Heme synthesis Flashcards
Heme
- ferrous protoporphyrin IX or heme b
- asymmetric
- asymmetric ring D has propionyl and methyl side chains reverse compared to other rings
- 85% synthesized in bone marrow in RBC precursors (other 15% is liver for cytochrome P450)
- also used by cytochromes of ETC, catalase, NO synthase, COX
- synthesized from succinyl-CoA and glycine
Heme synthesis compounds
Succinyl-CoA + gly –> δ-aminolevulinic acid (ALA)—>prophoilinognen (2 mol ALA per porphobilinogen)—–>hydroxymethylbilane (4 porphobilinogens, linear)–>uroporphyrinogen III—>coproporphyrinogen III—>—>protoporphyrin IX (red)—->with addition of ferrous iron is heme
First and last steps in mitochondria, the rest in cytosol
Heme synthesis enzymes
Enzymes:
ALA syntase—>ALA deydratase—>HMB synthase—>Uroporphyrinogne III (Co) synthase—?Uroporphyrinogen decarboxylase–>—>ferrochelatase
(ala synthase and ferrochelatase in mitochondria, others in cytosol)
All rxns irreversable
Heme synthesis in liver
- highly variable and tightly regulates
- mostly used for cytP450
- contains isoform ALAS1-expressed in most cells
- drugs increase ALAS1 activity as liver needs more for cyp
- derepressed at low intracellular heme concentration
- inibited by the buildup of Hemin by several mechanisms–>reduced transcription, instability of mRNA, inhibited import of enzyme from cytosol to mitochondria
Heme syntesis in erythroid cells
- connected to protein synthesis of globin chains, stimulated by EPO (released by kidneys at lo O2)
- want to accumulate heme
- synthesis of heme cointrolled by avalablity of intracellular iron
- Contain ALAS 2 isoform (only expressed in marrow and fetal liver), regulated by iron availablitiy and not inhibited by heme accumulation
- on X-chromosome
- defficiency is X-linked sideroblastic anemia
- mRNA has hairpin iron response riboswitch that recognizes iron–>downregulated at low iron
ALA synthase
- in mitochondria
- Succinyl-CoA + gly –> δ-aminolevulinic acid (ALA) + CO2 + CoA
- requires PLP
- decarboxylates glycine
Isoniazid
- drug used for tuberculosis that depletes PLP
- must provide vit B6 to patients
ALA dehydratase
2 ALA—>porphobilinogen
- aka porphobilinogen synthase
- uses zinc as cofactor
- has sulfhydryl groups
- inibited by lead
Porphobilinogen synthase
2 ALA—>porphobilinogen
- aka ALA dehydratase
- uses zinc as cofactor
- has sulfhydryl groups
- inibited by lead
Hydroxymethylbilane Synthase
4 Porphobilinogens—>hydroxymethlbilane (HMB) + NH3 (idk how many, probably 4)
- aka porphobilinogen deaminase
- HMB can spontaneous form a faulty porphyrin ring (symmetrical ring D, type I) if it is not immediately acted upon–>leads to photosensitivity, defects before that stage do not
Porhopbilinogen deaminase
4 Porphobilinogens—>hydroxymethlbilane (HMB) + NH3 (idk how many, probably 4)
- aka Hydroxymethylbilane Synthase
- HMB can spontaneous form a faulty porphyrin ring (symmetrical ring D, type I) if it is not immediately acted upon–>leads to photosensitivity, defects before that stage do not
Defects leading to photosensivity
if uroporphyrinogen III synthase is deficient, HMB will spontaneously convert to uroporphyrinogen I which can be converted to coproporyrinogen I. Both are red, accumulate in the skin, and lead to painful photosensitivity
Uroporphyrinogen III synthase
hydroxymethlbilane (HMB)—>uroporphyrinogen III
Uroporphyrinogen decarboxylase
in cytosol decarboxylates all acetyl chains of pyrrol rings to methyl groups
uroporphyrinogen III—->coproporyrinogen III
Formation of protoporphyrinogin IX
Coproporyrinogen III enters mitochondria and propionate side chains of rings A and B are decarboxylated to vinyl groups
Coproporyrinogen III oxidase (wiki looks like this is cytosol)–>protoporyrinogen II oxidase—>protoporphyrinogin IX
Ferrochelatase
protoporypryinogen IX—>heme
oxidizes and inserts Fe2+ (ferrous)
Lead ihibition of heme synthesis
- lead interacts with Zinc cofactors for ALA dehydratase=porphobolinogen synthase, and ferrochelatase
- mostly ALA and some protoporyrin IX acumulate in urine
Effect of B6 deficiency
PLP–>coenzyme for ALA synthase, can’t start heme synthesis–>sideroblastic anemia probs
Acute Intermittent Porphyria
- Defect in HMB synthase/porphobilinogen deaminase
- autosomal dominant
- hepatic porphyria (or maybe both I guess)
- ALA and porphobilinogen accumulate in blood and urine
- lack of synthesis of heme/hemin leads to increased ALA synthase activity (derepression)
- urine turns purple after 24 hrs exposure to light and air (porpobilinogen–>porpobilin), porphobilinogen can be detected with rapid dipstick
- severe abdomina pain/colic
- high agitated state, tachycardia, respiratory problems, nausea, confusion, mental disturbance (ALA works similar to GABA and can funtion as a neurotransmitter at high levels), weakenss of lower extremities
- barbituates lead to increased demand for heme for cyt P450 in liver and increased ALA synthase–>kill your patient
- onset can be triggered by specific drugs, infection, EtOH, abnormal estrogen metabolism
- treatment: pain meds, glucose (ALA synthesis is induced by hypoglycemia), IV saline, sometimes IV hemin
Congenital Erythropoietic Porpyria
- deficiency in erythroid cell specific uroporphyrinogen III synthase (liver isozyme uneffected, alternative splicing)
- HMB spontaneously converts to uroporphyrinogen I which will turn ito uroporphyrin I and coproporphyrin I and found in tissues and blood and urine (red)–>extremely painful photosensitivity
- autosomal recessive
- treated with bone marrow transplant
- severe damage to skin beginning in childhood, blisters, poor wound healing, ulcers, infections, hypertrichosis (often severe), reddish-brown teeth, “werewolf” features, hairy front and arms
- onset in childhood or earlier
Porphyria Cutanea Tarda
- deficiency of uroporphyrinogen III decarboxylase
- Type I sporadic (80%), Type II (familial, autosomal dominant 20%)
- most common Porphyria
- uroporphyrinogen III–>uroporphyrin III nonenzymatically
- uroporphyrin III found in blood and urine and tissues (red)
- red urine
- cutaneous lesions and accumulation of red pigment in skin and liver
- erosions and bullous lesions in sun-exposed areas from sun-damage, heal with scarring, pigment changes, and formation of small white papules
- often caused by chronic diesase of liver–>acquired PCT (hepatitis, EtOH abuse)
- treatment: avoidacne of sunlight, alcohol and iron
Enzyme deficiencies not leading to photosensitivity
- ALA dehydratase porphyria (accumulate ALA in blood and urine, autosomal recessive)
- Lead poining (affects ALA dehydratase adn ferrochelatase)
- HMB synthase deficiecny (AIP)
Enzyme deficiencies leading to photosensitivity
- Uroporphyrinogen III synthase (CEP)
- Uroporphyrinogen decarboxylase (PCT)
(coporoporphyrinogen oxidase (heredatry coproporphyria), protoporphyrinogen oxidase (variegate porphyria))
