The essential metabolic process of replenishing TCA cycle intermediates — a cornerstone of cellular energy metabolism and a window into metabolic disease.
Anaplerosis (from the Greek ana, “up,” and plerotikos, “to fill”) refers to the enzymatic reactions that replenish intermediates of the tricarboxylic acid (TCA) cycle. These intermediates are continuously siphoned off for biosynthetic purposes — amino acid synthesis, gluconeogenesis, heme production — and must be restored to maintain oxidative metabolism.
Without anaplerotic flux, the TCA cycle would grind to a halt. The cell’s central metabolic hub depends on a steady supply of four-carbon (C4) and five-carbon (C5) units to sustain the catalytic concentrations of oxaloacetate, α-ketoglutarate, succinyl-CoA, and other intermediates.
Four principal routes feed carbon into the TCA cycle, each active in different tissues and metabolic states.
Converts pyruvate to oxaloacetate (OAA). The primary anaplerotic enzyme in liver, kidney, and brain. Biotin-dependent. Activated allosterically by acetyl-CoA.
Glutaminase converts glutamine to glutamate, then glutamate dehydrogenase produces α-KG. Dominant anaplerotic pathway in rapidly dividing cells and tumors.
In certain tissues, PEPCK can run in the anaplerotic direction, converting PEP to oxaloacetate with CO₂ fixation.
Odd-chain fatty acids and branched-chain amino acids (valine, isoleucine) yield propionyl-CoA, carboxylated to succinyl-CoA via methylmalonyl-CoA. Requires vitamin B12.
When anaplerotic enzymes fail, the metabolic consequences are profound.
Pyruvate carboxylase deficiency presents with lactic acidosis, hypoglycemia, and neurological devastation in its severe (Type B) form. Methylmalonic acidemia disrupts the propionyl-CoA anaplerotic route, leading to metabolic crises. Propionic acidemia and fatty acid oxidation disorders further illustrate the clinical spectrum.
Triheptanoin (Dojolvi®, C7 oil) is an odd-chain triglyceride that provides propionyl-CoA for succinyl-CoA anaplerosis. FDA-approved for long-chain fatty acid oxidation disorders, it is being investigated for pyruvate carboxylase deficiency, epilepsy, and other conditions where anaplerotic insufficiency contributes to disease.
The Warburg effect is only half the story. Cancer cells have dramatically increased anaplerotic flux, primarily through glutamine-dependent anaplerosis. Oncogenes like MYC upregulate glutaminase expression, while KRAS rewires glutamine metabolism through transamination pathways.
This glutamine addiction has become a therapeutic target, with glutaminase inhibitors (e.g., CB-839/telaglenastat) in clinical trials for multiple tumor types. Understanding anaplerotic dependencies in tumors is reshaping cancer metabolism research and opening new avenues for metabolic therapy.