Purine nucleotide cycle

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The Purine Nucleotide Cycle is a

Finally, adenylosuccinate is cleaved by the enzyme adenylosuccinate lyase to release fumarate and regenerate the starting material of AMP:

Adenylosuccinate → AMP + Fumarate

A recent study showed that activation of HIF-1α allows cardiomyocytes to sustain mitochondrial membrane potential during anoxic stress by utilizing fumarate produced by adenylosuccinate lyase as an alternate terminal electron acceptor in place of oxygen. This mechanism should help provide protection in the ischemic heart.^[8]

Occurrence

The purine nucleotide cycle occurs in the

H₂O + ATP → H⁺ + ADP + P_i (Mg²⁺ assisted, utilization of ATP for muscle contraction by ATPase)

H⁺ + ADP + CP → ATP + Creatine (Mg²⁺ assisted, catalyzed by creatine kinase, ATP is used again in the above reaction for continued muscle contraction)

2 ADP → ATP + AMP (catalyzed by adenylate kinase/myokinase when CP is depleted, ATP is again used for muscle contraction)

Muscle at rest:

ATP + Creatine → H⁺ + ADP + CP (Mg²⁺ assisted, catalyzed by creatine kinase)

ADP + P_i → ATP (during anaerobic glycolysis and oxidative phosphorylation)

AMP can dephosphorylate to adenosine and diffuse out of the cell; the purine nucleotide cycle may therefore also reduce the loss of adenosine from the cell since nucleosides permeate cell membranes, whereas nucleotides do not.^[6]

Consequences

Aspartate and glutamate synthesis

As the purine nucleotide cycle produces ammonia (see below in ammonia synthesis), skeletal muscle needs to synthesize glutamate in a way that does not further increase ammonia, and as such the use of glutaminase to produce glutamate from glutamine would not be ideal. Also, plasma glutamine (released from the kidneys) requires active transport into the muscle cell (consuming ATP).^[11] Consequently, during exercise when the ATP reservoir is low (ADP>ATP), glutamate is produced from branch-chained amino acids (BCAAs) and α-ketoglutarate, as well as from alanine and α-ketoglutarate.^[12] Glutamate is then used to produce aspartate. The aspartate enters the purine nucleotide cycle, where it is used to convert IMP into S-AMP.^[10][13]

BCAAs + α-Ketoglutarate ⇌ Glutamate + Branch-chain keto acids (BCKAs) (catalyzed by Branched-chain aminotransferases (BCAT))

Alanine + α-Ketoglutarate ⇌ Pyruvate + Glutamate (catalyzed by alanine transaminase)

Oxaloacetic acid + Glutamate ⇌ α-Ketoglutarate + Aspartate (catalyzed by

aspartate aminotransferase

)

When skeletal muscle is at rest (ADP<ATP), the aspartate is no longer needed for the purine nucleotide cycle and can therefore be used with α-ketoglutarate to produce glutamate and oxaloacetic acid (the above reaction reversed).

α-Ketoglutarate + Aspartate ⇌ Oxaloacetic acid + Glutamate (catalyzed by

aspartate aminotransferase

)

Ammonia and glutamine synthesis

During exercise when the ATP reservoir is low (ADP>ATP), the purine nucleotide cycle produces ammonia (NH₃) when it converts AMP into IMP. (With the exception of AMP deaminase deficiency, where ammonia is produced during exercise when adenosine, from AMP, is converted into inosine). During rest (ADP<ATP), ammonia is produced from the conversion of adenosine into inosine by adenosine deaminase.

AMP + H₂O + H⁺ → IMP + NH₃ (catalyzed by AMP deaminase in skeletal muscle)

Adenosine + H₂O → Inosine + NH₃ (catalyzed by adenosine deaminase in skeletal muscle, blood, liver)

Ammonia is toxic, disrupts cell function, and permeates cell membranes. Ammonia becomes ammonium (NH₄⁺) depending on the pH of the cell or plasma. Ammonium is relatively non-toxic and does not readily permeate cell membranes.

Some metabolic myopathies involve the under- or over-utilization of the purine nucleotide cycle. Metabolic myopathies cause a low ATP reservoir in muscle cells (ADP > ATP), resulting in exercise-induced excessive AMP buildup in muscle, and subsequent exercise-induced hyperuricemia (myogenic hyperuricemia) through conversion of excessive AMP into uric acid by way of either AMP → adenosine or AMP → IMP.

During strenuous exercise, AMP is created through the use of the adenylate kinase (myokinase) reaction after the phosphagen system has been depleted of creatine phosphate and not enough ATP is being produced yet by other pathways (see above reaction in 'Occurrence' section). In those affected by metabolic myopathies, exercise that normally wouldn't be considered strenuous for healthy people, is however strenuous for them due to their low ATP reservoir in muscle cells. This results in regular use of the myokinase reaction for normal, everyday activities.

Besides the myokinase reaction, a high ATP consumption and low ATP reservoir also increases protein catabolism and salvage of IMP, which results in increased AMP and IMP. These two nucleotides can then enter the purine nucleotide cycle to produce fumarate which will then produce ATP by oxidative phosphorylation. If the purine nucleotide cycle is blocked (such as AMP deaminase deficiency) or if exercise is stopped and increased fumarate production is no longer needed, then the excess nucleotides will be converted into uric acid.

AMP deaminase deficiency (MADD)

AMP deaminase deficiency (formally known as myoadenylate deaminase deficiency or MADD) is a metabolic myopathy which results in excessive AMP buildup brought on by exercise. AMP deaminase is needed to convert AMP into IMP in the purine nucleotide cycle. Without this enzyme, the excessive AMP buildup is initially due to the adenylate kinase (myokinase) reaction which occurs after a muscle contraction.^[16] However, AMP is also used to allosterically regulate the enzyme myophosphorylase (see Glycogen phosphorylase § Regulation), so the initial buildup of AMP triggers the enzyme myophosphorylase to release muscle glycogen into glucose-1-P (glycogen→glucose-1-P),^[17] which eventually depletes the muscle glycogen, which in turn triggers protein metabolism, which then produces even more AMP. In AMP deaminase deficiency, excess adenosine is converted into uric acid in the following reaction:

AMP → Adenosine → Inosine → Hypoxanthine → Xanthine → Uric Acid

Glycogenoses (GSDs)

Myogenic

AMP + H₂O + H⁺ → IMP + NH₃

• AMP deaminase deficiency (MADD)
• Bioenergetic systems
• Glycogenoses
  (GSDs)
• Metabolic myopathies
• Phosphagen System (ATP-PCr)
• Protein catabolism
• Uric Acid § High uric acid

References