USMLE Step 1 · molecular mechanisms

Megaloblastic anemia has four doors in. Learn why each one opens.

B12 and the methyl-folate trap, folate deficiency, vitamin metabolism defects, and orotic aciduria all give the same smear. One lab value tells them apart, and we teach you which.

Try a free lesson See how it works

Example chain · the methyl-folate trap

LESION

No B12, so methionine synthase cannot demethylate 5-methyl-THF

TRAP

Folate is stuck as 5-methyl-THF, so the THF pool empties despite normal intake

DNA

No methylene-THF means no dTMP, so DNA synthesis stalls while RNA carries on

STEM

MCV above 100, six-lobed neutrophils, high homocysteine and MMA, and numb feet

The method

Every lesson, whatever the subject, runs the same four steps.

01

What is the normal job?

Thymidylate synthase turns dUMP into dTMP, and every megaloblastic anemia ends at that one step.

02

How does it break?

Missing B12, missing folate, a faulty vitamin pathway, or no UMP to start with.

03

What does the patient show?

Homocysteine and MMA split B12 from folate. Orotic acid in urine points to the pyrimidine block.

04

Where will the exam hide it?

Folic acid fixes the blood and leaves a B12 patient's nerves to degenerate. Learn the trap before it finds you.

Topics

Subject by subject, same four questions.

BIOCHEMISTRY

Pyrimidine synthesis and orotic aciduria

High orotic acid with normal ammonia is UMP synthase. Add high ammonia and it is OTC deficiency.

GENETICS

DNA repair syndromes

Nucleotide excision repair gives xeroderma pigmentosum. Mismatch repair gives Lynch syndrome.

CELL BIOLOGY

Vitamin B12 absorption

Haptocorrin, intrinsic factor, terminal ileum, transcobalamin II. Each step has its own disease.

PATHOLOGY

One-carbon metabolism

Folate, B12, homocysteine and methionine in one loop, and what a break at each step looks like.

PHARMACOLOGY

Antimetabolites

Methotrexate blocks DHFR, 5-FU blocks thymidylate synthase, hydroxyurea blocks ribonucleotide reductase.

IMMUNOLOGY

Lysosomal and trafficking defects

I-cell disease loses the mannose-6-phosphate tag, so enzymes leave the cell instead of reaching the lysosome.

What students say.

[STUDENT QUOTE — add a real testimonial here]

[NAME], [SCHOOL / YEAR]

[STUDENT QUOTE — add a real testimonial here]

[NAME], [SCHOOL / YEAR]

Start with one mechanism. See if it clicks.

Get a free lesson by email and judge for yourself.

molecularwhy.com