Porphyrin metabolism & Porphyrin metabolism & porphyriasporphyrias

What are porphyrinsWhat are porphyrins? ?

• PorphyrinsPorphyrins are cyclic compounds that bind metal ions (usually Fe2+ or Fe3+)

• Porphyrin + Metal = MetaloporphyrinMetaloporphyrin• Most prevalent metalloporphyrin in humans is hemeheme (metal here is iron

ion)

Heme consists ofHeme consists of:• One ferrous ion One ferrous ion (Fe2+) in the centre• Protoporphyrin IX Protoporphyrin IX (a tetrapyrrole ring)

Heme is the prosthetic group Heme is the prosthetic group of hemoglobin, myoglobin, cytochromes, catalase, perioxidases, NOS and tryptophan pyrrolase

So, heme + globin protein = hemoglobin

Structure of porphyrinsStructure of porphyrins• PorphyrinsPorphyrins 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 porphyrinstype III porphyrins are physiologically important in humans

- Protoporphyrin IX 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.

Heme- Fe2+ (ferrous) protoporphyrinHemin- Fe3+ (ferric) protoporphyrin

Biosynthesis of HemeBiosynthesis 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.

Key enz

Clinical importance of first step (ALA synthase control)Clinical importance of first step (ALA synthase control)::# When heme (end product) is produced in excessive amounts, heme is converted

to heminhemin. Hemin decreases action of ALA synthase in liver. (end product inhibition).The reverse occurs when heme biosynthesis is reduced.

# Drugs# Drugs as grisofulvin (antifungal), hydantoin & phenobarbital (anticonvulsant)

increase ALA synthase activity: as these drugs are metabolized by cytochrome p450 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.

Cytochrome P450 Monooxygenase System:Cytochrome P450 Monooxygenase System:• Cytochrome P450s (CYPs) are actually a superfamily of related, heme-heme-

containingcontaining monooxygenase enzymes 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:

RR-H + O2+ NADPH + H+ → RR-OH + H2O NADP+

where RR 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:Role of cytochrome P450 in detoxification of drugs & toxic compounds:

• It may itself activate or inactivate a drug drug

• It can make a toxic compound toxic compound more soluble, thus facilitating its excretion in the urine or feces.

Step 2Step 2: : Formation of porphobilinogenFormation of porphobilinogen:

2 molecules of -Amino levulinic acid (ALA) condense to form porphobilinogenporphobilinogen by the enzyme ALA ALA dehydratasedehydratase.

Clinical importanceClinical importance: ALA dehydratase enzyme is inhibited by heavy metals as

leadlead that results in anemia. (lead poisoning).

In this case: ALA in blood is elevated (lab investigation)

Biosynthesis of heme Biosynthesis of heme (cont.)

Further steps: Further steps: (in mitochondria) (in mitochondria)

Formation of protoporphyrin IXprotoporphyrin IX

Then, ferrous ions (Fe2+) are introduced ferrous ions (Fe2+) are introduced into protoporphyrin IXinto protoporphyrin IX, either:

simultaneously

or: enhanced by ferrochelatase ferrochelatase

Clinical importanceClinical importance:

Ferrochelatase enzyme is inhibited by lead

PorphyriasPorphyrias

PorphyriaPorphyria 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.

PorphyriaPorphyria means purple colour caused by pigment-like porphyrins in urine of patients. (Diagnosed by lab investigation) Most porphyrias show a prevalent autosomal dominant patternautosomal dominant pattern, except congenital eythropoietic porphyria, which is recessive

Clinical manifestations of porphyriasClinical manifestations of porphyrias: Two types of porphyriasTwo types of porphyrias:

erythropoietic (bone marrow) & hepatic Hepatic porphyrias areHepatic porphyrias are: acute & chronic porphyriasA- Neurological Manifestations: Generally, individuals with an enzyme defect priorprior to the synthesis of the tetrapyrrolestetrapyrroles manifest abdominal and neuropsychiatric signsB- Cutaneous Manifestations: Those with with tetrapyrrole intermediatestetrapyrrole 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 TardaPorphyria Cutanea Tarda• Chronic hepatic porphyria• The most common type of porphyria

• a deficiency in uroporphyrinogen decarboxylaseuroporphyrinogen 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 symptomscutaneous symptoms and urineurine that is red to brown in natural light and pink to red in fluorescent light

Acute Hepatic PorphyriasAcute 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 PorphyriasTypes of Porphyrias

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 HemeDegradation of Heme

Degradation of HemeDegradation of Heme