Heme synthesis

Question 1

Heme

Answer 1

• 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

Question 2

Heme synthesis compounds

Answer 2

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

Question 3

Heme synthesis enzymes

Answer 3

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

Question 4

Heme synthesis in liver

Answer 4

• 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

Question 5

Heme syntesis in erythroid cells

Answer 5

• 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

Question 6

ALA synthase

Answer 6

• in mitochondria
• Succinyl-CoA + gly –> δ-aminolevulinic acid (ALA) + CO2 + CoA
• requires PLP
• decarboxylates glycine

Question 7

Isoniazid

Answer 7

• drug used for tuberculosis that depletes PLP

- must provide vit B6 to patients

Question 8

ALA dehydratase

Answer 8

2 ALA—>porphobilinogen

• aka porphobilinogen synthase
• uses zinc as cofactor
• has sulfhydryl groups
• inibited by lead

Question 9

Porphobilinogen synthase

Answer 9

2 ALA—>porphobilinogen

• aka ALA dehydratase
• uses zinc as cofactor
• has sulfhydryl groups
• inibited by lead

Question 10

Hydroxymethylbilane Synthase

Answer 10

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

Question 11

Porhopbilinogen deaminase

Answer 11

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

Question 12

Defects leading to photosensivity

Answer 12

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

Question 13

Uroporphyrinogen III synthase

Answer 13

hydroxymethlbilane (HMB)—>uroporphyrinogen III

Question 14

Uroporphyrinogen decarboxylase

Answer 14

in cytosol decarboxylates all acetyl chains of pyrrol rings to methyl groups

uroporphyrinogen III—->coproporyrinogen III

Question 15

Formation of protoporphyrinogin IX

Answer 15

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

Question 16

Ferrochelatase

Answer 16

protoporypryinogen IX—>heme

oxidizes and inserts Fe2+ (ferrous)

Question 17

Lead ihibition of heme synthesis

Answer 17

• lead interacts with Zinc cofactors for ALA dehydratase=porphobolinogen synthase, and ferrochelatase
• mostly ALA and some protoporyrin IX acumulate in urine

Question 18

Effect of B6 deficiency

Answer 18

PLP–>coenzyme for ALA synthase, can’t start heme synthesis–>sideroblastic anemia probs

Question 19

Acute Intermittent Porphyria

Answer 19

• 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

Question 20

Congenital Erythropoietic Porpyria

Answer 20

• 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

Question 21

Porphyria Cutanea Tarda

Answer 21

• 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

Question 22

Enzyme deficiencies not leading to photosensitivity

Answer 22

• ALA dehydratase porphyria (accumulate ALA in blood and urine, autosomal recessive)
• Lead poining (affects ALA dehydratase adn ferrochelatase)
• HMB synthase deficiecny (AIP)

Question 23

Enzyme deficiencies leading to photosensitivity

Answer 23

• Uroporphyrinogen III synthase (CEP)
• Uroporphyrinogen decarboxylase (PCT)

(coporoporphyrinogen oxidase (heredatry coproporphyria), protoporphyrinogen oxidase (variegate porphyria))