New information  about branched chain amino acids and epilepsy.

PEPCK and its physiological roles

This site is dedicated to the enzyme phosphoenolpyruvate carboxykinase (PEPCK) and its physiological role in different tissues, including recent work of mine linking it to the Ketogenic Diet as treatment for epilepsy.

  PEPCK is found in many tissues throughout the body, and catalyzes the conversion of oxaloacetate to phosophoenol pyruvate.  In the process, one molecule of GTP is converted to GDP and a phosphate group is transferred to oxaloacetate.  There is also the release of one molecule of carbon dioxide.   PEPCK has been most intensely studied in the liver, where it catalyzes a critical step in the synthesis of glucose from protein amino acids and other substrates.  This pathway is called gluconeogenesis and helps maintain blood glucose levels when they fall.  Read more about gluconeogenesis here.

Glucose production from the liver is highly regulated, and PEPCK is very important in controlling gluconeogenesis.  The enzymatic activity of PEPCK in a cell is related to the amount of protein present and is controlled by the transcription of messenger RNA from the PEPCK gene.  Several hormones influence PEPCK transcription. Insulin lowers the amount of PEPCK mRNA and protein; and glucgon, glucocorticoids as well as retinoic acid will increase the levels of PEPCK expression.  Read about the molecular biology of PEPCK and its transcriptional regulation here.

Excess glucose production from the liver is one of the complications seen in people with type-II diabetes(non-insulin dependent diabetes).  One of the critical steps  in the overproduction of glucose in these patients is that insulin is no longer able to reduce PEPCK levels when blood glucose levels are normal or higher. Read about PEPCK and diabetes here.

A second role for PEPCK in adipose tissue is that of glyceroneogenesis.  This refers to the production of a glycerol molecule, and is very important for the synthesis of triglycerides and the release of fatty acids in to the blood stream.  This pathway has been exploited  clinically.  Increasing the levels of PEPCK in fat tissues is used to reduce blood triglycerides in patients with hypertriglycemia.  Read more about glyceroneogenesis and triglycerides here.

Besides its role in gluconeogenesis and glyceroneogenesis, PEPCK has a number of other physiological roles.  One of these roles is to remove excess metabolites from the Citric acid cycle, also know as the Kreb's cycle or the Tricarboxylic acid (TCA) cycle.   Certain amino acids are broken down for energy in a pathway containing  PEPCK by the processes of anaplerosis and cataplerosis.  Read more about anaplerosis and cataplerosis here.  Read more about branched chain amino acids and epilepsy here.

PEPCK is also expressed in the brain, however its physiological role in neurons is an enigma.  Recent work that I have done at the University of Wisconsin-Madison has shed some light on the role of PEPCK in the CNS.  While working on a treatment for epilepsy called the Ketogenic Diet, I discovered that increasing the flux of substrate through PEPCK had a very powerful anti-epileptic effect.  These data have led me to propose a model where PEPCK plays a critical role in the Ketogenic Diet, and is a new target for anti-epileptic drug discovery. 
Read about PEPCK and epilepsy here.

Very interestingly, the  mechansim by which PEPCK reduces epileptiform activity in the brain appears to be different than its roles in other tissues.   The other physiological roles of  PEPCK rely on changing the concentrations of the metabolic substrate oxalaoacetate, or the concentration of the reaction product PEP.  In contrast,my data suggests that PEPCK regulatates epileptiform activity by altering the cellular concentrations of GTP, GDP or the ratio of the two.  This may act by reducing high frequency synaptic transmission by limiting the availability of synpatic vescicles for release.

read about GTP and synaptic transmission here
read about synaptic transmission and glycolysis here

Copyright 2011 Steve Kriegler