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From Greek ana (up) + plerotikos (to fill). Anaplerosis is the replenishment of TCA cycle intermediates — the metabolic reactions that keep the engine running when its parts are consumed for other purposes.
TCA cycle intermediates are constantly being pulled away — for gluconeogenesis, amino acid synthesis, heme production, and fatty acid building. Without replenishment, the cycle stalls and energy production collapses.
Anaplerotic reactions feed new carbon skeletons back into the cycle. Pyruvate carboxylase (→ OAA), glutaminolysis (→ α-KG), and odd-chain fatty acid oxidation (→ succinyl-CoA) are the three major routes.
Triheptanoin (Dojolvi®) is the first and only FDA-approved anaplerotic therapy. Its C7 fatty acid chains produce propionyl-CoA, which becomes succinyl-CoA — directly replenishing the cycle where it matters most.
TCA cycle enzyme deficiencies cause devastating neurological disease. But heterozygous loss of the same genes — SDH, FH, IDH — drives cancer through oncometabolite accumulation. The cycle connects rare disease to oncology.
Two carbons enter each turn as acetyl-CoA. Two leave as CO₂ — becoming the air you exhale. The TCA cycle is why you breathe. It has been spinning in your cells since the moment you were conceived.
The TCA cycle predates oxygen in Earth's atmosphere. It likely ran in reverse in early anaerobic life, fixing CO₂ into organic molecules. It is one of the oldest metabolic pathways — perhaps 4 billion years old.
Each turn of the TCA cycle extracts the energy stored in acetyl-CoA's carbon bonds, capturing it as electron carriers (NADH, FADH₂) and direct energy (GTP), while releasing CO₂.
The gateway reaction. A 4-carbon molecule grabs a 2-carbon fuel to form 6-carbon citrate.
A molecular rearrangement via dehydration-rehydration. Aconitase's iron-sulfur cluster is sensitive to oxidative stress.
First carbon exhaled as CO₂. First NADH captured. IDH mutations produce oncometabolite D-2-HG.
Second CO₂ released. Another NADH. DLD is shared with PDH — one mutation disables both.
GTP born through substrate-level phosphorylation. This is where triheptanoin delivers its payload.
The only enzyme in BOTH TCA and electron transport. SDH IS Complex II.
Biallelic FH loss = devastating IEM. Heterozygous = HLRCC with aggressive renal cancer.
The wheel completes. Final NADH captured. OAA is regenerated, ready for another turn.
~10 ATP per turn · 2 turns per glucose · ~30–32 ATP total from oxidative phosphorylation
Therapies that replenish TCA cycle intermediates — from the only FDA-approved anaplerotic drug to investigational compounds.
Triglyceride of three C7 chains. β-oxidation yields acetyl-CoA + propionyl-CoA → methylmalonyl-CoA → succinyl-CoA, directly replenishing the TCA cycle.
Approved June 2020 for LC-FAOD. 86% reduction in major clinical events.
→ Succinyl-CoAGlutamine → glutamate → α-ketoglutarate via GDH. Directly replenishes TCA. Dominant anaplerotic pathway in rapidly dividing cells and cancer.
→ α-KetoglutarateFound in dairy fat and ruminant meat. β-oxidation yields propionyl-CoA → succinyl-CoA. Same mechanism as triheptanoin.
→ Succinyl-CoADirectly enters TCA as α-ketoglutarate. Used in burn patients and surgical recovery. Emerging interest in aging research.
→ α-KetoglutarateMedium branched-chain fatty acids. Preclinical data shows improved TCA intermediate profiles vs. heptanoate in VLCAD/LCHAD/TFP/CPT-II fibroblasts.
→ Succinyl-CoAThe PRIMARY anaplerotic reaction: pyruvate + CO₂ + ATP → oxaloacetate. Allosterically activated by acetyl-CoA. When deficient, the entire TCA cycle starves.
→ OxaloacetateTCA cycle enzyme defects cause some of the rarest and most severe inherited metabolic diseases. Partial loss of the same genes drives cancer — connecting rare disease to oncology.
Succinate accumulation inhibits α-KG-dependent dioxygenases, causing DNA hypermethylation and pseudo-hypoxia. Drives paraganglioma, pheochromocytoma, GIST, and renal cell carcinoma.
Neomorphic mutations convert α-KG to D-2-hydroxyglutarate — an oncometabolite rewiring epigenetics. Found in >70% of low-grade gliomas, ~20% of AML. FDA drugs: ivosidenib, enasidenib, vorasidenib.
Biallelic: severe encephalopathy, fumaric aciduria. Heterozygous: hereditary leiomyomatosis + aggressive type 2 papillary RCC. Fumarate = oncometabolite.
SUCLA2: encephalomyopathy with mtDNA depletion and methylmalonic aciduria. SUCLG1: fatal infantile lactic acidosis. The link between the TCA cycle and the mitochondrial genome.
Three types: Type A (infantile), Type B (neonatal, severe), Type C (benign). When the primary anaplerotic enzyme fails, OAA cannot be replenished, gluconeogenesis halts.
VLCAD, LCHAD, TFP, CPT-I/II, CACT. Cannot generate acetyl-CoA from long-chain fats. TCA intermediates deplete. Triheptanoin (Dojolvi) is FDA-approved for these conditions.