Pyruvate: What is it? Functions, Structure, Cellular Respiration and Pyruvate Generation

It is a very important biological molecule.

It is involved in a number of biological processes and is essential in cellular respiration .

It is commonly found as one of the end products of glycolysis , which is then transported to the mitochondria to participate in the citric acid cycle. In the absence of oxygen, or when oxygen demand exceeds supply, pyruvate can undergo fermentation to produce lactate.

Both pyruvate and lactate can be used to regenerate glucose.

There is growing evidence that it can directly influence nuclear activity and epigenetic modifications, forming the interface between the genome and the metabolic state of the cell.

Also called pyruvic acid, it is an organic molecule and consists of a 3-carbon backbone.

Pyruvate functions

Pyruvate is required in no fewer than six metabolic pathways. It is involved in the synthesis and decomposition pathways.

The primary function of the molecule is to act as the transport molecule that carries carbon atoms to the mitochondria for complete oxidation to carbon dioxide.

At the end of glycolysis in the cytoplasm, pyruvate molecules generated from glucose are transported to the matrix of the mitochondria through two proteins: Mitochondrial Pyruvate carriers 1 and 2 (MPC1, MPC2).

Within the matrix of mitochondria, an important multi-enzyme complex called pyruvate dehydrogenase complex (PDC) catalyzes decarboxylation and oxidation reactions in order to generate acetyl coenzyme A (acetyl-CoA).

The first enzyme in this complex is called pyruvate dehydrogenase and it removes the carboxylic acid group (decarboxylates) from the molecule.

The result of this reaction leaves a two-carbon molecule that contains a methyl group and a carbonyl group.

The second and third PDC enzymes then oxidize the carbonyl carbon and catalyze a covalent bond to CoA through a thioester bond. This thioester bond can be hydrolyzed with the release of energy.

In fact, the hydrolysis of this bond releases more energy than the conversion of ATP to ADP and thus also provides the initial impetus for the first steps of the citric acid cycle.

Recently, attention has been drawn to the role of pyruvate molecules in influencing the acetylation of histone molecules throughout the genome.

Histone acetylation is an epigenetic modification that can change the overall transcriptional activity of the cell and influence the cell cycle and mitosis.

This histone modification requires the presence of acetyl-CoA. Acetyl-CoA is also generated through PDC in the nucleus, through the transport of the entire enzyme complex from the mitochondria to the nucleus.

The concentration of this complex in the nucleus depends on the cell cycle, the external environment, and the availability of growth factors and nutrients. In the absence of sufficient PDC activity, the cell’s transition to mitosis (specifically, DNA synthesis during S phase) is hampered.

Another enzyme associated with pyruvate metabolism that is also present in the nucleus is pyruvate kinase, the enzyme involved in the last glycolysis reaction, which generates pyruvate from PEP.

This kinase plays an interesting role within the nucleus, phosphorylating nuclear proteins using PEP as a phosphate donor.

This, in turn, leads to the generation of pyruvate, which can be used by the PDC to create acetyl-CoA.

Phosphorylation of key residues in histones also enhances their acetylation, once again a crucial step in cell progression from the G1 to S phase of the cell cycle.

If aerobic respiration is not possible, pyruvate can be fermented to lactate in the cytoplasm to generate NADH and thus increase the availability of ATP to the cell.

The enzyme involved in pyruvate fermentation can also catalyze the reverse reaction, forming pyruvate from lactate.

This is particularly important in liver cells, where this is an essential process during the recovery period after exercise.

Additionally, pyruvate functions as one of the starting points for gluconeogenesis, allowing the cell to generate glucose from sources other than carbohydrates.

This process is important for the functioning of the brain during fasting, since the tissues in the brain use glucose as their primary source of energy.

Pyruvate is also involved in the generation of non-essential amino acids, as well as in many biochemical pathways that involve lipid metabolism.

Pyruvate and cellular respiration

Pyruvate molecules are formed during a series of important reactions called glycolysis.

Glycolysis is the breakdown pathway for glucose molecules and the first step in cellular respiration. Glycolysis is the complete opposite of gluoconeogenesis because a 6-carbon molecule breaks down into two 3-carbon compounds.

It is extremely important for mammals because it is the beginning of our energy cycle.

When we eat carbohydrates, such as cookies, potatoes, and bread, our bodies absorb glucose into the bloodstream.

Once glucose breaks down, pyruvate molecules are formed. These molecules continue to produce more energy for cells.

Structure

This molecule is the conjugate base of pyruvic acid, a three-carbon molecule that contains a carboxylic acid group and a ketone functional group.

The chemical formula for pyruvic acid is C 3 H 4 O 3 and for its deprotonated form it is C 3 H 3 O 3.

The carbon atom that forms the carboxylic acid is often called the first carbon atom, and the number increases along the main carbon chain, away from the end of the carboxylic acid.

In pyruvate, the ketone group is attached to the second carbon atom, also known as the α-carbon, since it is closer to the main functional group; the third carbon comprises a methyl group.

It is, therefore, the simplest α-keto acid and according to the official IUPAC nomenclature, it is called α-keto propanoic acid.

It contains three atoms that can act as a hydrogen bond donor and one atom that can be a hydrogen bond acceptor.

Like other keto acids, pyruvic acid can also tautomerize from its ketone form to its enol form, which contains a double bond and an alcohol.

This is particularly important in the last step of glycolysis.

Other α-ketoacids involved in cellular respiration include oxaloacetic acid, α-ketoglutaric acid, and oxalosuccinic acid.

Pyruvate generation

Pyruvate is generated by two main methods, through the glycolytic pathway and through amino acid metabolism.

While proteins supply almost 10% of the body’s energy needs, only some amino acids are channeled through pyruvate to the cellular respiratory machinery.

Those that do are classified as glucogenic amino acids, while others that generate acetyl-CoA or acetoacetate are classified as ketogenic amino acids.

Lactate produced by anaerobic fermentation can also regenerate pyruvate, especially through the activity of enzymes in the liver. Other minor sources include intermediates of the citric acid cycle.

Glycolysis

Glycolysis begins with the six-carbon monosaccharide – glucose. In the early steps of this biochemical pathway, glucose undergoes phosphorylation and isomerization to produce fructose-6-phosphate.

Another phosphorylation reaction facilitates the splitting of this hexose sugar into two 3-carbon molecules: glyceraldehye phosphate (G3P) and dihydroxy acetone phosphate (DHAP).

These initial steps require energy input and use two ATP molecules for each glucose molecule, but result in the major transformation of one hexose into two triose molecules.

Thereafter, G3P is converted to pyruvic acid, which exists as its conjugate base at physiological concentration and pH.

This process occurs through a set of five biochemical reactions, releasing two ATP molecules and one NADH molecule for each G3P molecule.

The penultimate molecule in this chain of reactions is called phosphoenol pyruvate (PEP). PEP is the phosphorylated ester of pyruvate in its isomeric enol form.

PEP loses a phosphate group to generate pyruvate and the remaining phosphate released is transferred to ADP, forming ATP.

This reaction is catalyzed by an enzyme called pyruvate kinase (PK).

The reaction forms one of the rate limiting steps of glycolysis that can determine the overall reaction rate, as it is one of the slowest reactions in the chain.

For all practical purposes, it is irreversible, unlike most enzyme-catalyzed reactions, especially since pyruvate often moves rapidly into the mitochondria or ferments to form lactate.

When glucose needs to be generated from sources other than carbohydrates (gluconeogenesis), for example, changing concentrations of reactants and products do not induce PK to catalyze the reverse reaction, forming PEP from pyruvate.

In fact, during gluconeogenesis, PK is inactivated through phosphorylation and PEP is diverted into a different cascade of reactions.

Amino Acid Metabolism

Six major amino acids can be metabolized to produce pyruvate: alanine, cysteine, serine, glycine, threonine, and tryptophan.

Of these, alanine and serine have three carbon atoms and are therefore the easiest to transform. These reactions involve a single enzyme that essentially catalyzes the replacement of the amine functional group by a ketone.

Enzymes are also called transaminases for this reason. Cysteine, although it also contains three carbon atoms, has to undergo an additional step to remove the sulfur atom.

Glycine, on the other hand, has only two carbon atoms. Therefore, it is first converted to a three-carbon amino acid – serine – before undergoing deamination.

The action of the enzyme serine dehydratase catalyzes its conversion to pyruvate.

In a similar strategy, three alkyl groups of tryptophan are first converted to alanine before being transformed into a pyruvate molecule by the action of the enzyme alanine transaminase.

Threonine follows an even longer path, first being converted to glycine and then to serine before being acted upon by serine dehydratase.