Cataplerosis and Anaplerosis

Cataplerosis and anaplerosis refer to two biochemical processes related to the Kreb’s cycle, also known as the citric acid cycle and Tricarboxylic Acid Cycle (TCA cycle).  The Kreb’s cycle is a series of enzymatic reactions that takes place in a cell’s mitochondria. These reactions help breakdown carbohydrate and fats provides the primary source of energy in most cells.  In general, glucose and other carbohydrates as well as fats are broken down in to molecules that contain two carbon atoms before they enter the cycle.  The Kreb’s cycle further breaks the molecules down to carbon dioxide and water and harnesses the energy of these reactions for cellular processes.  Anaplerosis and cataplerosis, as described below, may a very important function for PEPCK in the brain.  Neurons cannot make a glucose via gluconeogenesis, and do not store triglycerides so the process of glyceroneogenesis probably is not important.  However, there is a substantial flux of substrate through PEPCK in the brain that may be related to the metabolism of the amino acid neurotransmitter glutamate.

The ‘cycle’ part of the Kreb’s cycle refers to the fact that the two-carbon molecule that is to be utilized must be attached to a larger molecule to be processed.  Generally, the two-carbon molecule is added to four-carbon molecule to make a six-carbon molecule.  The two added carbons are sequentially removed to provide energy and the original four-carbon molecule is regenerated, and can join with a new two-carbon molecule and undergo another round.  The four- and five- carbon intermediates generally are produced from amino acids, by a number of pathways.  The addition of four- and five-carbon molecules to the pool of metabolites of the Kreb’s cycle is termed anaplerosis.  However, only about half of the 20 or so naturally occurring amino acids in the human body are able to enter the Kreb’s cycle by anaplerosis. In contrast, cataperosis refers to enzymatic reactions that lower the concentration of Kreb’s cycle intermediates. 

Two primary amino acids that enter the Kreb’cycle are glutamate that is converted to alpha-ketoglutarate and aspartate that is converted to oxaloacetate.  Both of these reactions are near thermodynamic equilibrium.  This means that the net reaction can move either in to or out of the Kreb’s cycle, depending on the relative concentrations on each side of the chemical equation.  Thus these reactions can be either cataplerotic, or anaplerotic.

PEPCK is part of the cataplerotic pathway.  The reactant of PEPCK is oxaloacetate (OA), and OA is a four-carbon intermediate of the Kreb's cycle.  The PEP molecule that is produced can then proceed through gluconeogenesis to become a full glucose molecule.  Only about half of the amino acids can enter the Kreb’s cycle via anaplerosis, and subsequently be converted to glucose.  The remaining amino acids can be exported from the liver for energy, but they will be converted to ketone bodies.  Thus amino acids can be divided in to two classes-  Gluconeogenic amino acids and Ketogenic amino acids.  In regards to the Ketogenic Diet as a treatment for epilepsy, one prediction from my model is that altering the balance between ketogenic amino acids and gluconeogenic amino acids in the diet could increase its efficacy.  In fact recent work on branched chain amino acids and epilepsy provide support for this prediction.

Other Anaplerotic substrates and the Ketogenic Diet

Triheptanoin oil and odd carbon fatty acids

Neurosci Lett. 2008 Mar 21;434(1):66-70.
Effects of short-term and long-term treatment with medium- and long-chain triglycerides ketogenic diet on cortical spreading depression in young rats.

de Almeida Rabello Oliveira M, da Rocha Ataíde T, de Oliveira SL, de Melo Lucena AL, de Lira CE, Soares AA, de Almeida CB, Ximenes-da-Silva A.
Laboratório de Eletrofisiologia e Metabolismo Cerebral, Instituto de Ciências Biológicas e da Saúde, Universidade Federal de Alagoas, 57.010-020, Maceió, AL, Brazil.

The ketogenic diet (KD) is a high fat and low carbohydrate and protein diet. It is used in the clinical treatment of epilepsy, in order to decrease cerebral excitability. KD is usually composed by long-chain triglycerides (LCT) while medium-chain triglycerides (MCT) diet is beginning to be used in some clinical treatment of disorders of pyruvate carboxylase enzyme and long-chain fatty acid oxidation. Our study aimed to analyze the effects of medium- and long-chain KD on cerebral electrical activity, analyzing the propagation of the phenomenon of cortical spreading depression (CSD). Three groups of weaned rats (21 days old) received, for 7 weeks, either a control (AIN-93G diet), or a MCT-KD (rich in triheptanoin oil), or a LCT-KD (rich in soybean oil). They were compared to another three groups (21 days old) receiving the same diets for just 10 days. CSD propagation was evaluated just after ending the dietary treatments. Results showed that short-term KD treatment resulted in a significant reduction of the CSD velocity of propagation (control group: 4.02+/-1.04mm/min; MCT-KD: 0.81+/-1.46mm/min and LCT-KD: 2.26+/-0.41mm/min) compared to the control group. However, long-term treatment with both KDs had no effect on the CSD velocity (control group: 3.10+/-0.41mm/min, MCT-KD: 2.91+/-1.62mm/min, LCT-KD: 3.02+/-2.26mm/min) suggesting that both short-term KDs have a positive effect in decreasing brain cerebral excitability in young animals. These data show for the first time that triheptanoin has an effect on central nervous system.

Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism. Hakimi P, Johnson MT, Yang J, Lepage DF, Conlon RA, Kalhan SC, Reshef L, Tilghman SM, Hanson RW. Nutr Metab (Lond). 2005 Nov 21;2:33. [PDF]

The key role of anaplerosis and cataplerosis for citric acid cycle function. Owen OE, Kalhan SC, Hanson RW.  J Biol Chem. 2002 Aug 23;277(34):30409-12 [PDF]

Cerebral metabolism of [1,2-13C2]acetate as detected by in vivo and in vitro 13C NMR. Cerdan S, Kunnecke B, Seelig J.  J Biol Chem. 1990 Aug 5;265(22):12916-26.

Copyright 2011 Steve Kriegler.