1. Porphyrin metabolism & porphyrias

2. What are porphyrins ?
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, perioxidases, NOS and tryptophan pyrrolase
So, heme + globin protein = hemoglobin

3. Structure of porphyrins
Porphyrins are cyclic molecules formed by 4 pyrrole (tetrapyrrole) rings linked by methenyl bridges.
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
Porphyrinogens
are porphyrin precursors intermediate between porphobilinogen & protoporphyrin
Porphobilinogen Porphyrinogens Protoporphyrins
(A), Pyrrole ring; (B), porphin ring; (C), protoporphyrin IX.

4. (A), Pyrrole ring; (B), porphin ring; (C), protoporphyrin IX.

5. Biosynthesis of Heme
Heme synthesis occurs in all cells except RBCs 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.

6. PORPHYRIAS Agent Orange GLYCINE + SuccinylCoA
Mitochondria
GLYCINE + SuccinylCoA
Agent Orange
ALA synthase
3p21/Xp11.21
d-aminolevulinic acid(ALA)
ALA-dehydratase
Deficiency porphyria
ALA dehydratase
9q34
Porphobilinogen(PBG)
Acute intermittent
porphyria
PBG deaminase
11q23
hydroxymethylbilane
Uroporphyrinogen III
cosynthase
Congenital erythropoietic
porphyria
10q26
uroporphyrinogen III
Uroporphyrinogen
decarboxylase
Prophyria
cutanea tarda
1q34
coprophyrinogene III
Coproporphyrinogen
oxidase
Herediatary
coproporphyria 9
Protoporphyrinogene IX
Protoporphyrinogen
oxidase
Variegate
porphyria
protoporphyrin IX
1q14
Ferrochelatase
Erythropoietic
protoporphyria
Heme
18q21.3

7. Clinical importance of first step (ALA synthase control):
Heme synthesis occurs in all cells except RBCs 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.
Clinical importance of first step (ALA synthase control):
# 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.

8. Cytochrome P450 Monooxygenase System:
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.
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.
The name P450 reflects the absorbance at 450 nm by the protein.
Role of cytochrome P450 in detoxification of drugs & toxic compounds:
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.

9. Biosynthesis of heme (cont.)
Step 2: Formation of porphobilinogen:
2 molecules of d-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)

10. 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

11. 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 porphyrins and their precursors depending on location of block of the heme synthesis pathway.
These porphyrins & 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

12. Clinical manifestations of porphyrias:
Two types of porphyrias:
erythropoietic (bone marrow) & hepatic
Hepatic porphyrias are: acute & chronic porphyrias
A- Neurological Manifestations:
Generally, individuals with an enzyme defect prior to the synthesis of the tetrapyrroles manifest abdominal and neuropsychiatric signs
B- Cutaneous Manifestations:
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)

13. 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
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.

15. Types of Porphyrias

16. Reticulo-endothelial System (RES)
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