Metabolism of Heme

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serum

platelet

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 globin
hemoglobin
heme
 pyrrole rings
heme

Heme is a derivative of the porphyrin. Porphyrins are cyclic

compounds formed by fusion of 4 pyrrole rings linked by
methenyl bridges.
Heme is the prosthetic group of hemoglobin, myoglobin,
& cytochromes.
- most common porphyrin in humans is heme
- one ferrous group in tetrapyrrole ring

- heme proteins (hemoproteins) are rapidly synthesized and

degraded
** 6 to 7 g per day hemoglobin turned over
- cyclic compounds that bind metals
- usually iron
- Fe+2 = ferrous
- Fe+3 = ferric
 Synthesis of heme
• The substrates mainly include succinyl-CoA, glycine, Fe2+ .
• Heme can be synthesized by almost all the tissues in the
body which require hemoproteins.
• Major sites of synthes is liver and bone marrow
(erythroblasts: reticulocyte, prorubricyte)
- cytochrome p450 in liver
- hemoglobin in bone marrow
- heme production equal to globin synthesis in marrow
- variable in liver dependent on heme pool balance

Inside RBCs, heme is synthesized in the normoblasts, but

not in the matured ones .
Inside RBCs, heme is
synthesized in the
normoblasts, but not in
the matured ones .
First & second
steps of heme
synthesis
 Step 1
In mitochondrion
① Heme synthesis begins with condensation of glycine &
succinyl-CoA, with decarboxylation, to form -
aminolevulinic acid (ALA).

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.
Accordingly, heme concentration is reduced resulting in stimulation of
action of ALA synthase.
 ALA Synthase is the committed step of the heme
synthesis pathway, & is usually rate-limiting for the
overall pathway.
 Regulation occurs through control of gene
transcription. 
 Heme functions as a feedback inhibitor, repressing
transcription of the ALA Synthase gene in most cells.
 A variant of ALA Synthase expressed only in developing
erythrocytes ,is regulated instead by availability of iron
in the form of iron-sulfur clusters.
 Step 2

2 molecules of d-Amino levulinic acid (ALA) condense

enzyme ALA dehydratase to form

porphobilinogen.

• The succeeding few reactions occur in the cytoplasm.

one ALA condenses with another molecule of ALA to form
porphobilinogen(PBG).

• The condensation involves removal of 2 molecules of water

and the enzyme is ALA dehydratase .
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
 Summary
① Major sites of synthesis is liver and bone marrow
(erythroblasts). Matured red blood cells have no
mitochondria, so can’t make heme.

② The substrates mainly include succinyl-CoA, glycine,

Fe2+ .
③ First and last 3 reactions take place in mitochondria -
others in cytoplasm
Summary of biosynthesis of heme

Glycine + Succinyl CoA

Enzyme: ALA Synthase STEP 1

PLP

-Amino levulinic acid (ALA)

Enzyme: ALA dehydratase. STEP 2

porphobilinogen

FURTHER STEPS

Protoporphyrin IX

Ferrous ion (Fe2+ ) introduction of iron

Enzyme: ferrochelatase
heme
 Porphyria
 Porphyria is a name given to a group of metabolic
disorders. These disorders cause the individual to
accumulate "porphyrins" or "porphyrin precursors" in
their body. which in turn causes an abundance of
the porphyrins.

 In porphyria, the cells do not convert porphyrins

to heme in a normal manner.
 Porphyrias

Porphyrias are genetic diseases in which

activity of one of the enzymes involved in
heme synthesis is decreased (e.g., PBG
Synthase, Porphobilinogen Deaminase, etc…).

Symptoms vary depending on

★ the enzyme
★ the severity of the deficiency
★ whether heme synthesis is affected primarily in
liver or in developing erythrocytes.
Common Symptom of Porphyrias
 Common Symptom of Porphyrias

1. Occasional episodes of severe neurological

symptoms.

 had acute bouts of abdominal pain and mental confusion

 permanent nerve damage and even death can result, if not

treated promptly.
 elevated -aminolevulinic acid (ALA), arising from
derepression of ALA Synthase gene transcription, is
considered responsible for the neurological symptoms.
2. Photosensitivity is another common
symptom.
◆formation of superoxide radicals.
◆skin damage may result from exposure to light.

**This is attributable to elevated

levels of light-absorbing
pathway intermediates and
their degradation products.
3. Changing color in the urine.
• Porphyrins build up in the body and are excreted in the
urine and stool in excessive amounts.

• When present in very high

levels, they cause the
urine to have a
spectacular port wine
normal
color.
• King George III - Mad King George
had acute bouts of abdominal pain and
mental confusion
- may have been porphyria sufferer
- complicated by all the drugs his doctors gave him

• vampires and werewolves?

- some have put forth that porphyrias misinterpreted
in Middle Ages
- consider photosensitivity, red blood (even teeth)
hypertrichosis
 Porphyrias

• Can be grouped into erythropoietic porphyria and hepatic

porphyria
- hepatic can be acute or chronic

• Caused by hereditary or acquired defects in heme

synthesis
— genetic diseases: the enzymes of heme synthesis
— Liver disfunction, lead poisoning
 Acute hepatic porphyrias
• Acute hepatic porphyria is a result of a deficiency of
one of the enzymes in the heme biosynthesis pathway.

• These deficiencies result in an accumulation of the

precursors of porphyrins in the liver (delta-aminolevulinic
acid, ALA and porphobilinogen, PBG)

• Similar symptoms - acute attacks of gastrointestinal pain,

neurologic / psychologic, cardiovascular.

When an acute attack is confirmed, urgent treatment with an injection

of human hemin and/or perfusion of carbohydrates is required.
Management includes the prevention of attacks (by avoiding causal
factors) and the protection of skin from the light in cases of cutaneous
manifestations.
 Erythropoietic Porphyrias

• Due to the inheritance of 2 mutant alleles for the gene

encoding the enzyme uroporphyrinogen III synthase.

• symptoms include:
- skin rashes and blisters early in childhood
- cholestatic liver cirrhosis and progressive liver failure

Treatment for Porphyrias

- medical support for vomiting and pain
- hemin, decreases ALA synthase synthesis
- avoidance of sunlight and precipitating drugs, factors
 Porphyria Cutanea Tarda

- a chronic porphyria
- liver and erythroid tissues
- deficiency in uroporphyrinogen decarboxylase
- often no symptoms until 4th or 5th decade

clinical expression determined by many factors:

- hepatic iron overload
- exposure to sunlight
- hepatitis B or C
- HIV
symptoms include:
- cutaneous rashes, blisters
- urine that is red to brown in natural light, or
pink to red in UV light
 Acquired Porphyrias

- Hexochlorobenzene used as a fungicide in Turkey in 1950s

- thousands of children ate bread from treated wheat

- They acquired porphyria cutanea tarda

due to inhibition of uroporphyrinogen
decarboxylase

- Due to hypertrichosis - referred to locally

as the “monkey children”
 Acquired Porphyrias

lead poisoning
-inhibition of ferrochelatase ALA dehydratase
- displaces Zn+2 at enzyme active site

children
- developmental defects
- drop in IQ
- hyperactivity
- insomnia
- many other health problems

adults
- severe abdominal pain
- mental confusion
- many other symptoms