Download Porphyrin Metabolism & Porphyrias

Porphyrin metabolism &
porphyrias
HMIM224
What are porphyrins ?
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Porphyrins are cyclic compounds that bind metal ions (usually Fe2+ or
Fe3+)
Porphyrin + Metal = Metaloporphyrin
Most prevalent metalloporphyrin in humans is heme (metal here is iron
ion)
Heme consists of:
One ferrous ion (Fe2+) in the centre
Protoporphyrin IX (a tetrapyrrole ring)
Heme is the prosthetic group of hemoglobin, myoglobin, cytochromes,
catalase, tryptophan pyrrolase
So, heme + globin protein = hemoglobin
Structure of porphyrins
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Porphyrins are cyclic molecules formed by 4 pyrrole (tetrapyrrole) rings linked by
methenyl bridges.
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Different porphyrins vary in the nature of side chains that are attached to each of the 4
pyrrole rings
Protoporphyrin IX contains vinyl, methyl & propionate
Distribution of side chains
- Side chains can be ordered around tetrapyrrole nucleus in 4 different ways designated
I, II, III & IV series.
Only type III porphyrins are physiologically important in humans
- Protoporphyrin IX is a member of type III series
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Porphyrinogens
are porphyrin precursors
intermediate between porphobilinogen & protoporphyrin
Porphobilinogen
Porphyrinogens
Protoporphyrins
Methenyl
Side
bridge
Chains
Pyrrole
ring
Structure of Porphyrin
Determine the type of porphyrin
Structure and Properties of Iron Protoporphyrin IX
propionate
methyl
pyrrole ring
vinyl
Derived from protoporphyrin IX
Pattern of side chains defines isomer
Binds metals: Heme- Fe2+ (ferrous)
Hemin- Fe3+ (ferric)
Zinc protoporphyrin (ZnPP)- Zn2+
Extended conjugation across ring system
Biosynthesis of Heme
Overview of Heme Synthesis
Heme
Succinyl CoA + Glycine
Protoporphyrin IX
ALA synthase
-aminolevulinic acid
Protoporphyrinogen IX
Coproporphyrinogen III
mitochondrial matrix
cytoplasm
-aminolevulinic acid
Porphobilinogen
Uroporphyrinogen III
Uroporphyrinogen I
Coproporphyrinogen III
Coproporphyrinogen I
Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on
enzymes and electron transport chain. By weight, the major locations of heme synthesis are
the liver and the erythroid progenitor cells of the bone marrow.
Biosynthesis of heme
Site of biosynthesis: Liver & Bone Marrow (erythryoid producing cells)
Steps:
Step 1: Formation of -amino levulinic acid (ALA): in mitochondria
(Rate Controlling Step)
Glycine
(nonessential amino acid)
+
Succinyl CoA
(intermediate of citric acid cycle)
Enzyme: ALA Synthase
Coenzyme: Pyridoxal Phosphate (PLP)
-Amino levulinic acid (ALA)
Biosynthesis of heme (cont.)
Clinical importance of first step:
When heme (end product) is produced in excessive amounts, heme is converted
to hemin.
Hemin decreases action of ALA synthase in liver. (end product inhibition).
The reverse occurs when heme biosynthesis is reduced.
Drugs as grisofulvin (antifungal), hydantoin & phenobarbital (anticonvulsant)
increase ALA synthase activity:
as these drugs are metabolized by cytochrome p450 in liver resulting in more
consumption of heme (component of cytochrome).
Accordingly, heme concentration is reduced resulting in stimulation of action of
ALA synthase.
ALA
Synthesis of
ALAS 1
Decreased heme
Synthesis of CYP 450 is increased
Metabolised by CYP 450
Large Amount of Drug intake
Biosynthesis of heme (cont.)
Cytochrome P450 Monooxygenase System:
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Cytochrome P450s (CYPs) are actually a superfamily of related, heme-containing
monooxygenase enzymes that participate in abroad variety of reactions.
This system performs different functions in two separate locations in cells.
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The over-all reaction catalyzed by a cytochrome P450 enzyme is:
R-H + O2+ NADPH + H+→R-OH + H2O NADP+
where R may be a steroid, drug, or other chemical.
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The name P450 reflects the absorbance at 450 nm by the protein.
Role of cytochrome P450 in detoxification of drugs & toxic compounds:
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It may itself activate or inactivate a drug
It can make a toxic compound more soluble, thus facilitating its excretion in the urine or
feces.
Biosynthesis of heme (cont.)
Step 2: Formation of porphobilinogen:
2 molecules of -Amino levulinic acid (ALA) condense to form
porphobilinogen by the enzyme ALA dehydratase.
Clinical importance:
ALA dehydratase enzyme is inhibited by heavy metals as lead that
results in anemia. (lead poisoning).
In this case: ALA in blood is elevated (lab investigation)
Biosynthesis of heme (cont.)
First &
second steps
of heme
synthesis
Biosynthesis of heme (cont.)
Further steps: (in mitochondria)
Formation of protoporphyrin IX
Then, ferrous ions (Fe2+) are introduced into protoporphyrin IX, either:
simultaneously
or: enhanced by ferrochelatase
Clinical importance:
Ferrochelatase enzyme is inhibited by lead
Biosynthesis of heme (cont.)
Further
steps of
heme
synthesis
Summary of biosynthesis of heme
Glyine
Enzyme:
+
Succinyl CoA
STEP 1
ALA Synthase
PLP
-Amino levulinic acid (ALA)
Enzyme: ALA dehydratase.
STEP 2
porphobilinogen
FURTHER STEPS
Protoporphyrin IX
Ferrous ion (Fe2+ )
Enzyme: ferrochelatase
introduction of iron
heme
Overview of Heme Synthesis
Heme
Succinyl CoA + Glycine
Protoporphyrin IX
ALA synthase
-aminolevulinic acid
Protoporphyrinogen IX
Coproporphyrinogen III
uroporphyrinogen
decarboxylase
mitochondrial matrix
cytoplasm
-aminolevulinic acid
Porphobilinogen
Uroporphyrinogen III
Uroporphyrinogen I
Coproporphyrinogen III
Coproporphyrinogen I
Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on
enzymes and electron transport chain. By weight, the major locations of heme synthesis are
the liver and the erythroid progenitor cells of the bone marrow.
Porphyrias
Porphyria are rare inherited defects in heme synthesis.
An inherited defect in an enzyme of heme synthesis results in accumulation of one
or more of porphyrin precursors depending on location of block of the heme
synthesis pathway.
These precursors increase in blood & appear in urine of patients.
Porphyria means purple colour caused by pigment-like porphyrins in urine of
patients. (Diagnosed by lab investigation)
Most porphyrias show a prevalent autosomal dominant pattern, except
congenital eythropoietic porphyria, which is recessive
Porphyrias (cont.)
Clinical manifestations of porphyrias:
Two types of porphyrias: erythropoietic (bone marrow) & hepatic
Hepatic porphyrias are: acute & chronic porrphyrias
Generally, individuals with an enzyme defect prior to the synthesis of the
tetrapyrroles manifest abdominal and neuropsychiatric signs
Those with tetrapyrrole intermediates show photosensitivity with formation
of reactive oxygen species (ROS) that damage membranes by oxidation resulting
in the following effects:
- Skin blisters, itches (pruritis)
- Skin may darken, grow hair (hypertrichosis)
Porphyria Cutanea Tarda
• Chronic hepatic porphyria
• The most common type of porphyria
• a deficiency in uroporphyrinogen decarboxylase
• Clinical expression of the enzyme deficiency is influenced by
various factors, such as exposure to sunlight, the presence of
hepatitis B or C
• Clinical onset is during the fourth or fifth decade of life.
• Porphyrin accumulation leads to cutaneous symptoms and
urine that is red to brown in natural light and pink to red in
fluorescent light
Porphyrias (cont.)
Acute Hepatic Porphyrias
e.g. Acute Intermittent Porphyria
• Porphyrias leading to accumulation of ALA and porphobilinogen cause
abdominal pain and neuropsychiatric disturbances, ranging from
anxiety to delirium.
• Symptoms of the acute hepatic porphyrias are often precipitated by
administration of drugs such as barbiturates and ethanol.
Types of Porphyrias
Degradation of Heme
Degradation of Heme
RBCs last 120 days
then,
degraded by
Reticulo-endothelial System (RES)
(in liver & spleen)
Hemoglobin (released from RBCs)
Heme
+
globin (reused)
Biliverdin
Bilirubin
Liver
Bile
Intestine
feces
Degradation of Heme