Metabolic pathways

Heme synthesis (porphyrias)

Glycine + succinyl-CoA → ALA (ALA synthase, PLP; rate-limiting; ALAS1 repressed by heme, induced by P450-inducing drugs, hormones and fasting). Two ALA → PBG (ALA dehydratase, Zn — lead). Four PBG → hydroxymethylbilane (PBG deaminase — AIP) → uroporphyrinogen III (ring closure) → copro'gen III (UROD — PCT) → proto'gen IX → protoporphyrin IX → heme (ferrochelatase — lead, EPP). Blocks BEFORE ring closure accumulate linear ALA/PBG → neurovisceral attacks; blocks AFTER accumulate photoactive porphyrins → cutaneous photosensitivity.

Click any metabolite on the map for its reactions. Source: FMK-08.4 Porphyrins, heme & bile pigments.

Reactions

Conditions that live on this map

Acute intermittent porphyria (AIP)ALA dehydratase deficiency porphyriaCongenital erythropoietic porphyria (Gunther disease, CEP)Erythropoietic protoporphyria (EPP)GivosiranHereditary coproporphyria (HCP)Isoniazid-induced vitamin B6 (pyridoxine) deficiencyIV hemin (hematin) for acute porphyriaLead poisoningMethemoglobinemiaPorphyria cutanea tarda (PCT)Variegate porphyria (VP)X-linked sideroblastic anemia

Blue pills sit on one specific arrow; grey ones are whole-pathway problems. Each opens the full condition card, which links back here with the arrow lit.

Facts worth knowing

Rate-limiting step

• Rate-limiting enzyme of heme synthesis and its cofactor — ALA synthase — pyridoxal phosphate (vitamin B₆)
• Rate-limiting enzyme of heme synthesis (porphyrias) — ALA synthase (ALAS1 liver / ALAS2 erythroid) (Mitochondrial matrix; ties heme to the TCA cycle via succinyl-CoA. ALAS2 (X-linked, erythroid) is iron-regulated — its mutations cause X-linked sideroblastic anemia, not a porphyria. Isoniazid antagonises B₆ and can impair the step.)

Regulation

• How an oral contraceptive can trigger an acute porphyria attack — Steroid hormones induce hepatic cytochrome P450 (a heme protein) → free heme pool falls → ALAS1 derepressed → ALA/PBG surge past a half-capacity PBG deaminase
• Why IV glucose treats a mild acute attack — Carbohydrate loading suppresses ALAS1 induction (the 'glucose effect')

Treatment

• Mainstay of an acute porphyria attack — IV hemin — repletes the free heme pool and re-represses ALAS1 (Plus IV glucose, stop porphyrinogenic drugs; givosiran (siRNA vs ALAS1 mRNA) for recurrent attacks)

Toxin

• The two heme-synthesis enzymes inhibited by lead — ALA dehydratase and ferrochelatase (Signature: microcytic anemia, basophilic stippling, ↑ ALA, ↑ zinc protoporphyrin, PBG normal)

Diagnosis

• Lab discriminator: lead poisoning vs acute intermittent porphyria — Lead: ALA ↑, PBG normal. AIP: ALA AND PBG markedly ↑
• Bedside clue for excess porphyrins in urine or blister fluid — Coral-pink fluorescence under a Wood's (UV) lamp

Classification

• Rule of thumb for porphyria symptoms by position of the block — Before ring closure (steps 1–3) = neurovisceral (AIP); after ring closure (4–8) = cutaneous (PCT, EPP); HCP and VP straddle both
• Why ALA and PBG cause pain and psychosis but never blisters — They are linear, not yet a conjugated tetrapyrrole — only the closed ring absorbs light (Soret band ~400 nm)

Enzyme deficiency

• Most common porphyria overall — Porphyria cutanea tarda (UROD) (Often acquired: hepatitis C, alcohol, estrogen, iron overload)
• Woman on OCPs with colicky abdominal pain, confusion, tachycardia and urine that turns port-wine on the windowsill — Acute intermittent porphyria (PBG deaminase) (PBG oxidises and polymerises non-enzymatically in light and air)
• Deficiency of ALA synthase (ALAS1 liver / ALAS2 erythroid) causes… — ALAS2 (erythroid isoform) — X-linked sideroblastic anemia: microcytic anemia with ring sideroblasts and iron-loaded mitochondria; responds to pyridoxine (Mitochondrial matrix; ties heme to the TCA cycle via succinyl-CoA. ALAS2 (X-linked, erythroid) is iron-regulated — its mutations cause X-linked sideroblastic anemia, not a porphyria. Isoniazid antagonises B₆ and can impair the step.)
• Deficiency of ALA dehydratase (porphobilinogen synthase) causes… — ALA dehydratase-deficiency porphyria (rare, AR) — neurovisceral only; ALA ↑ with normal PBG, like lead poisoning (2 ALA → PBG. Cytosol.)
• Deficiency of PBG deaminase (hydroxymethylbilane synthase, HMBS) causes… — Acute intermittent porphyria (AD, ~50% activity) — colicky abdominal pain without peritoneal signs, vomiting, neuropsychiatric symptoms, motor neuropathy, tachycardia/hypertension; urine darkens to port-wine on standing; markedly ↑ urine PBG (and ALA); no photosensitivity; attacks after P450 inducers, OCPs/luteal phase, fasting; treat with IV hemin, IV glucose, givosiran (4 PBG → linear tetrapyrrole. Still BEFORE ring closure — accumulated ALA/PBG are not photoactive.)
• Deficiency of Uroporphyrinogen III synthase (cosynthase) causes… — Congenital erythropoietic porphyria (Günther, AR) — hydroxymethylbilane cyclises non-enzymatically into the dead-end type I isomer; severe photosensitivity and mutilation from infancy, red urine, erythrodontia (RING CLOSURE — the line that separates neurovisceral (before) from cutaneous (after) porphyrias.)
• Deficiency of Uroporphyrinogen decarboxylase (UROD) causes… — Porphyria cutanea tarda (the MOST common porphyria; often acquired with hepatitis C, alcohol, estrogen, iron overload) — blisters and skin fragility on sun-exposed skin, hypertrichosis, onset 4th–5th decade; tea-coloured urine with ↑ uroporphyrin that fluoresces coral-pink under Wood's lamp; no acute attacks; treat with phlebotomy, low-dose hydroxychloroquine, treat HCV (4 acetate → methyl. Cytosol.)
• Deficiency of Coproporphyrinogen oxidase causes… — Hereditary coproporphyria (AD) — straddles the line: acute neurovisceral attacks AND cutaneous photosensitivity (Re-enters the mitochondrion; 2 propionate → vinyl.)
• Deficiency of Protoporphyrinogen oxidase causes… — Variegate porphyria (AD) — acute attacks AND photosensitivity
• Deficiency of Ferrochelatase causes… — Erythropoietic protoporphyria (marrow origin) — painful, burning photosensitivity WITHOUT frank blistering from childhood; protoporphyrin in RBCs and skin; hepatobiliary disease from biliary protoporphyrin in severe cases (Inner mitochondrial membrane. When iron can't be inserted, zinc is — zinc protoporphyrin is the lab marker.)

Compare

• PCT vs EPP — PCT: hepatic, UROD, adult onset, blistering, acquired triggers. EPP: erythropoietic, ferrochelatase, childhood onset, burning without blisters, liver risk

Structure

• Which iron state binds O₂ reversibly, and what the other one is called — Fe²⁺ (ferrous). Fe³⁺ = methemoglobin — cyanosis unresponsive to O₂, chocolate-brown blood; methylene blue