Methylmalonsäure (MMA): the pathway in the body · Biomarker & Urine Analysis

Methylmalonsäure (MMA) is part of the pathway “Vitamin B12”. This page shows the whole pathway; the station of Methylmalonsäure (MMA) is highlighted.

Where this laboratory value sits: Methylmalonyl-CoA — from propionyl-CoA. Methylmalonyl-CoA arises from the breakdown of some amino acids and of odd-chain fatty acids. If it builds up, it is split into methylmalonic acid. Source 4

In brief

Vitamin B12 is a vitamin with a cobalt atom at its centre. The body uses it in two active forms: as cofactor of methionine synthase in the cytosol and of methylmalonyl-CoA mutase in mitochondria. When little B12 is available, homocysteine and methylmalonyl-CoA build up.

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. B12 in food → B12 + haptocorrin Pepsin · Stomach acid Stomach acid and the enzyme pepsin release B12 from protein. It binds at once to haptocorrin, a shielding protein from saliva. Haptocorrin keeps B12 intact in the acidic stomach. Source 1↑ supplies Haptocorrin binds B12 tightly and holds it in the acidic stomach, where intrinsic factor hardly binds it. B12 thus stays intact until it reaches the duodenum. established physiology Source 1
   ⚖ When the balance tips

   too much — If a lot of B12 sits on haptocorrin, its handover depends entirely on the breakdown of this protein by pancreatic enzymes; only then does B12 become free for intrinsic factor.

   too little — If little stomach acid is present, less B12 is released from dietary protein; less of it reaches haptocorrin, and the rest passes on through the gut with the protein.

   established physiology · Source 1

2. B12 + haptocorrin → B12 + intrinsic factor Pancreatic proteases Pancreatic enzymes break down haptocorrin. B12 now binds to intrinsic factor, which is made by the parietal cells of the stomach. Only bound to intrinsic factor does B12 later enter the gut cell. Source 1↑ supplies Intrinsic factor is the key to absorption: only bound to it is B12 recognised by the receptor cubam. It binds almost only true cobalamin, hardly any B12-like substances without vitamin activity. established physiology Source 1
   ⚖ When the balance tips

   too much — More intrinsic factor does not bring unlimited absorption: the number of cubam receptors in the last section of the small intestine limits how much B12 gets in per meal.

   too little — If the parietal cells make little intrinsic factor, B12 stays unbound after haptocorrin is broken down; the receptor does not recognise it, and only a small part reaches the blood by passive diffusion.

   established physiology · Source 1

3. B12 + intrinsic factor → Into the gut cell Cubam receptor · Calcium The receptor cubam recognises the complex of B12 and intrinsic factor. This step needs calcium. Once the receptor is saturated, only a little B12 gets in by other means. Source 1, 5↑ supplies Cubam brings the complex into the gut cell by folding in the membrane. There intrinsic factor is broken down in the lysosome and B12 is released. Calcium holds the binding of the complex to the receptor. established physiology Source 1, 5
   ⚖ When the balance tips

   too much — Once the receptor is saturated, further B12 passes the gut wall only by passive diffusion, and only a small fraction of the amount offered.

   too little — If little calcium is available at the receptor, cubam binds the complex less well. In a study under metformin, the reduced absorption was reversed with additional calcium.

   observed in studies · Source 1, 5

4. Into the gut cell → Holotranscobalamin · Transcobalamin The gut cell releases B12 bound to transcobalamin into the blood. This form is called holotranscobalamin; cells can absorb it. When little B12 comes from the gut, this form falls early. Source 1↑ supplies Holotranscobalamin is the share of B12 in the blood that cells can absorb. The larger part is bound to haptocorrin and reaches almost only the liver. established physiology Source 1
   ⚖ When the balance tips

   too much — Once transcobalamin is saturated with B12, further B12 in the blood binds to haptocorrin; unbound B12 is excreted by the kidneys in the urine.

   too little — If little B12 comes from the gut, holotranscobalamin falls early, before the haptocorrin-bound B12 in the blood declines; less is then available for the cells to absorb.

   established physiology · Source 1

5. B12 in the cell → Methylcobalamin Active form in the cytoplasm. It is the cofactor of methionine synthase. When little of it is available, homocysteine builds up and folate stays trapped. Source 3↑ supplies Methylcobalamin passes the methyl group from 5-methyltetrahydrofolate to homocysteine. It thus links the folate cycle with the methionine cycle; the freed tetrahydrofolate is available again for other folate pathways. established physiology Source 3
   ⚖ When the balance tips

   too much — More methylcobalamin does not speed up the step beyond the amount of methionine synthase; the enzyme and its supply of 5-methyltetrahydrofolate set the limit.

   too little — If little methylcobalamin is available, methionine synthase stalls: homocysteine builds up, and folate stays trapped as 5-methyltetrahydrofolate, because the cell has no other way to convert this form back.

   established physiology · Source 3

6. B12 in the cell → Adenosylcobalamin Active form in the mitochondrion. It is the cofactor of methylmalonyl-CoA mutase. When little of it is available, methylmalonyl-CoA builds up. Source 4↑ supplies In methylmalonyl-CoA mutase, adenosylcobalamin starts a rearrangement via a radical: a carbon group moves within the molecule, so that methylmalonyl-CoA becomes succinyl-CoA. established physiology Source 4
   ⚖ When the balance tips

   too much — Once the mutase is loaded with adenosylcobalamin, further B12 in the mitochondrion brings no additional conversion; the enzyme itself then sets the limit.

   too little — If little adenosylcobalamin is available, the mutase works more slowly: methylmalonyl-CoA builds up and is split into methylmalonic acid, which passes into the blood and urine.

   established physiology · Source 4

7. Homocysteine → Methionine Methionine synthase · 5-methyl-THF (folate) Methionine synthase transfers a methyl group from 5-methyltetrahydrofolate to homocysteine, forming methionine again. If this step stalls, less methionine forms and homocysteine builds up. Source 3↑ supplies Methionine is an essential amino acid and the starting material for SAM. Its regeneration from homocysteine keeps the cycle going, so that the same building blocks carry methyl groups again and again. established physiology Source 3
   ⚖ When the balance tips

   too much — If a lot of methionine is present, more SAM forms; SAM then slows MTHFR, which makes 5-methyltetrahydrofolate, and directs homocysteine more strongly into the path to cysteine.

   too little — If little methionine is regenerated, less SAM forms; the cell then keeps homocysteine in the cycle more strongly, and less of it goes into the path to cysteine.

   established physiology · Source 3

8. Methionine → SAM MAT · ATP Methionine and ATP form S-adenosylmethionine, the main methyl group donor of the cell. SAM also controls how much homocysteine returns to methionine. Source 3↑ supplies SAM donates its activated methyl group to numerous methyltransferases. At the same time it controls the cycle: it slows MTHFR and stimulates cystathionine β-synthase, the entry into the path to cysteine. established physiology Source 3
   ⚖ When the balance tips

   too much — If SAM builds up, MTHFR is slowed more strongly, less 5-methyltetrahydrofolate forms, and homocysteine increasingly drains into the path to cysteine.

   too little — If little SAM is available, methylation runs more slowly, and the brake on MTHFR eases; the cell then makes more 5-methyltetrahydrofolate.

   established physiology · Source 3

9. SAM → Methylation Methyltransferases Methyltransferases transfer methyl groups from SAM to DNA, proteins and other molecules; this forms homocysteine again. If the intermediate SAH builds up, these transfers slow down. Source 3↑ supplies Methyl groups switch genes off and on, modify proteins and are needed to build substances such as creatine and phosphatidylcholine. Each transfer produces SAH, which is cleaved to homocysteine. established physiology Source 3
   ⚖ When the balance tips

   too much — If many methylations run, a lot of SAM is used up and a lot of homocysteine forms; regeneration to methionine must then keep pace, otherwise homocysteine builds up.

   too little — If SAH builds up because homocysteine does not drain away, it slows the methyltransferases; methyl groups are then transferred less often to DNA, proteins and other molecules.

   established physiology · Source 3

10. Methylmalonyl-CoA → Succinyl-CoA MM-CoA mutase Methylmalonyl-CoA mutase converts methylmalonyl-CoA into succinyl-CoA; adenosylcobalamin is the cofactor. This is how these breakdown products enter energy metabolism. Source 4↑ supplies Succinyl-CoA replenishes the citric acid cycle with intermediates. This makes the breakdown of these amino acids and fatty acids usable for energy production. established physiology Source 4
    ⚖ When the balance tips

    too much — If a lot of succinyl-CoA forms, it moves on to succinate in the citric acid cycle and is processed together with the other supply.

    too little — If the mutase works slowly, less succinyl-CoA forms by this route; the citric acid cycle then gets its intermediates mainly via other pathways.

    established physiology · Source 4

11. Succinyl-CoA → Citric acid cycle Succinyl-CoA is an intermediate of the citric acid cycle, the central hub of energy metabolism. If the mutase works slowly, less supply arrives from this side. Source 4↑ supplies The citric acid cycle breaks down carbon skeletons to carbon dioxide and supplies electrons for the respiratory chain, where ATP is made. Succinyl-CoA from the B12-dependent route is one of its inflows. established physiology Source 4

Further stations

• B12 in food — bound to protein Vitamin B12 occurs almost only in foods of animal origin, where it is bound to protein. The body does not make it itself; what it needs comes from food. Source 1↑ supplies Food is the only source: the body does not make B12 itself. Bound to protein, it reaches the stomach and is released only there, before it starts the multistep path of absorption. established physiology Source 1
  ⚖ When the balance tips

  too much — If a lot of B12 arrives with a meal, the intrinsic factor route absorbs only a limited amount; a small part of the rest reaches the blood by passive diffusion, the remainder passes on through the gut.

  too little — If little B12 arrives, the body draws on its store, mainly in the liver; because it recovers most of the B12 from bile, this store empties only slowly.

  established physiology · Source 1

• B12 in the cell — released in the lysosome Cells absorb holotranscobalamin via the receptor CD320, release B12 and convert it into two active forms. If little B12 gets in, both enzymes lose their cofactor at once. Source 2, 3↑ supplies After uptake via CD320, the lysosome breaks down transcobalamin. B12 leaves the lysosome, and the cell distributes it along two paths: into the cytoplasm to methionine synthase and into the mitochondrion to the mutase. established physiology Source 2, 3
  ⚖ When the balance tips

  too much — Once methionine synthase and the mutase are loaded with their cofactor, further B12 in the cell brings no additional enzyme activity.

  too little — If little B12 enters the cell, both active forms become scarce; methionine synthase and methylmalonyl-CoA mutase lose their cofactor at the same time.

  established physiology · Source 3, 2

• Homocysteine — amino acid Homocysteine is formed when methionine has given up methyl groups. If it builds up, more S-adenosylhomocysteine (SAH) forms, which slows methylation. Source 3↕ both, depending on amount The amount decides: as a building block, homocysteine is converted back to methionine or leaves the cycle via transsulfuration to cysteine. If it builds up, it slows methylation via SAH. established physiology Source 3
  ⚖ When the balance tips

  too much — If homocysteine builds up, the cleavage of S-adenosylhomocysteine (SAH) reverses: SAH accumulates and slows the methyltransferases, so that fewer methyl groups are transferred.

  too little — If little homocysteine is formed, for example because little methionine is turned over, less starting material is available for regenerating methionine and for the path to cysteine.

  established physiology · Source 3

• Methylmalonyl-CoA — from propionyl-CoA Methylmalonyl-CoA arises from the breakdown of some amino acids and of odd-chain fatty acids. If it builds up, it is split into methylmalonic acid. Source 4↑ supplies Via methylmalonyl-CoA, carbon skeletons from the amino acids valine, isoleucine, methionine and threonine and from odd-chain fatty acids enter the citric acid cycle. established physiology Source 4
  ⚖ When the balance tips

  too much — If methylmalonyl-CoA builds up, it is split into methylmalonic acid, which passes into the blood and urine; propionyl-CoA upstream builds up as well.

  too little — If little methylmalonyl-CoA is formed because little of these amino acids and fatty acids is broken down, less succinyl-CoA enters the citric acid cycle by this route.

  established physiology · Source 4

Cofactors in this pathway

• Folate — As 5-methyl-tetrahydrofolate it supplies the methyl group for methionine synthase; trapped in this form without B12 Source 3In the ORY catalogue as a laboratory value: Folsäure
• Calcium — The Cubam receptor takes up the B12–intrinsic factor complex only with calcium, which holds the binding Source 1, 5
• Gastric acid — Together with the enzyme pepsin it releases B12 from dietary protein; with little acid, more B12 stays bound to protein Source 1
• Methionine — Formed at methionine synthase and, with ATP, builds the methyl group donor SAM; less of it forms without B12 Source 3In the ORY catalogue as a laboratory value: Methionin

What acts on this pathway

• Acid-reducing drugs — Less stomach acid can reduce the release of B12 from dietary protein. The product information for proton pump inhibitors mentions this link. Source 6
• Metformin — Lower B12 levels have been described with metformin. In one study, the reduced uptake was reversed by additional calcium — a pointer to the calcium-dependent step. Source 5

Sources

1. Nielsen MJ, Rasmussen MR et al. Vitamin B12 transport from food to the body's cells — a sophisticated, multistep pathway. Nat Rev Gastroenterol Hepatol 2012 · PubMed 22547309
2. Quadros EV, Nakayama Y et al. The protein and the gene encoding the receptor for the cellular uptake of transcobalamin-bound cobalamin. Blood 2009 · PubMed 18779389
3. Froese DS, Fowler B et al. Vitamin B12, folate, and the methionine remethylation cycle — biochemistry, pathways, and regulation. J Inherit Metab Dis 2019 · PubMed 30693532
4. Takahashi-Iñiguez T, García-Hernandez E et al. Role of vitamin B12 on methylmalonyl-CoA mutase activity. J Zhejiang Univ Sci B 2012 · PubMed 22661206
5. Bauman WA, Shaw S et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care 2000 · PubMed 10977010
6. US prescribing information Pantoprazole (DailyMed), section 5.7 Cyanocobalamin (Vitamin B-12) Deficiency · Prescribing information

Whole pathway: Vitamin B12

Related pathways

• Methylation: methionine and homocysteine — homocysteine
• Threonine — methylmalonyl-coa
• Branched-chain amino acids — succinyl-coa
• Biotin — methylmalonyl-coa
• Citric acid cycle — succinyl-coa

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