Eric Holland OMS-I · ex-software engineer

Learn / Metabolism

Metabolic pathways

Every FMK pathway as a clickable map. Pick one pathway to hammer it — next step, enzyme, regulator, cofactor, and the facts that get tested (NADPH and who needs it, rate-limiting steps, deficiencies) — or set it to all pathways for a mixed drill. Every answer says which enzyme and which pathway.

Pathway
Heme synthesis (porphyrias) · Mitochondria (steps 1, 6–8) and cytosol (steps 2–5); ~85% in marrow erythroid precursors, the rest mostly liver (P450 turnover). Enzymes sit beside the arrows, ★ = rate-limiting, ⊕/⊖ = activators/inhibitors (toggle), −ATP +NADH = what the step spends and makes (toggle ⚡), dashed = allosteric signal, shaded bands = compartment. Drag to pan.
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Why the ring matters

Four pyrroles, joined in a line, then closed

Porphobilinogen is a single pyrrole. Four of them are strung together head-to-tail into a linear chain, and only then closed into a macrocycle. That closure is the line the whole classification hangs on: what accumulates before it is linear and cannot absorb light, and what accumulates after it is a ring that can.

① Porphobilinogen (PBG) one pyrrole ring 2 ALA → 1 PBG N A P CH₂NH₂ A = acetate · P = propionate the CH₂NH₂ arm becomes the bridge PBG deaminase 4 PBG joined head to tail AIP blocks HERE ② Hydroxymethylbilane four pyrroles in a LINE — not a ring linear · colourless · NOT photoactive N A P N A P N A P N A P C C C HOCH₂ ALA and PBG pile up behind a block here → NEUROVISCERAL: pain, neuropathy, psych. No rash. Uro'gen III synthase RING CLOSES ring D FLIPS (cosynthase) ③ Uroporphyrinogen III CLOSED macrocycle — 4 rings, 4 bridges ring D is REVERSED (A and P swapped) C C C C N A P A N A P B N A P C N P A D now oxidisable to a conjugated porphyrin → CUTANEOUS: blisters, photosensitivity oxidise ferrochelatase inserts Fe²⁺ ④ Heme protoporphyrin IX + Fe²⁺ — fully conjugated, absorbs ~400 nm C C C C N M V N M V N M P N P M Fe²⁺ FOUR rings, ONE iron — the whole molecule is one big ring BEFORE ring closure — steps 1–3 ALA and PBG are LINEAR. No conjugated ring, so they cannot absorb light — but they are neurotoxic. Abdominal pain without peritoneal signs, neuropathy, psychiatric symptoms, autonomic instability. Never a rash. (AIP) AFTER ring closure — steps 4–8 Closed porphyrinogens auto-oxidise to conjugated porphyrins, which absorb hard at ~400 nm (Soret) → photosensitivity. (PCT, CEP, EPP) Uroporphyrinogen itself is colourless — the methylene (C) bridges are not conjugated. Photoactivity arrives with oxidation, which happens readily once the ring exists. Without cosynthase the linear chain cyclises on its own into the type I isomer (ring D NOT flipped) — a dead end, and the lesion in congenital erythropoietic porphyria.
MITOCHONDRION — step 1 CYTOSOL — steps 2–5 MITOCHONDRION — steps 6–8Glycine + succinyl-CoAGlycine + succinyl-CoAδ-Aminolevulinic acid (ALA)δ-Aminolevulinic acid (ALA)Porphobilinogen (PBG)Porphobilinogen (PBG)Hydroxymethylbilane (LINEAR tetrapyrrole)Hydroxymethylbilane (LINEARtetrapyrrole)Uroporphyrinogen IIIUroporphyrinogen IIICoproporphyrinogen IIICoproporphyrinogen IIIProtoporphyrinogen IXProtoporphyrinogen IXProtoporphyrin IXProtoporphyrin IXHEME (Fe²⁺ in the ring)HEME (Fe²⁺ in the ring)① ALA SYNTHASE ★rate-limiting — PLP (B₆) ·heme ⊖② ALA DEHYDRATASE — Zn²⁺ ·⊖ LEAD #1③ PBG DEAMINASE — AIP(acute, NO rash)④ RING CLOSES HERE —uro'gen III synthase · CEP⑤ UROD — PCT, commonestporphyria⑥ COPRO'GEN OXIDASE — HCP(acute + skin)⑦ PROTO'GEN OXIDASE — VP(acute + skin)⑧ FERROCHELATASE — Fe²⁺ ·⊖ LEAD #2 · EPP

Heme synthesis (porphyrias)

Hydroxymethylbilane (linear tetrapyrrole)

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