Heme Catabolism/Anabolism

What are the initial substrates for heme synthesis? G+S

Glycine and succinyl-CoA

What is the rate-limiting enzyme in heme synthesis?

Aminolevulinic acid synthase (ALAS) (ALAS we have Blood!)

Where does ALAS function?

Mitochondria

What regulates ALAS activity?

Feedback inhibition by free heme

Where does heme synthesis occur?

Mitochondria and cytosol (intermediate steps in cytosol)

What enzyme inserts Fe²⁺ into protoporphyrin IX?

Ferrochelatase

What enzymes are inhibited by lead? (an iron LAD!)

ALAD (aminolevulinic acid dehydratase) and ferrochelatase

What is the role of cytochrome P450 in heme demand?

Induction of CYP enzymes increases heme turnover, stimulating ALAS

What causes porphyrias?

Enzyme deficiencies in the heme biosynthetic pathway==> porphyria=disturbance of heme biosynthesis

What accumulates in porphyrias?

Heme precursors (porphyrins or porphyrinogens)

What are symptoms of Acute Intermittent Porphyria (AIP)?

Abdominal pain, neuropathy, port-wine urine, no photosensitivity :: A Cute Puppy Vampire Exsanguinates …P.U.U.P.Fe  

What enzyme is deficient in Acute Intermittent Porphyria?

Porphobilinogen deaminase(those POR people) A Cute Puppy Vampire Exsanguinates …P.U.U.P.Fe

What are symptoms of Congenital Erythropoietic Porphyria (CEP) aka Gunther Disease?

Blistering photosensitivity, hemolytic anemia, red fluorescent teeth

What enzyme is deficient in CEP?

Uroporphyrinogen III synthase A Cute Puppy Vampire Exsanguinates …P.U.U.P.Fe

What are symptoms of Porphyria Cutanea Tarda (PCT)?

Chronic blistering photosensitivity, ↑ liver enzymes (Photoblistering Common Type>PCT)

What enzyme is deficient in PCT?

Uroporphyrinogen decarboxylase A Cute Puppy Vampire Exsanguinates …P.U.U.P.Fe

What are symptoms of Variegate Porphyria (VP)?

Mixed: blistering photosensitivity + neurovisceral symptoms

What enzyme is deficient in VP?

Protoporphyrinogen oxidase A Cute Puppy Vampire Exsanguinates …P.U.U.P.Fe

What are symptoms of Erythropoietic Protoporphyria (EPP)?

Painful non-blistering photosensitivity, gallstones, RUQ pain

What enzyme is deficient in EPP?

Ferrochelatase A Cute Puppy Vampire Exsanguinates …P.U.U.P.Fe

What is unconjugated bilirubin?

Lipid-soluble, bound to albumin, measured indirectly

What is conjugated bilirubin?

Water-soluble, glucuronidated, measured directly

What causes Gilbert Syndrome?

Mild ↓ UGT1A1 activity → mild unconjugated hyperbilirubinemia

Gilbert’s mild and uncongugated

What causes Crigler-Najjar Syndrome Type I?

Absent UGT1A1 activity → severe unconjugated hyperbilirubinemia

What causes Crigler-Najjar Syndrome Type II?

Partial UGT1A1 deficiency → intermediate severity

What causes Dubin–Johnson Syndrome?

MRP2 defect → conjugated hyperbilirubinemia, black liver(epinephrine build up); Mr. Johnson can’t give Billy a ride today

What causes Rotor Syndrome? (Every motor/rotor needs energy(OATs)

OATP defect which prevents retention of bilirubin→ conjugated hyperbilirubinemia, no liver pigmentation

How do drugs cause hyperbilirubinemia?

Displace bilirubin from albumin → ↑ free unconjugated bilirubin

Where does heme degradation occur?

Reticuloendothelial system (macrophages in spleen, liver, bone marrow)

What enzyme opens the heme ring?

Heme oxygenase

What are the products of heme breakdown?

Biliverdin, CO, Fe²⁺

What converts biliverdin to bilirubin?

Biliverdin reductase

How is bilirubin transported in blood?

Bound to albumin (unconjugated)

What enzyme conjugates bilirubin in hepatocytes?

UDP-glucuronosyltransferase (UDPGT/UGT1A1)

What transporter secretes conjugated bilirubin into bile?

MRP2 (ABCC2)

What is the fate of conjugated bilirubin in the gut?

Converted to urobilinogen → stercobilin (feces) or urobilin (urine)

What causes neonatal jaundice?

↑ RBC turnover + immature UDPGT(UDP glucouronyltransferase-conjugates bilirubin) activity

What is kernicterus?

Bilirubin deposition in neonatal brain → irreversible damage