ADP to form ATP  in the electron transport chain

Functions of ATP

1) The ATP is used for many cell functions including transport work moving substances across cell membranes.

2) It is also used for mechanical work, supplying the energy needed for muscle contraction. It supplies energy not only to heart muscle (for blood circulation) and skeletal muscle (such as for gross body movement), but also to the chromosomes and flagella to enable them to carry out their many functions.

3) A major role of ATP is in chemical work, supplying the needed energy to synthesize the multi-thousands of types of macromolecules that the cell needs to exist.

4) ATP is also used as an on-off switch both to control chemical reactions.Phosphorylation of certain enzymes can increase or decrease their activities.

5) c AMP produced from ATP acts as second messenger for the hormonal action.

6) ATP allows the coupling of thermodynamically unfavorable reactions to favorable ones

Generally, ATP is connected to another reaction—a process called coupling which means the two reactions occur at the same time and at the same place, usually utilizing the same enzyme complex. Release of phosphate from ATP is exothermic (a reaction that gives off heat) and the reaction it is connected to is endothermic (requires energy input in order to occur). The terminal phosphate group is then transferred by hydrolysis to another compound, a process called phosphorylation, producing ADP, phosphate (Pi) and energy.

ATP can donate single phosphate, two phosphates or even Adenosine moiety to suitable acceptors for the formation of important biological compounds.

A) Single phosphate transfer

i) The phosphorylation of glucose to glucose 6-phosphate, the first reaction of glycolysis , is highly endergonic and cannot proceed under physiologic conditions.

ATP 2

To take place, the reaction must be coupled with another—more exergonic—reaction such as the hydrolysis of the terminal phosphate of ATP.

ATP3

When (1) and (2) are coupled in a reaction catalyzed by hexokinase, phosphorylation of glucose readily proceeds in a highly exergonic reaction that under physiologic conditions is irreversible. Many “activation” reactions follow this pattern.

ii) Phosphorylation of glycerol

 

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Figure-8- Showing the phosphorylation of glycerol. Phosphorylation of glycerol is required for esterification to form trlacylglycerol, Glycerol kinase is absent in the adipose tissue.

B) Two phosphates transfer

i) Activation of fatty acids

During the process of activation of fatty acid before oxidation, ATP is converted to AMP with the release of pyrophosphate, which can subsequently be hydrolyzed to inorganic phosphates.

atp4

 Figure-9- showing the activation of fatty acid, a requirement for the complete oxidation of fatty acids in the mitochondria.

ii) Activation of amino acids

Amino acids are activated before incorporation into the growing peptide chain . The activation process can be represented as follows-

 

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Figure-10- showing the activation of amino acid, a requirement for incorporation of amino acid in the growing peptide chain during translation.

AMP, formed as a consequence of several activating reactions involving ATP, is recovered by rephosphorylation to ADP.

Adenylyl Kinase (Myokinase) interconverts Adenine Nucleotides

This enzyme is present in most cells. It catalyzes the following reaction:

ATP5

Figure-11- showing the inter conversion of adenine nucleotides

This allows:

(1) High-energy phosphate in ADP to be used in the synthesis of ATP.

(2) AMP, formed as a consequence of several activating reactions involving ATP, to be recovered by rephosphorylation to ADP.

(3) AMP to increase in concentration when ATP becomes depleted and act as a metabolic (allosteric) signal to increase the rate of catabolic reactions, which in turn lead to the generation of more ATP .

C) Transfer of adenosine moiety-

This takes place during activation of Methionine to S- Adenosyl Methionine (Active Methionine), which is a methyl group

donor in the body.
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Figure-12- Showing the transfer of adenosine moiety to Methionine to form active Methionine (S-Adenosyl Methionine).

Why is ATP  considered the universal energy currency of cells why not other nucleotides like CTP, UTP etc ?

The other  nucleotides -GTP, CTP and UTP , do participate in metabolic reactions but ATP by virtue of the ease with which it can donate single phosphate, two phosphates, or even Adenosine moiety is considered a better nucleotide in energy transfer reactions . GTP has a role in gluconeogenesis and in the process of translation ; CTP is required for phospholipid and triacylglycerol synthesis , while UTP is required for glycogen synthesis and  also in Uronic pathway for the synthesis of  glycosaminoglycans and for detoxification reactions.

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