Malat (Äpfelsäure): the pathway in the body · Biomarker & Urine Analysis

Malat (Äpfelsäure) is part of the pathway “Citric acid cycle”. This page shows the whole pathway; the station of Malat (Äpfelsäure) is highlighted.

Where this laboratory value sits: Malate — malic acid. Fumarase adds a water molecule across the double bond. This produces malate. Malate also carries hydrogen back and forth between the cytoplasm and the mitochondrion. Source 1

In brief

The citric acid cycle is a chain of enzyme steps in the mitochondrion that forms citrate, alpha-ketoglutarate, succinate, fumarate and malate. It breaks acetyl-CoA down to CO₂ and loads electron carriers for the respiratory chain. Its intermediates also serve as building blocks.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Pyruvate → Acetyl-CoA PDH complex · Vitamin B1 (TPP), Lipoic acid The pyruvate dehydrogenase complex removes one carbon atom as CO₂ and transfers the rest to coenzyme A. It needs thiamine (vitamin B1) and lipoic acid. If acetyl-CoA builds up, it slows the complex itself. Source 3↑ supplies Acetyl-CoA is the fuel of the cycle: its acetyl group is joined with oxaloacetate to form citrate and broken down to CO₂. The PDH complex needs B1, B2 (FAD), B3 (NAD⁺), B5 (in coenzyme A) and lipoic acid for this. established physiology Source 3, 1
   ⚖ When the balance tips

   too much — If acetyl-CoA builds up together with NADH, both slow the PDH complex directly and via its kinases; less acetyl-CoA is then made from pyruvate.

   too little — If little thiamine, lipoic acid or coenzyme A is available, the PDH complex cannot keep up; pyruvate is converted to acetyl-CoA more slowly, and the cycle gets less fuel from sugar.

   established physiology · Source 3

2. Acetyl-CoA → Citrate Citrate synthase · Oxaloacetate Citrate synthase joins acetyl-CoA with oxaloacetate to form citrate. With six carbon atoms, it is the largest station of the cycle. Part of it leaves the mitochondrion and serves to build fatty acids. Source 1↑ supplies Citrate moves on in the cycle to isocitrate. Part of it leaves the mitochondrion; in the cytoplasm ATP citrate lyase splits it and supplies acetyl-CoA for building fatty acids. established physiology Source 1
   ⚖ When the balance tips

   too much — If citrate builds up, more of it is exported into the cytoplasm and split there into acetyl-CoA and oxaloacetate; more carbon thus flows into building fatty acids.

   too little — If little oxaloacetate or acetyl-CoA is available, citrate synthase makes less citrate, and all following steps receive less supply.

   established physiology · Source 1

3. Citrate → Isocitrate Aconitase · Iron-sulphur cluster Aconitase shifts an OH group within the molecule. This produces isocitrate, which is easier to convert in the next step. The following step helps set how fast the cycle runs. Source 1↑ supplies Isocitrate is the substrate of isocitrate dehydrogenase, one of the steps that help set the pace of the cycle. Here NAD⁺ is loaded to NADH for the first time, and its electrons go to the respiratory chain. established physiology Source 1
   ⚖ When the balance tips

   too much — If plenty of NADH and ATP slow isocitrate dehydrogenase, isocitrate builds up; because aconitase works in both directions, more citrate then also stays in place.

   too little — If aconitase works more slowly, for example because its iron-sulphur centre is incomplete, little isocitrate forms, and citrate builds up before this step.

   established physiology · Source 1

4. Isocitrate → Alpha-ketoglutarate Isocitrate DH · NAD⁺ Isocitrate dehydrogenase splits off CO₂ and loads NAD⁺ to NADH. Alpha-ketoglutarate is also the starting material for the amino acid glutamate. Enzymes that remodel DNA and proteins also need alpha-ketoglutarate. Source 1, 2↕ both, depending on amount Alpha-ketoglutarate is a crossroads: supplied from glutamine, it replenishes the cycle; drawn off as glutamate, it removes carbon from it. Enzymes that remodel DNA and proteins also need it as a co-substrate. established physiology Source 1, 2
   ⚖ When the balance tips

   too much — If plenty of alpha-ketoglutarate is available, the dioxygenases that depend on it and remove methyl groups from DNA and histones work more readily; this is described mainly in cell culture.

   too little — If little alpha-ketoglutarate is available, the following cycle steps and these dioxygenases slow down; the cell can resupply it from glutamine via glutamate.

   observed in studies · Source 2, 1

5. Alpha-ketoglutarate → Succinyl-CoA α-KG dehydrogenase · Vitamin B1 (TPP), NAD⁺ A second enzyme complex splits off CO₂ again; it also works with thiamine. Succinyl-CoA is, in addition, a building block for the red blood pigment. With little thiamine, less succinyl-CoA forms. Source 1↑ supplies Succinyl-CoA supplies the energy for the next step and is the starting material for haem, the core of the red blood pigment. Alpha-ketoglutarate dehydrogenase needs thiamine, lipoic acid, FAD, NAD⁺ and coenzyme A for this. established physiology Source 1, 3
   ⚖ When the balance tips

   too much — If succinyl-CoA builds up together with NADH, both slow alpha-ketoglutarate dehydrogenase; alpha-ketoglutarate then builds up before this step.

   too little — If little thiamine is available, alpha-ketoglutarate dehydrogenase cannot keep up; less succinyl-CoA forms for the cycle and for building haem.

   established physiology · Source 1, 3

6. Succinyl-CoA → Succinate Succinate thiokinase · GDP Releasing the bond to coenzyme A frees energy; the cell first stores it as GTP. Succinate remains. Outside the cycle, succinate also acts as a signalling substance. Source 1↕ both, depending on amount Succinate moves on in the cycle and passes electrons directly to the respiratory chain. Outside the mitochondrion it acts as a signalling substance: it slows enzymes that break down the hypoxia factor HIF and binds to its own receptor. observed in studies Source 2, 1
   ⚖ When the balance tips

   too much — If succinate builds up, it inhibits the prolyl hydroxylases, and HIF is not broken down even with enough oxygen. If built-up succinate is converted rapidly, reactive oxygen species form at complex I in animal models.

   too little — If little succinate is available, succinate dehydrogenase receives less substrate, and fewer electrons pass to the respiratory chain by this route.

   observed in studies · Source 2

7. Succinate → Fumarate Succinate DH · FAD Succinate dehydrogenase is also part of the respiratory chain. It removes two hydrogen atoms and transfers them to FAD. From here electrons pass directly to the respiratory chain. Source 1↕ both, depending on amount Fumarate forms when succinate dehydrogenase passes electrons via FAD to the respiratory chain. In larger amounts fumarate binds to sulphur groups of proteins and alters them; this is described mainly in cell models. observed in studies Source 2, 1
   ⚖ When the balance tips

   too much — If fumarate builds up, it inhibits the alpha-ketoglutarate-dependent dioxygenases, as succinate does, and alters cysteines in proteins; this is shown mainly in cell culture.

   too little — If succinate dehydrogenase works more slowly, for example when little FAD is available, less fumarate forms, and succinate builds up before this step.

   observed in studies · Source 2, 1

8. Fumarate → Malate Fumarase · Water Fumarase adds a water molecule across the double bond. This produces malate. Malate also carries hydrogen back and forth between the cytoplasm and the mitochondrion. Source 1↑ supplies Malate is processed further to oxaloacetate. Via the malate-aspartate shuttle it also carries hydrogen from the cytoplasm into the mitochondrion, where it goes to the respiratory chain. established physiology Source 1
   ⚖ When the balance tips

   too much — If malate builds up, the equilibrium of malate dehydrogenase lies far on its side; it only drains away when oxaloacetate is used up quickly.

   too little — If little malate is available, little oxaloacetate forms as well, and the cycle can accept less acetyl-CoA.

   established physiology · Source 1

9. Malate → Oxaloacetate Malate DH · NAD⁺ Malate dehydrogenase loads NAD⁺ to NADH once more. The resulting oxaloacetate picks up the next acetyl-CoA – and the cycle starts again. With little oxaloacetate, acetyl-CoA finds no partner. Source 1↑ supplies Oxaloacetate accepts each new acetyl-CoA and keeps the cycle going. If the cell draws it off, for example to aspartate or glucose, it has to replenish it, for instance from pyruvate via pyruvate carboxylase. established physiology Source 1
   ⚖ When the balance tips

   too much — If plenty of oxaloacetate is available, more of it is drawn off to aspartate or into new glucose formation; the throughput of the cycle is then limited by the supply of acetyl-CoA.

   too little — If little oxaloacetate is available, acetyl-CoA finds no partner; it builds up, and the cycle runs more slowly until supply arrives from pyruvate or amino acids.

   established physiology · Source 1

Further stations

• Pyruvate — from sugar breakdown Breaking down sugar produces pyruvate in the cytoplasm. It is moved into the mitochondrion, where the citric acid cycle runs. There it becomes the main supplier of acetyl-CoA from sugar. Source 3↑ supplies Pyruvate is the main supplier of acetyl-CoA from sugar: in the mitochondrion the PDH complex converts it, and its carbon feeds the citric acid cycle. established physiology Source 3
  ⚖ When the balance tips

  too much — If a lot of pyruvate arrives, it inhibits the kinases that switch off the PDH complex; the complex stays active and converts more pyruvate to acetyl-CoA.

  too little — If little pyruvate arrives, less acetyl-CoA forms from sugar; the cycle then draws its acetyl-CoA more from the breakdown of fatty acids.

  established physiology · Source 3, 1

Cofactors in this pathway

• Vitamin B1 (thiamine) — As thiamine pyrophosphate, cofactor of the PDH complex and alpha-ketoglutarate dehydrogenase; without it pyruvate stalls Source 3, 1
• NAD⁺ — Accepts electrons at three steps of the cycle and becomes NADH in the process; NADH brings them to the respiratory chain Source 1In the ORY catalogue as a laboratory value: NAD⁺ (Nicotinamidadenindinukleotid)
• Vitamin B2 (FAD) — As FAD, electron carrier of succinate dehydrogenase and the dehydrogenase complexes; FADH₂ feeds the respiratory chain Source 1, 3
• Coenzyme A — Carries the acetyl and succinyl groups between the enzymes of the cycle; without it no acetyl group enters the cycle Source 1, 3
• Lipoic acid — Cofactor in the PDH complex and in alpha-ketoglutarate dehydrogenase; with little of it, both complexes cannot keep up Source 3
• Iron — Part of the iron-sulphur centres of aconitase and succinate dehydrogenase; without them the conversion of citrate stalls Source 1In the ORY catalogue as a laboratory value: Eisen
• Magnesium — Binds thiamine pyrophosphate in the active site of the PDH complex; so the complex can convert pyruvate Source 3In the ORY catalogue as a laboratory value: Magnesium

Sources

1. Arnold PK, Finley LWS. Regulation and function of the mammalian tricarboxylic acid cycle. J Biol Chem 2023 · PubMed 36581208
2. Martínez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 2020 · PubMed 31900386
3. Patel MS, Nemeria NS, Furey W et al. The pyruvate dehydrogenase complexes: structure-based function and regulation. J Biol Chem 2014 · PubMed 24798336

Whole pathway: Citric acid cycle

Related pathways

• Branched-chain amino acids — succinyl-coa
• Biotin — oxaloacetate
• GABA, glutamate and glutamine — succinate
• Lactate and pyruvate — oxaloacetate
• Liver enzymes — oxaloacetate

As of 2026-09-16. Draft written by Claude to schema v2; sources checked in PubMed; expert review pending
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