Anaplerotic reactions

Anaplerotic reactions (from the Greek Ana= 'up' and Plerotikos= 'to fill') are those that form intermediates of a metabolic pathway. Examples of such are found in the Tricarboxylic acid (TCA) Cycle (also called the Krebs or citric acid cycle). In normal function of this cycle for respiration, concentrations of TCA intermediates remain constant; however, many biosynthetic reactions also use these molecules as a substrate. Anaplerosis is the act of replenishing TCA cycle intermediates that have been extracted for biosynthesis (in what are called cataplerotic reactions).

The TCA Cycle is a hub of metabolism, with central importance in both energy production and biosynthesis. Therefore, it is crucial for the cell to regulate concentrations of TCA Cycle metabolites in the mitochondria. Anaplerotic flux must balance cataplerotic flux in order to retain homeostasis of cellular metabolism ^[1].

Reactions of anaplerotic metabolism

There are 4 major reactions classed as anaplerotic, yet the production of oxaloacetate from pyruvate has, it is estimated, the most physiologic importance.

From	To	Reaction	Notes
Pyruvate	oxaloacetate	pyruvate + HCO3- + ATP oxaloacetate + ADP + Pi + H2O	This reaction is catalysed by pyruvate carboxylase, an enzyme activated by Acetyl-CoA, indicating a lack of oxaloacetate. It occurs in animal mitochondria. Pyruvate can also be converted to L-malate, another intermediate, in a similar way.
Aspartate	oxaloacetate	-	This is a reversible reaction forming oxaloacetate from aspartate in a transamination reaction, via aspartate transaminase.
Glutamate	α-ketoglutarate	glutamate + NAD+ + H2O NH4+ + α-ketoglutarate + NADH + H+.	This reaction is catalysed by glutamate-dehydrogenase.
β-Oxidation of fatty acids	succinyl-CoA	-	When odd-chain fatty acids are oxidized, one molecule of succinyl-CoA is formed per fatty acid. The final enzyme is methylmalonyl-CoA mutase.

The malate is created by PEP carboxylase and malate dehydrogenase in the cytosol. Malate, in the mitochondrial matrix, can be used to make pyruvate (catalyzed by malic enzyme) or oxaloacetic acid, both of which can enter the citric acid cycle.

Diseases of anaplerotic metabolism

Pyruvate carboxylase deficiency is an inherited metabolic disorder where anaplerosis is greatly reduced. Other anaplerotic substrates such as the odd-carbon-containing triglyceride Triheptanoin can be used to treat this disorder.

References

1. ^ Owen O, Kalhan S, Hanson R (2002). "The key role of anaplerosis and cataplerosis for citric acid cycle function". J. Biol. Chem. 277 (34): 30409–12. doi:10.1074/jbc.R200006200. PMID 12087111. http://www.jbc.org/cgi/content/full/277/34/30409.