Heme Metabolism

(synthesis)Dr. Marian Maher

Lecturer of Medical Biochemistry and Molecular Biology

Intended Learning Outcomes ILOs

1. Describe the structure of Porphyrins

2. List important heme-proteins

3. Describe steps of heme biosynthesis

4. Identify the regulation of heme synthesis

5. Define Porphyrias

6. Identify clinical manifestations of porphyrias

7. List different types of porphyrias

8. Describe the treatment of porphyrias

Structure Of Porphyrins

They are cyclic compounds formed from:

▪ 4 pyrrole rings

linked by methenyl

bridges

▪ 4 methyl , 2

propionyl and 2

vinyl groups

connected to the

pyrrole rings

▪They constitute a system of

conjugated double bonds which

absorb light

▪ Porphyrinogens are reduced

forms of porphyrins .They contain

methyl (- CH2-) rather than

methenyl bridges (-HC=).

So,

they have no conjugated double

bonds and colorless .

Porphyrins form complexes

with metal ions , that bind

to Nitrogen of pyrrole

rings.:

Iron porphyrins (Heme),

Magnesium porphyrins

(Clorophyll).

▪ Haemoglobin

▪ Myoglobin

▪ Cytochromes of electron transport chain (cyt

aa3,cyt.c)

▪ cytochrome 450

▪ Catalse and Peroxidase (degradation of H2O2), ,

▪ Tryptophan pyrrolase (Oxidation of tryptophan),

▪ Cytoplasmic guanyl cyclase (activated by NO) .

Some important heme-proteins

Biosynthesis of Heme

The principal tissues involved in hemebiosynthesis are the bone marrow

and the liver.Heme biosynthetic pathway is partly mitochondrial and partly cytosolic.

The reactions are Irreversible.

Steps:

The initial

reaction and the last three

steps in the formation of

porphyrins occur

in mitochondria, whereas the

intermediate steps of the

biosynthetic

pathway occur in the cytosol

(A pyrrol)

(tetrapyrrol)

▪ Glycine and succinyl coenzyme A that condense

to form ALA by mitochondrial ALA synthase

(ALAS) .

▪ This reaction requires pyridoxal phosphate (PLP)

▪ It is the committed and rate-limiting step in

porphyrin biosynthesis.

▪ There are two isoforms of ALAS, 1 and 2.

▪ Erythroid tissue produces only ALAS2.

TCA cycle

COASH

All true about Hemophilia except:

A.Can occur due to Factor IX deficiency

B. Inherited as an autosomal recessive

C. Can occur due to Factor VIII deficiency

D.Can occur due to Factor XI deficiency

▪ By Zn-containing ALA dehydratase

(porphobilinogen synthase)

▪ It is extremely sensitive to inhibition

by heavy metal ions e.g. lead that

replace thezinc .

▪ This inhibition cause the elevation in

ALA and the anemia seen in lead

poisoning.

(-)

(cytosolic enzyme)

The condensation of four

porphobilinogens produces the

linear tetrapyrrole,

hydroxymethylbilane,

Hydroxymethylbilane,which is

isomerized and cyclized by uroporphyrinogen III

Synthase to produce the

asymmetric uroporphyrinogen III.

This cyclic tetrapyrrole undergoes decarboxylation of its acetate groups, generating coproporphyrinogen III.

Thesereactions occur in the cytosol.

CH2 CH

(IX)

(IX)

enters the mitochondrion,

2 CO2

inhibited bylead

zinc

CO2

Fe

▪ ALA synthase is the rate

limiting regulatory enzyme

▪ Excess heme in bone marrow

is converted to hemin by

oxidation of Fe2+to Fe3+.

Hemin acts as an

aporepressor which

decreases its synthesis .

Regulation of Heme Synthesis

▪ hypoxia and availability of intra-

cellular iron increases the

activity of ALA synthase due to

increase erythropoietin hormone

▪ Substances metabolized by

cytochrome P450 increases the

activity of ALA synthase e.g.

barbiturates , alcohol and

carcinogens.

Drugs that metabolized by cytochrome P450 monooxygenase in the liver .

Synthesis of cytochrome P450,

Consumption of hemea component of cytochrome P450

proteins.

The concentration of heme in liverCells.

The synthesis of ALAS1 (derepression),

▪ ALA dehydratase and

ferrochelatase inhibited by

Lead poisoning

A group of diseases

collectively called

porphyrias are associated

with abnormalities in

biosynthesis of heme.

They are characterized by

accumulation and excretion

of porphyrins or porphyrin

precursors.

Disorders of Heme Synthesis ( Porphyrias)

“Porphyria” refers to the purple color caused by

pigment-like porphyrins in the urine of some patients

with defects in heme synthesis.

The porphyrias are classified as erythropoietic or

hepatic (chronic or acute)

depending on whether the enzyme deficiency occurs in

the erythropoietic cells of the bone marrow or in the

liver.

The exact prevalence of porphyria is unknown, but

it probably ranges from 1 in 500 to 1 in 50,000

people worldwide.

For some forms of porphyria, the prevalence is

unknown because many people with a genetic

mutation associated with the disease never

experience signs or symptoms.

▪ Most of porphyrias are inherited as autosomal

dominant manner except congenital erythropoietic

porphyria (recessive).

▪ However acquired porphyrias can result from lead

poisoning. The toxic effect of lead is due to inhibition

of ferrochelatase.

• Low levels of ALA synthase cause no porphyria (only anemia).

Overall, porphyria cutanea tarda is the most common type of porphyria.

❑ Enzyme deficiency early in pathway before formation of cyclic

tetrapyroles :

only abdominal pains and neuro-psychiatric symptoms are present as

in acute intermittent porphyria which is characterized by deficiency

of the enzyme porphobilinogen deaminase

❑ Enzyme deficiency late in pathway after formation of porphyrinogen :

Porphyrinogens are oxidized to their corresponding porphyrins which react with molecular oxygen to form reactive oxygen

species that cause oxidative damage of cells.

photosensitivity (skin inflammation damage with ultimate disfigurement and scaring.) in response

to visible light

Porphyria cutanea tarda which is the (most common type).

Due to low levels of Uroporphyrinogen decarboxylase

❑ Individuals with an enzyme defect prior to the

synthesis of the tetrapyrroles manifest

abdominal and neuropsychiatric signs.

Clinical manifestations:

❑ Whereas those with enzyme defects leading to

the accumulation of tetrapyrrole intermediates show

photosensitivity that is, their skin itches and burns

(pruritus) when exposed to visible light.

❑ The accumulation of these toxic intermediates is

the major pathophysiology of the porphyrias.

❑ Drugs that cause induction of cytochrome P450 e.g.

steroids , alcohol, Phenobarbital ,are

contraindicated for porphyria patients because they

precipitate attacks.

❑ The severity of symptoms of porphyrias can be

diminished by intravenous injection of hemin which

decreases synthesis (represses) ALA synthase.

❑ Avoidance of sunlight and ingestion of B-carotenes

(anti-oxidant), are helpful in photosensitivity.

❑ A high-carbohydrate diet is typically recommended;

in severe attacks, a glucose 10% infusion is

commenced, which may aid in recovery

Treatment