Liver Metabolism 6: Porphyrin Metabolism Flashcards
What are porphyrins?
Cyclic compounds that readily bind metal ions usually ferrous or ferric ions forming metalloporphyrins
- *most common one in humans is the heme group
Function is to serve as prosthetic groups for hemoglobin, myoglobin, cytochromes in the ETC, CYP P450 enzymes and catalase
What is the structure of heme porphyrin?
One Fe+ ion coordinated in the center of the tetrapyrrole ring of the protoporphyrin 4
What is the state of iron molecules in hemoglobin/myoglobin/cytochrome molecules/catalase?
Hemoglobin = ferrous state (Fe2+)
Myoglobin - ferrous state (Fe2+)
Cytochrome enzymes = ferric state (Fe3+)
Catalase enzymes = ferric state (Fe3+)
What are the substrates for heme biosynthesis?
Glycine amino acids
Succinyl-CoA
What are the 3 stages of biosynthesis of heme?
1) synthesis of the parole ring
2) conversion to a tetrapyrrole
3) incorporation of iron
What is the beginning enzyme in heme biosynthesis?
Aminolevulinic acid synthase (ALAS)
- in liver = ALAS-1
- in erythroid tissues = ALAS-2
this is the rate-limiting committed step
- Possess feedback inhibition by excess here with ferrous groups (the more heme that is present, the less ALAS-1/2 work)
- represses the transcription of the gene
- increases degradation of the mRNA
- decreases the import of the enzyme into the mitochondria
X-linked sideroblastic anemia
Caused by Loss-of-function in ALS2 (enzyme subtype found in erythroid tissues).
Results in reduction in the amount of heme which prevents these cells from making enough hemoglobin overall
The reduced production of heme leads to buildup of excess iron in cells
- which triggers increased uptake of iron in cells that cant be bound
cells get really big and have iron granules in them
What kind of pharmaceutical agents can affect ALAS subtype 1?
Administration of large numbers of drugs that are metabolized by microsomal CYP monooxygenase system
- results in significant increase in hepatic ALAS1 activity**
Why does anemia occur in lead poisoning?
Because excess lead leads to ALA dehydratase (ALAD) and ferrochelatase enzyme inhibition
- reduces amount of heme groups that can be produced
in lead poisoning, high levels of ferrochelatase and ALAD will be present
Porphyrias
Rare inherited (AD is more common but can be AR) defects that cause defective enzymes somewhere along the heme synthesis pathway - results in lowered heme and increased porphyrins/porphyrin precursors
Can be breaker into hepatic or erythropoietin conditions
Symptoms depend on what enzymes are defective
- if enzymes BEFORE formation of tetrapyrrole ring are affected = neuropsychiatric signs/abnormalities
- enzymes AFTER formation of tetrapyrrole ring are affected = photosensativity
both show purple-red urine
What is the final enzyme required for heme production?
Ferrochelatase
Chronic liver porphyria (cutanea Tarda (PCT))
the most common porphyria and the only chronic porphyria of the liver
About 80% of cases are aquired and not inherited
- defects in uroporphyrinogen decarboxylase which causes a build up of uroporphyrin-3
- if inherited is AD
Usually present in the 40-50s ages
Presents with cutaneous symptoms (photosensitivity) and red-brown urine that is pink with fluorescent light
Acute liver porphyrias
Includes the following
1) Acute intermittent porphyria (AIP)
- autosomal dominant disorder
- deficiency = hydroxymethylbilane
- build up of porphobillinogen
2) Variegate porphyria (VP)
- autosomal dominant disorder
- deficiency = protoporphyrinogen oxidase
- build up of protoporphyringoen 9
3) hereditary coproporphyria (HCP)
- autosomal dominant disorder
- deficiency = coproporphyringoen 3 oxidase
Symptoms
- acute GI symptoms
- neuropsychiatric disorders
- soft motor signs
- (+/-) photosensitivity
Congenital erythropoietin porphyria (CEP)
1) Congenital erythropoietin porphyria (CEP)
- Chronic autosomal recessive disorder that is caused by a deficiency in uroporphyrinogen-3 synthase
- causes build up of uroporphyrinogen-1 and coprophyrinogen-1
2) erythropoietic protoporphyria (EPP)
- chronic autosomal dominant disorder that is caused by a deficiency in ferrochelatase enzymes
- causes build up of protoporphyrin
- Both show same Symptoms*:
- photosensitivity
- pain
- vomiting and nausea
Steps in heme degradation
1) senescent red cells are taken in by macrophages in blood vessels and spleen
2) heme is broken down to unconjugated bilirubin inside macrophages
3) unconjugated bilirubin is attached to albumin in blood and transported to the liver
4) bilirubin is then uptaken via facilitated diffusion by the liver and conjugated with glucuronic acid
5) conjugated bilirubin is secreted into bile and intestine, where glucuronic acid is removed by bacteria and converted to urobillinogen
6) some of the urobilinogen is taken up in the gut and enters portal blood to participate in the enterohepatic urobillinogen cycle or transported to the kidney to give urine its yellow color
7) rest of urobillinogen is oxidized by intestinal bacteria to Brown stercobilin and excreted via feces
