PORPHYRIN METABOLISM Flashcards
Porphyrins
Cyclic compounds that bind (chelate) metal ions tightly.
Heme
An iron-binding compound responsible for
crucial processes such as oxygen transport in blood and muscle, electron transport in
mitochondria, and metabolism of fat-soluble compounds in the liver.
Structure of Porphyrins
Cyclic molecules formed by the linkage of 4 pyrrole rings through methenyl bridges.
The central pocket can be occupied by a metal ion.
• Iron -> heme
• Cobalt -> cobalamine (vitamin B12)
• Magnesium -> chlorophyll in plants
Hemeproteins
- Mitochondrial cytochromes (cytochrome A,B,C)
- Hemoglobin and myoglobin
- Cytochrome P450 (CYP) enzymes
- Catalase
Physiological roles of heme proteins
• Generation of membrane H+ gradient required for ATP synthesis via electron transport chain by Mitochondrial cytochromes
• Oxygen transport in blood and muscle by Hemoglobin and myoglobin
• Metabolism of fat-soluble compounds; formation of
cholesterol, steroids, and arachidonic acid metabolites by Cytochrome P450 (CYP) enzymes
• Hydrolysis of H2O2 (Hydrogen peroxide) by Catalase
Heme biosynthesis
- Heme is made primarily by liver- and bone marrow
- ALA synthase catalyzes the condensation of glycine and succinyl CoA to form δ-aminolevulinic acid (ALA) in an irreversible reaction. [1st rate limiting step]
- Transcription of ALA synthase mRNA is suppressed by hemin, the oxidized (Fe3+) form of heme, and by glucose.
- ALA dehydrase condenses 2 molecules of ALA to form the pyrrole compound porphobilinogen (PBG).
- Hydroxymethylbilane synthase condenses 4 molecules of PBG to form hydroxymethylbilane. [2nd rate-limiting step].
- Uroporphyrinogen synthase catalyzes ring closure of hydroxymethylbilane to form uroporphyrinogen I
- Uroporphyrinogen III cosynthase isomerizes the D ring side chains of uroporphyrinogen I to form uroporphyrinogen III.
- Uroporphyrinogen III is the common precursor of chlorophyll, cobalamine, and heme, in organisms that make those compounds.
- A series of decarboxylation and oxidation reactions convert uroporphyrinogen III into protoporphyrin IX.
- Significantly, porphyrins are purple and fluorescent, whereas PBG and the porphyrinogens are colorless and do not fluoresce until they are oxidized.
- Finally, ferrochelatase catalyzes the introduction of iron (Fe2+) into protoporphyrin IX to form heme.
Disease states caused by abnormal heme synthesis
- Acute porphyrias
- Non-acute porphyrias
- Lead poisoning
- Iron-deficiency anemia
Acute porphyrias
Autosomal dominant disorders characterized by blockade of the early, rate limiting steps of the heme biosynthetic pathway, causing decreased production of heme (and hemin). eg. acute intermittent porphyria
Acute intermittent porphyria (AIP)
• Caused by deficiency of hydroxymethylbilane synthase leading to decreased production of heme
• Attacks are usually precipitated by ingestion of drugs and other chemicals that induce the production of CYP enzymes, consuming heme. This exacerbates the relative shortage of heme, triggering an increase in ALA synthase levels and subsequent accumulation of ALA and PBG in the liver which causes abdominal pains
• Structural similarities causes ALA to antagonize GABA receptors in the brain, causing psychosis
• Diagnosis made by measuring PBG in urine and PCR test for gene mutation in family members
Treatment is by intravenous hemin & glucose and by avoiding CYP inducers
Non-acute porphyrias
• Primarily acquired diseases associated with liver damage, but some diseases are genetic
• Blockade of normal heme biosynthetic pathway occurs at specific steps beyond the formation of hydroxymethylbilane, causing accumulation of abnormal porphyrin derivatives in the liver and skin,
leading to liver damage and photosensitive skin rashes, respectively.
• Heme production and ALA levels are normal, because both ALA synthase and hydroxymethylbilane synthase activities are increased through compensatory regulation mechanisms.
• There are no neuropsychiatric symptoms since ALA levels are normal.
• Example of this group is porphyria cutanea tarda
Porphyria cutanea tarda (PCT)
- PCT is caused by reduced uroporphyrinogen decarboxylase activity (one of the enzymes involved in the synthesis of protoporphyrin IX), leading to accumulation of uroporphyrins, which are abnormal metabolites.
- Treat with regular phlebotomy, which helps to remove the excess porphyrin metabolites from the body.
- Patients should avoid alcohol, other liver toxins, and excess sunlight.
Lead poisoning
• Lead inhibits ALA dehydrase and ferrochelatase
• Clinical profile includes all the symptoms of AIP (due to inhibition of liver ALA dehydrase) plus anemia (due to inhibition of bone marrow heme
synthesis).
Iron-deficiency anemia
• Some of the enzymes involved in heme biosynthesis in the bone marrow are erythroid-specific isoforms, which are regulated by different signals than their liver-specific counterparts.
• Most importantly, the translation of erythroid ALA synthase mRNA is stimulated by iron. Therefore, the lack of iron leads to a decrease in
erythroid heme synthesis, causing anemia.
• ALA synthase mRNA is one of several transcripts containing an iron-response element (IRE) sequence, which renders it susceptible to
regulation by iron. Other mRNA molecules containing IRE sequences encode proteins involved in iron transport and storage.
Degradation of heme
• Heme degradation occurs in the spleen and liver.
• Heme oxygenase catalyzes the first two steps of heme degradation, in which NADPH and O2 are used to convert heme to biliverdin, a green pigment. In addition, the bound iron molecule is released when the heme ring is broken.
• Biliverdin reductase uses NADPH to reduce biliverdin to form bilirubin, a fatsoluble, yellow-red pigment.
• Serum albumin carries bilirubin through the bloodstream to the liver. In liver cells, bilirubin glucuronyltransferase conjugates 2 molecules of glucuronic acid to bilirubin to form bilirubin diglucuronide, a water-soluble compound that is
secreted in bile.
• In the intestine, bacteria reduce bilirubin diglucuronide to form urobilinogen, a colorless compound. Most of the urobilinogen is eventually oxidized to form stercobilin, a brown compound that is gives feces its characteristic color.
• However some urobilinogen is reabsorbed into blood and transported to the kidney, where it is converted into the yellow compound urobilin, which gives urine its characteristic color.
Jaundice
A disorder caused by increased levels of bilirubin in the blood, in which the skin and sclerae turn yellow.
Bilirubin can also cross the blood-brain barrier and cause encephalopathy.
Types of jaundice
• Hemolytic Jaundice: Caused by red cell lysis, e.g. in sickle cell anemia
↑ unconjugated bilirubin
• Obstructive Jaundice: Caused by blockage of the bile ducts, e.g. by gallstones
↑ conjugated bilirubin
• Hepatocellular Jaundice: Caused by liver cell damage, e.g. by hepatitis
↑ “liver enzymes” AST, ALT
• Neonatal Jaundice: Caused by relatively low levels of bilirubin glucuronyltransferase activity during early infancy. This condition is treated by administration of blue fluorescent light to convert bilirubin into
water-soluble metabolites.
