Heme Biosynthesis And Porphyrias Flashcards Preview

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Flashcards in Heme Biosynthesis And Porphyrias Deck (24):


-protoporphyrin IX
-4 pyrrole rings with either mthyl, vinyl, or carboxylic sidechains
-cofactor in transcription, translation, miRNA processing


Functions of Cytochrome P450 Enzymes in Liver

•  Phase I Liver Detoxification
•  Detoxify xenobiotic sources of toxicity, chemicals,
alcohols and carcinogens - converting them into water and oxygen
•  Bilirubin metabolism
•  Synthesis of Vitamin D
•  Cholesterol synthesis
•  Synthesis of bile and bile acids


Porphyrin precursors

–  ALA and PBG
–  Water soluble and are excreted and measured in urine
–  Biologically inactive



–  Larger molecules whose aqueous solubility varies in part
based on the number of carboxylic acid side chains in the
–  Biologically active
–  Reduced form



–  Molecules detected and measured in clinical laboratories –  Oxidized
–  Oxidation creates an extended conjugation system that
allows the molecules to absorb visible light.
–  This property results in clinical manifestations of disease
because release of the absorbed energy produces reactive
oxygen species that damage tissue. In the lab the
spectrophotometric and fluorescent properties are used to
detect the compounds in body fluid specimens.


First Step of Heme Synthesis

-δ-ALA is formed in the mitochondria and transported to the
-pyridoxal phosphate (vit b6 is necessary cofactor)
•  Committed step, highly regulated
•  Housekeeping or ALAS1
•  Erythroid-specific or ALAS2
-Sideroblastic anemia results from mutation in ALAS2


Second Step of Heme Biosynthesis

-2 molecules of ALA condense to form Porphobilinogen
(PBG) by ALA dehydratase (ALAD)
-Zinc-containing enzyme
-1st precursor pyrole synthesized
-Inhibited by lead (Pb)


Third Step of Heme Biosynthesis

-Synthesis of Hydroxymethylbilane by Porphobilinogen deaminase-PBGD
-4 PBG are joined into an extended linear tetrapyrole intermediate
by porphobilinogen deaminase
-Acute Intermittent Porphyria occurs when PBGD is mutated


Fourth Step of Heme Biosynthesis

-either UroIII synthase catalyzes an intramolecular rearrangement and ring closure into uroporphyrinogen III
-at high [hydroxymethylbilane], spontaneous arrangement into uroI-->coproI


Fifth Step of Heme Biosynthesis

-uroporphyrinogenIII converted to coproporphyrin via UROIII decarboxylase
-mutations in this enzyme leads to porphyria cutanea tarda


Final Step of Heme Biosynthesis

-protoporphyrin IX gets Fe2+ added via ferrochelatase
-inhibited by Pb
-Associated disease: erythropoietic protoporphyria


Mechanisms of Regulation of ALAS1 in LIVER

1)Allosteric feedback inhibition of the enzyme by Heme, Hemin, hematin

2) Inhibition of newly synthesized ALAS protein
transport from cytosol to mitochondria by heme

3) Repression of transcription of ALAS by heme,
insulin and glucose.

4) Induction by Peroxisome proliferator-activated receptor γ coactivator 1α

5) Induction by 4 Ms (menstruation, medication, malady, malnutrition)
-medication can be alcohol, barbs, steroids, sulfa drugs



-Peroxisome proliferator-activated receptor γ coactivator 1α
-induces ALAS1 transcription


Mechanism of Induction of ALAS in the Liver

Increased p450 usage--> decrease [Heme]---> induction of heme synthesis


Mechanisms of Regulation of ALAS2 in Erythroid cells

-Repression of translation of ALAS2 by low iron
cellular content through an iron response element sequence, IRE.
-Fe deficiency leads to binding of IRP to IRE, inhibiting ALAS2 translation, since there is no point in making heme without Fe.


Sideroblastic Anemia

-Heterogeneous group of disorders
with 2 common features:
–  Ring sideroblasts in the bone marrow
–  Impaired heme biosynthesis
- microcytic and hypochromic
- Disturbed mitochondrial metabolism
- Fe granules in cytoplasm

X-linked mutation, mtDNA mutation, isoniazid, alcohol, Pb, B6 deficiency


Diagnosis of Lead Poisoning

-Accumulation of ALA in urine due to ALAD
-Zinc protoporphyrin (ZPP) in blood
-Basophilic stippling in peripheral smear


Congenital Erythropoietin Porphyria

Autosomal recessive



-partial deficiency is PBGD (hydroxymethylbilane synthase or uroporphyrinogen I synthase)
-accumulation of ALA and/or PBG is neurotoxic
-no skin lesions
-Only 10 % develop disease, all are at risk for primary liver cancer
•  periodic attack of abdominal colic, gastrointestinal disturbances, paralyses, psychiatric disorders
-Triggered by 4 Ms and low heme, since low heme turns off inhibition of ALA synthase
-PBG in urine is oxidized to porphobilin upon standing, which gives a dark-brown color to urine, and often referred to as ‘port-wine reddish urine’


Treatment for AIP

1.  Avoid precipitating factors
2.  Glucose loading (carbohydrate)
3.  Administer Hemin/Hematin
•  End product / Feedback
inhibition of ALAS by heme



-autosomal dominant, most common porphyria
-can also be caused by environmental trigger
-UROD deficiency (the decarboxylase)
-clinical onset in 40's-50's

Symptoms: bullae, milia, dark pink fluorescent urine, Hypertrichosis in the malar region, heliotrope, sclerodermoid plaque on scalp.

Clinical Expression Influenced By
Alcohol, Hepatic iron overload, Exposure to sunlight, Presence of hepatitis B or C, or HIV infections, Hydrochlorobenzene (1952 incident in Turkey)
•  Fungicide used for agricultural wheat


Detection of PCT

Coral red fluorescence of urine
•  Uroporphyrins to coproporphyrins 3:1 to 5:1
•  Fractionation of serum porphyrins.
•  A predominance of 7-8-
carboxyl porphyrin fractions reflecting a uroporphyrinogen decarboxylase (UROD) defect
•  UROD enzyme activity assay in
red blood cells
•  Mutation analysis of genes
encoding UROD


Treatment of PCT

Remove environmental exposures
•  Avoid alcohol, tobacco,
estrogen therapy
•  Sunscreens
•  Chelation with desferrioxamine
(iron chelator)
•  Phlebotomy (BLEEDING)
•  Reduces iron stores, which
improves heme synthesis
disturbed by iron-mediated
inhibition of uroporphyrinogen
decarboxylase (UROD).


EPP (erythropoietic protoporphyria)

Mutations in Ferrochelatase
•  Autosomal dominant inheritance
•  Presentation in early childhood
•  Severe cutaneous photosensitivity
•  Burning, stinging pain with sunlight
•  Subsequent skin changes
•  Chronic liver disease in later life