# Vitamin B12 and Folate Metabolism

> Vitamin B12 and folate metabolism for MBBS Biochemistry — one-carbon transfer, folate trap, megaloblastic anaemia and key exam points.

- Canonical URL: https://prepelephant.com/topics/mbbs/biochemistry/vitamin-b12-and-folate-metabolism
- Exam / course: MBBS · Subject: Biochemistry
- Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team
- First published: 2026-10-02
- Last updated: 2026-10-02
- How to cite: "Vitamin B12 and Folate Metabolism", PrepElephant, https://prepelephant.com/topics/mbbs/biochemistry/vitamin-b12-and-folate-metabolism

## Direct answer

Vitamin B12 (cobalamin, containing cobalt) and folate are B-complex vitamins that work together in one-carbon metabolism and DNA synthesis, so deficiency of either causes megaloblastic anaemia. Only B12 deficiency additionally damages the nervous system, producing subacute combined degeneration of the spinal cord. B12 is absorbed in the terminal ileum only when bound to gastric intrinsic factor, whereas folate is absorbed in the jejunum.

## What you must remember

- B12 has two active forms: methylcobalamin, the cofactor for methionine synthase (homocysteine plus N5-methyl THF yielding methionine and THF), and adenosylcobalamin, the cofactor for methylmalonyl-CoA mutase.
- Folate is reduced to tetrahydrofolate by dihydrofolate reductase; THF carries one-carbon units (N5-methyl, N5,N10-methylene, N10-formyl) for purine synthesis and for thymidylate synthesis (dUMP to dTMP by thymidylate synthase).
- The folate trap: without B12, N5-methyl THF cannot donate its methyl group, folate becomes metabolically trapped and a functional folate deficiency follows — this shared chemistry explains the identical anaemia.
- Laboratory separation: B12 deficiency raises both homocysteine and methylmalonic acid; folate deficiency raises homocysteine alone.
- Causes of B12 deficiency include pernicious anaemia, gastrectomy, ileal disease or resection, blind loop syndrome, fish tapeworm infestation and strict vegan diets; body stores last several years. Folate deficiency follows poor intake, pregnancy, alcoholism, malabsorption and drugs such as methotrexate, trimethoprim and phenytoin; stores last only a few months.
- Clinical picture: glossitis, diarrhoea, macrocytic anaemia with hypersegmented neutrophils, raised MCV and raised LDH; B12 deficiency adds peripheral neuropathy, spastic paraparesis and loss of position and vibration sense.
- Never give folate alone when B12 deficiency is possible — it corrects the blood picture while allowing neurological damage to progress.

## Common confusion

The classic confusion is deciding which deficiency is standing in front of you. Megaloblastic anaemia with neurological signs, a vegan or post-gastrectomy history points to B12; pregnancy, alcoholism or antifolate drugs point to folate. When the picture overlaps, methylmalonic acid settles it. Also remember that methotrexate blocks dihydrofolate reductase while 5-fluorouracil blocks thymidylate synthase — two different steps of the same folate pathway.

## Exam-focused takeaway

Theory answers should explain the one-carbon pool, the two B12-dependent reactions, the folate trap and a tabulated comparison of the two deficiencies. Viva examiners ask why folate masks B12 neuropathy and why B12 stores outlast folate stores. MCQs repeatedly test dUMP to dTMP, methylmalonic acid as the discriminator, intrinsic factor and terminal ileum absorption, and the drug targets in folate metabolism.

## Frequently asked questions

### Why does B12 deficiency cause neurological disease but folate deficiency does not?

B12 is needed for methylmalonyl-CoA mutase and maintaining myelin; folate plays no role in that reaction, so the spinal cord and peripheral nerves are spared in pure folate deficiency.

### What is the folate trap?

In B12 deficiency, N5-methyl THF cannot release its methyl group to methionine synthase, so folate is trapped in a form unavailable for DNA synthesis.

### Which biochemical test distinguishes the two deficiencies?

Plasma methylmalonic acid, raised only in B12 deficiency; homocysteine is raised in both.

### Where are the two vitamins absorbed?

Folate in the jejunum; B12 in the terminal ileum, but only as a complex with intrinsic factor secreted by gastric parietal cells.

### Why must B12 deficiency be excluded before treating with folate?

Folate reverses the megaloblastic anaemia but does not prevent, and may worsen, the progressive neurological damage of B12 deficiency.