THE UNIVERSITY OF ZAMBIA

 
SCHOOL OF MEDICINE
 
DEPARTMENT OF PHYSIOLOGICAL SCIENCES

PGY 3419 (BIOCHEMISTRY & GENETICS)

Heme Metabolism-Lecture

Dr Lubinda Mukololo
Email: mlubinda@unza.zm
Heme Metabolism

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Heme

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 Biosynthesis of Heme
• Synthesized in almost all mammalian tissues. Mitochondrial and
cytosolic. Synthesis is most active in born marrow and liver for
incorporation into hemoglobin and cytochromes, respectively.

• Two starting materials are Succinyl-CoA and Glycine

• Rxn catalysed by δ-aminolevulinate synthase (ALA synthase). Rate-

limiting rxn.

• The product of this reaction is δ-aminolevulinate (ALA)

• Pyridoxal phosphate (PLP) serves as coenzyme for ALA synthase

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• Synthesis of ALA occurs in mitochondria

• in the cytosol, two molecules of ALA condense. The rxn is

catalysed by ALA dehydratase. The product is porphobilinogen
(PBG).

• ALA dehydratase is a zinc-containing enzyme and is sensitive to

inhibition by heavy metals, particularly lead.

• Lead poisoning results in high levels of ALA in the absence of

elevation of porphobilinogen

• ALA is toxic to the brain.

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• The formation of a cyclic tetrapyrrole ie, a porphyrin—
occurs by condensation of four molecules of PBG to
form a linear tetrapyrrole, hydroxymethylbilane
(HMB).

• HMB cyclizes and is converted to uroporphyrinogen III,

which is decarboxylated to coproporphyrinogen III

• Coproporphyrinogen III then enters the mitochondria,

where it is oxidized to protoporphyrinogen IX.

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• Protoporphyrinogen IX is oxidized to
protoporphyrin IX.

• The final step in heme synthesis involves the

incorporation of ferrous iron into protoporphyrin
in a reaction catalyzed by ferrochelatase (heme
synthase).

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ALA Synthase Is the Key Regulatory Enzyme
• Heme and hematin (a derivative of oxidized heme)
act both as a repressor of the synthesis of ALA
synthase and as an inhibitor of its activity.

• In the liver, heme biosynthetic enzymes are

regulated depending on changing metabolic
requirements.

• In erythroid progenitors, the pathway is regulated

to permit a high steady level of heme synthesis
and regulation is tied to the availability of iron.
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 Phophyrias

- Genetic heme synthesis disorders that can cause

nerve (neurological ) or skin (dermatological)
problems

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Two major types:

• Cutaneous porphyrias (porphyrias affecting

the skin). Photosensitivity and shrunken gums

• Acute porphyrias (porphyrias affecting the

nervous system).

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 Causes

• Hereditary - can be passed from parents to

their children. Can be autosomal dominant
or recessive, or even X linked, with
dominant being the most common.

• Symptoms do not occur right away; usually

people don’t realize they have it until a
trigger causes symptoms to appear.
• Effects can vary: can be life threatening.

• Onset triggered by various conditions. 12

Possible Triggers:

• Alcohol consumption,
smoking, sunlight, stress,
certain medications,
eating disorders, HIV
infection, iron or lead
accumulation, Hepatitis C
etc.

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 Symptoms

• Symptoms vary in Cutaneous and Acute porphyria

Cutaneous:
-occur continuously
-oversensitivity to sunlight
-blisters on exposed skin → itching and swelling

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 Symptoms

Acute:
-occur spontaneously or develop with time
-pain in abdomen, chest, limbs, back
-constipation & urinary retention
-muscle weakness and seizures

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• Clinical symptoms are due to lack of heme and accumulation of
biosynthetic intermediates.

• Acute intermittent porphyria, porphobilinogen deaminase is

the affected enzyme. Both porphobilinogen and δ-ALA
accumulate. Porphobilinogen is excreted through the urine
and, through spontaneous oxidation, forms a characteristic
red pigment.

• Accumulation of δ-aminolevulinate causes clinical symptoms.

This metabolite competitively inhibits the binding of γ-
aminobutyrate (GABA), an inhibitory neurotransmitter, to
its receptors, which likely causes both psychiatric
(agitation, confusion) and neurological symptoms (nausea,
abdominal pain).
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Congenital erythropoietic porphyria (CEP)
• caused by homozygous mutation in the uroporphyrinogen
III synthase gene.

• Uroporphyrin I and coproporphyrin I are found in

plasma, red blood cells, urine, and feces.

• Porphyrins are also deposited in the teeth and bones,

giving them a reddish-brown colour.

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Porphyria cutanea tarda
• the most common form of porphyria. The deficient
enzyme is uroporphyrinogen decarboxylase.

• The accumulating uroporphyrinogen distributes

throughout the body and becomes oxidized non-
enzymatically to the non-physiological product
uroporphyrin III.

• In the skin, uroporphyrin III can absorb photons and

then react with molecular oxygen to produce reactive
oxygen species; the latter inflict the skin tissue
damage.

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 Variegate porphyria
• caused by heterozygous mutation in the gene coding for
protoporphyrinogen oxidase.

• characterized by cutaneous manifestations, including

increased photosensitivity, blistering, skin fragility with
chronic scarring of sun-exposed areas, post-
inflammatory hyperpigmentation, passage of dark urine,
confusion, convulsions, and muscular weakness.
• The porphyrins, when exposed to light of wavelength,
400nm are thought to become “excited” and then react
with molecular oxygen to form oxygen radicals. These
radicals injure lysosomes and other organelles. Damaged
lysosomes release their degradative enzymes, causing
variable degrees of skin damage, including scarring.
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 Other factors that can inhibit heme synthesis

• iron depletion

• deficiency of vitamin B : can result from

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malnutrition, inflammatory intestinal diseases or

malabsorption. Vitamin B (pyridoxin) is the
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precursor of pyridoxal phosphate, the coenzyme in

δ-aminolevulinate synthase.

• Lead poisoning: causes inhibition of ALA

dehydratase.
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 Heme catabolism

• Catabolism of heme produces Bilirubin

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• Lifespan of RBCs is 120 days

• Hemoglobin is destructed, globin degraded to

constituent a.a.

• Iron of heme enters the iron pool.

• Porphyrin is degraded by phagocytic macrophages of

the liver, spleen, lymph and bone marrow.

• Catabolism of heme is carried out by an endoplasmic

reticulum enzyme system called heme oxygenase.

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• The iron in heme is oxidized to the ferric form and
with the aid of NADPH, the α-methenyl bridge
between pyrroles I and II of the porphyrin is
broken.

• Ferric ion is released, carbon monoxide is produced,

along with biliverdin, the linear tetrapyrrole
compound.

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• In mammals, a soluble enzyme called biliverdin
reductase reduces biliverdin to produce
bilirubin, a yellow pigment.

• It is estimated that 1 g of hemoglobin yields 35

mg of bilirubin. The daily bilirubin formation in
human adults is approximately 250–350 mg.
Biliverdin

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• Further metabolism of bilirubin occurs primarily in
the liver.

• Process involves:

- uptake of bilirubin by liver cells,

- conjugation of bilirubin with glucuronate in the

endoplasmic reticulum, and

- secretion of conjugated bilirubin into bile.

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• Bilirubin is solubilized by non-covalent binding to
albumin.

• In the liver, the bilirubin is removed from albumin

and taken up by hepatocytes- by a carrier-
mediated system.

• In hepatocytes, bilirubin binds Ligandin (Protein Y),

which keeps it soluble prior to conjugation, as well
as prevent efflux of bilirubin back into the blood
stream.

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• Hepatocytes convert bilirubin to a polar form by
conjugating it to glucuronic acid molecules.

• The conjugation of bilirubin is catalyzed by UDP-

glucuronosyl-transferase.

• The enzyme is mainly located in the endoplasmic

reticulum, uses UDP-glucuronic acid as the
glucuronosyl donor.

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• Bilirubin is first converted to bilirubin
monoglucuronide and then is subsequently converted
to diglucuronide. Most of the bilirubin excreted in
the bile of mammals is in the form of bilirubin
diglucuronide.

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• conjugated bilirubin is secreted into bile by active
transport

• The protein involved is MRP-2 (multidrug resistance-like

protein 2), also called multi-specific organic anion
transporter (MOAT).

• As the conjugated bilirubin reaches the terminal ileum of

the large intestine, the glucuronides are removed by
specific bacterial enzymes (β-glucuronidases), and is
reduced by intestinal bacteria to a group of colorless
compounds called urobilinogens.

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• About half of the urobilinogens is reabsorbed and
taken to the liver to constitute the
enterohepatic urobilinogen cycle. It then enters
circulation and is excreted as urobilin (yellow
pigment in urine) by the kidneys.

• The remaining urobilinogens formed in the colon are

reduced to brown stercobilin and excreted in the
feces.

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Hyperbilirubinemia causes Jaundice

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• Hyperbilirubinemia: bilirubin in the blood exceeding
1 mg/dL (17.1 µmol/L).

• May be due to the production of more bilirubin than

the normal liver can excrete, or

• May result from damaged liver’s inability to excrete

bilirubin produced in normal amounts.

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• Hyperbilirubinemia may be classified as:

- Retention Hyperbilirubinemia - due to

overproduction, or

- Regurgitation Hyperbilirubinemia - due to efflux

into the bloodstream because of biliary
obstruction.

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• In the absence of hepatic damage, obstruction of
the excretory ducts of the liver—by preventing
the excretion of bilirubin—will also cause
hyperbilirubinemia.

• In all these situations, bilirubin accumulates in the

blood, and when it reaches approximately 2–2.5
mg/dL, it diffuses into the tissues, which then
become yellow. The condition is called jaundice or
icterus.

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END
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