L-26 Porphyrin Metabolism

Front 1

Step 1 of Heme Synthesis

Back 1

Succinyl A + Glycine ––ALA Synthase––> ALA


XLSA

Front 2

Step 2 of Heme Synthesis

Back 2

ALA ––ALA Dehydrogenase––> PBG (pyrole)


ADP

Front 3

Step 3 of Heme Synthesis

Back 3

PBG (pyrole) ––PBG deaminase––> Preuroporphyrinogen


AIP

Front 4

Step 4 of Heme Synthesis

Back 4

Preuroporyphyrinogen III ––URO cosynthetase––> Uroporphyrinogen


CEP

Front 5

Step 5 of Heme Synthesis

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Uroporphyrinogen ––Uroporphyrinogen decarboxylase––> Coproporphyrinogen III


PCT

Front 6

Step 6 of Heme Synthesis

Back 6

Coproporphyrinogen III ––CP oxidase––> Protoporphorynogen


HCP

Front 7

Step 7 of Heme Synthesis

Back 7

Protoporphyrinogen ––Protoporphyrinogen oxidase––> Protoporphyrin


VP

Front 8

Step 8 of Heme Synthesis

Back 8

Protoporphyrin ––Ferrochelatase––> Heme


EPP

Front 9

Porphyrins

Back 9

Porphyrins are organic ring molecules that serve as a cofactor for proteins and enzymes.


Tetrapyrroles that bind metal ion such as iron in the center.


Strongly colored, impart color to blood bile, urine, feces.

Front 10

General Porphyrin Shapes

Back 10

PBG (pyrole) ––URO synthase––> Preuroporphyrinogen (tetrapyrole) ––URO cosynthase––> Uroporphyrinogen III (closed ring)

Front 11

Spectra of Porphyrins

Back 11

Oxidized or O2 bound porphyrins are red
Reduced or CO bound porphyrins are blue


Some porphyrins fluoresce (except those with Fe or Pb bound)

Front 12

Sites of Heme Biosynthesis

Back 12

Bone marrow – Hemoglobin for RBCs (continuous, 80%)
Liver – p450 for detoxification (sporadic, 15%)

Front 13

Control of Heme Biosynthesis

Back 13

Controlled at ALAS gene – first stage of heme biosynthesis.
In liver, drugs and xenobiotics stimulate heme synthesis; heme modulates ALAS1 transcription and translocation.
In bone marrow, Fe levels modulate translation of ALAS2 mRNA.

Front 14

Heme Breakdown (I)

Back 14

Dying RBCs release Heme.
Heme oxygenase removes Fe, decarboxylases, and opens ring to form bileverdin.
Bileverdin reductase converts bileverdin to bilirubin.
Excess bilirubin causes jaundice and is an antioxidant.

Front 15

Bilirubin excretion via bile

Back 15

Bilirubin in bile is transported to gut and transformed to urobilinogen. Urobilinogen is either transported to kidney, or converted to stercobilin (promoted by microbes) and then excreted.

Front 16

Bilirubin excretion via liver

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Bilirubin in liver is bisglucuronidated (makes it more soluble) into bilirubin diglucoronide. Bilirubin diglucoronide is either excreted in urine or transported to intestine. Ends up being secreted in gut.

Front 17

Acute Intermittent Porphyria (AIP)

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Defect in PBG Deaminase (PBG –> Preuroporphyrinogen)
Autosomal dominant, common porphyria
More common in Sweden and psychiatric hospitals.
Acute episodes of abdominal pain, tachycardia, and neuropathy induced by alcohol and drugs
Diagnosis: Elevated urinary PBG, ALA; normal fecal porphyrins (different from HCP/VP)
Treatment: IV heme arginate and glucose for acute episodes

Front 18

Porphyria Cutanea Tarda (PCT)

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Defect in URO Decarboxylase (uroporphyrinogen –> coproporphyrinogen)
Most common porphyria
Poorly penetrant autosomal dominant familial; 2/3 are sporadic.
Chronic blistering lesions, red urine without neural involvement.
Relation with familial hemachromatosis, Hep C, and HIV.
Exacerbated by ethanol.
Treatment: Phlebotomy, chloroquine

Front 19

Erythropoietic Porphyria (EPP)

Back 19

Defect in Ferrochelatase (Protoporphyrin –> Heme)
Autosomal recessive, third most common porphyria
Photosensitive skin, but less scarring than CEP.
Free protoporphyrin in RBC, which makes RBCs fluorescent.
Treat with beta–carotene which quenches skin reaction.
EPP is rarely caused by ALAS2 mutation (excess protoporphyrin)

Front 20

Lead poisoning

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Pb inhibits ALAD, mimicing ADP and AIP.
Abdominal pain, nausea, cognitive deficits, encephalopathy, seizures
Blood lead > 0.5 uM is poisoning
Increased RBC Zn protoporphyrin
Main route is ingestion, stomach acid releases Pb
Treatment: remove Pb source, then chelation

Front 21

Photodynamic Therapy

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Exploits photosensitizers (porphyrins) that localize in tumors; illumination kills cancer cells selectively.
Photosensitizers include ALA and heme derivatives. May be applied topically or systemically.
Developed for skin tumors, Barrett's esophagus, head, neck, oral cavity, lung, bladder, others.