PORPHYRINS &

HEME METABOLISM
•HEME- a derivative of
porphyrin
Porphyrins
•cyclic compounds formed by linkage of 4 pyrrole
rings through methenyl bridges ( = C — )
•Can readily bind metals
•Since an atom of iron is present,HEME is a
FERROPROTOPORPHYRIN
Porphyrins
•Heme – hgb, myoglobin, cytochromes,
catalase, tryptophan pyrrolase
•characteristic: forms complexes with
metal ions thru the nitrogen atom in each
pyrrole ring
PROTEINS FUNCTIONS
Hemoglobin Transport of oxygen in blood
Myoglobin Storage of oxygen in muscle
Cytochrome C Involvement in ETC
Cytochrome P450 Hydroxylation of xenobiotics
Catalase Degradation of hydrogen
peroxide
Tryptophan pyrolase Oxidation of tryptophan
PORPHYRIN SIDE CHAINS
Methyl -- CH3

Vinyl -- CH2-CH3

Acetate -- CH2-COOH

Proprionate -- CH2-CH2-COOH
Kinds of Porphyrins and Their Side Chains
• Porphyrins are named and classified by the 2 side chains of each
constituent pyrrole
Porphyrin Side Chains

Uroporphyrin 4 acetate, 4 propionate

Coproporphyrin 4 methyl, 4 propionate

Protophorphyrin 4 methyl, 2 vinyl, 2 propionate

 A for acetate M for methyl
P for proprionate V for vinyl

Other examples of porphyrins

Addition of Iron to protoporhyrin IX produces heme
HEME SYNTHESIS
ALA synthase is the rate-limiting enzyme for
porphyrin biosynthesis
ALA synthase is the rate-limiting enzyme
• Synthesis of ALA synthase is repressed and
existing enzyme is inhibited by heme, the end
product of the pathway.

• This is a typical example of end-product or

feedback inhibition.
• Present in the MITOCHONDRIA
ALA Dehydratase
•2 molecules of ALA condense to form
porphobilinogen catalyzed by ALA dehydratase
•also known as porphobilinogen synthetase
•this enzyme is a sulfuhydryl zinc-requiring
enzyme very sensitive to inhibition by heavy
metals like lead (lead poisoning)
ALA dehydratase is found only
in the cytosol
Note:
The pyrrole are
connected by
methylene bridges
(-CH2-) hence their
initially in colorless
state, until they are
oxidized by light
transforming them
into colored
phorphyrins
Formation of Porphyrin
Condensation of 4 porphobilinogens in a linear
form called hydroxymethylbilane
• catalyzed by Urophorphyrinogen I synthase
• also called Porphobilinogen deaminase or
hydroxymethylbilane synthase
Note:
The pyrrole are
connected by
methylene bridges
(-CH2-) hence their
initially in colorless
state, until they are
oxidized by light
transforming them
into colored
phorphyrins
Formation of Porphyrin
Hydroxymethylbilane transformed to:
a. Type I urophorphyrinogen - by spontaneous
cyclization
OR
b. Type III urophorphyrinogen - by
urophorphyrinogen III synthase
DISORDERS OF HEME SYNTHESIS
•PORPHYRIAS – group of inborn errors
of metabolism of heme characterized
by increased production and excretion
of HEME
 DNA mutations

Abnormalities of Heme
synthesis ENZYMES

Accumulation of ALA and Accumulation of porphyrinogens in

PBG and/or decrease in skin and tissues
Heme in cells and body fluids

Spontaneous oxidation of
porphyrinogens and porphyrins
Neuropsychiatric signs and
symptoms/ Abdominal pain

Photosensitivity
PCT Porphyria Cutanea Tarda
• Defect: Uroporphyrinogen
decarboxylase
• Skin blistering
Variegate Porphyria
• Enzyme defect:
protoporphyrinogen oxidase
• Photosensitivity
• Urine is coloured
ACUTE INTERMITTENT PORPHYRIA
HEME DEGRADATION
Heme Catabolism
•Under normal conditions, humans have
approximately 200 Billion erythrocytes
destroyed in their bodies
•That’s about 6g of hemoglobin in a 70-kg
person daily!
•The end product of heme catabolism is
BILIRUBIN
Where do end-products go?
• The GLOBIN portion may be re-utilized to make
another hemoglobin or it may be degraded into
amino acids which are reused by the body
• The IRON portion enters the iron pool in the body
and is re-used also
• The porphyrin portion is also degraded in the
reticuloendothelial cells of the liver, spleen and bone
marrow
Heme Oxygenase
•catabolism of heme is carried out by a
complex microsomal enzyme system
called HEME OXYGENASE
•presence of HEME induces activity of this
enzyme
Heme Oxygenase
•it utilizes NADPH and O2 and cleaves the
methanol bridges between 2 pyrrole rings to
form biliverdin
•simultaneously, ferrous iron (Fe2+) is oxidized
to ferric iron (Fe3+) and is released from the
ring
 Heme Catabolism
Heme In the presence of NADPH and oxygen, heme
oxygenase adds a hydroxyl group to the α-
NADPH methenyl bridge between pyrroles I and
II.Ferrous iron is oxidized to ferric form.
heme oxygenase
O2 NADP
With the further addition of oxygen,
ferric iron is released, carbon monoxide
is produced, and biliverdin results from
Fe
3+ the splitting of the tetrapyrrole ring.
O CO
2
Biliverdin

NADPH

biliverdin reductase NADP

The central methenyl bridge between pyrroles III and IV of biliverdin is
reduced to a methylene group by biliverdin reductase, which converts
it to bilirubin.

Bilirubin
End-products
•biliverdin (green pigment)
•carbon monoxide (CO)
•ferric ion (Fe3+)
Fate of Biliverdin
•Biliverdin is excreted as is in amphibians
and birds
•We, and other mammals, further degrade
biliverdin into bilirubin (yellow pigment) by
the enzyme Bilirubin reductase
Bilirubin
• Because of its chemical structure, bilirubin
is liphophilic therefore insoluble in
aqueous solution
• So how is it transported from peripheral
tissues to the liver for further
degradation?
• by binding non-covalently to albumin
Significance
•Certain drugs (like sulfonamides and
salicylates) can displace bilirubin from
albumin, releasing bilirubin in the plasma
where it then can enter the CNS and
damage the neurons
Bilirubin Excretion into Bile
• Conjugated bilirubin is then secreted into the bile
canaliculi in the liver

• This transport is an active, energy-dependent and rate-

limiting process facilitated by the protein MRP-2
(multidrug-resistance-like protein-2), also called MOAT
(multispecific organic anion transporter) located in the
plasma membrane of the canaliculi

• This step is easily affected by any liver impairment

HEPATIC JAUNDICE (INTRA-HEPATIC JAUNDICE)
Gilbert’s Dubin-Johnson
Crigler-Najjar
Syndrome Syndrome
Syndrome

2 deficits:
Conjugation deficit •Conjugation deficit
Bilirubin excretion deficit
(Glucuronyl transferase) •Transport deficit

Could lead to severe • Unable to export bilirubin

unconjugated out of the liver
Conjugation deficit
hyperbilirubinemia • Retention of conjugated
bilirubin in the liver

Has two types:

• Crigler-Najjar Syndrome Blockage of bilirubin excretion to

Transport deficit
TYPE I the canaliculi
• Crigler-Najjar Syndrome
• TYPE II
 HEPATIC JAUNDICE (INTRA-HEPATIC JAUNDICE)

01
Crigler-Najjar •Total absence of glucuronyl transferase
Syndrome TYPE I: in the liver

•Kernicterus (bilirubin-induced brain

dysfunction)
•Partial absence of glucuronyl
transferase
Crigler-Najjar
Syndrome TYPE II: •Milder than type I since there is still
enzyme activity available
Crigler-Najjar syndrome
02 Gilbert’s syndrome

❑genetically inherited condition

❑Conjugation deficit
o problem in breaking down the
bilirubin at a normal rate
o Mild icterus
❑Transport deficit
o ligandin is deficient
03 Dubin-Johnson Syndrome

❑rare genetic syndrome

❑unable to move bilirubin out of the liver

o Retention of conjugated bilirubin in
the liver
o black colored liver
❑bilirubin excretion deficit
Dubin-Johnson Syndrome