Haem metabolism

1. HAEM(HEME) METABOLISM
LEVEL 200
OHENEBA HAGAN

2. Objectives
• Haem synthesis
• Regulation of haem synthesis
• Catabolism of haem
• Regulation of haem catabolism
• Clinical importance of haem metabolism

3. Haem
Porphyrin+Fe
Some important human
haemoproteins are;
haemoglobin, myoglodin,cytochromes,
catalase, tryptophan pyrrolase
In plants Porphyrin+Zinc- photosynthetic
pigment chlorophyll
N
N
N
N
CH3 HC
CH3
S CH2
CH3
CH S CH2
CH3
CH2
CH2
COO-
CH3
H3C
CH2CH2
-
OOC
protein
protein
Fe

4. Haem Synthesis
Takes place in the bone marrow and liver
Starts with condensation of glycine and
succinyl CoA in the mitochondria
Condensation reaction is catalysed by a-
aminolevulinate synthase (ALA synthase)
In the liver its ALA synthase I and in the
bone marrow its ALA synthase II.
Co-factor needed for this reaction is
pyridoxal phosphate
This reaction is the rate limiting step of
haem synthesis

OOC CH2 CH2 C S-CoA
O
+ 
OOC CH2 NH3
+

OOC CH2 CH2 C
O
CH2 NH3
+
CO2CoA-SH
H+succinyl-CoA glycine
-aminolevulinate (ALA)
-Aminolevulinic
AcidSynthase

5. Haemsynthesis
(cont.)

6. ① It is regulated by repression mechanism. Heme
inhibits the synthesis of ALA synthesis by acting as a
corepressor. The feedback regulatory effect is a typical
example of end-product inhibition.
1. ALA synthase
Major site of regulation is at the level of ALA synthase.
Regulation of heme synthesis

7. ② ALA synthase is also allosterically inhibited by
haematin.
When there is excess of free heme without globin
chains to bind with, the Fe++ is oxidized to Fe+++ forming
hematin. Haematin will inhibit ALA synthase to prevent
excessive unwanted production of haem.
Haematin will also inhibit the translocation of ALA synthase
from the cytoplasm into the mitochondria where its substrate,
succinyl CoA is formed. thus heme synthesis is inhibited till
there are sufficient globin chains to bind with.

8. ③ Lack of Vit B6 will decrease the synthesis of ALA.
Drugs like INH (isonicotinic acid hydrazide) that decrease
the availability of pyridoxal phosphate may also affect
heme synthesis.
4. Drugs that induce cytochrome P450 eg barbiturates
griseofulvin induce ALAS 1 synthesis. In patients with
porphyria these drugs can precipitate attacks

9. 2. Haem synthesis may be inhibited by heavy metals.
the steps catalyzed by ALA dehydratase and
ferrochelatase are inhibited by lead.
3. erythropoietin, EPO
The kidneys also secrete a hormone called erythropoietin.
The function of erythropoietin is to stimulate the production
of red blood cells. The kidney produces 85~95% of the body's
erythropoietin so when the kidney is damaged (kidney disease or
failure), not enough erythropoietin is produced to maintain
normal red blood cell levels. This leads to anemia.

10. Clinical Correlates
(Porphyria)
• Rare genetic diseases in which
activity of one of the enzymes
involved in heme synthesis is
decreased (e.g., PBG Synthase,
Porphobilinogen Deaminase,
etc…)
• Usually inherited in autosomal
dominant except congenital
erythropoeitic porphyria
• Symptoms depend on enzyme
affected, organ involved
• Symptoms are usually acute or
cutaneous
• Acute symptoms usually involves
enzymes before
uroporphobilinogen
(accumulation of ALA, PBG).
Includes abdominal pains and
neuropsychiatric symptoms
• Cutaneous symptoms results
from enzyme deficiencies from
uroporphobilinogen. Substrates
accumulate in skin leading to
oxidized products.
Photosensitvity –skin damage

12. Diagnosis and Treatment

13. • From family pedigree
• History of abdominal
pain+neuropsychiatric symptoms
• Photosensitive skin rashes
• Urine which changes colour on
exposure to sunlight (red)
• medical support for vomiting and
pain
• hemin, decreases ALA synthase
synthesis
• Consumption of large amounts of
carbohydrates
• avoidance of sunlight and
precipitating drugs, factors
• Avoid drugs that induce
cytochrome P450 eg barbiturates

14. Haem catabolism
Cytochrome has high turnover rate
Red blood cells have life span of 60-120 days
When haemoproteins are destroyed they yield haem
70% of haem from red blood cells
Haem is eventually converted to bilirubin for excretion

15. Extravascular Pathway for RBC Destruction
(Liver, Bone marrow,
& Spleen)
Haemoglobin
Globin
Amino acids
Amino acid pool
Haem Bilirubin
Fe2+
Excreted
Phagocytosis & Lysis

16. Haem degradation
• Takes place in the ER of
reticuloendothelial system of
spleen,liver,bone marrow
• CO monoxide produced is exhaled
(can be used to quantify haem
turnover rate)
• In birds and amphibians the green
biliverdin is excreted
• Bilirubin is sparingly soluble and must
be transported bound to albumin
• Bilirubin is transported to the liver for
elimination

17. • Bilirubin is taken up in the
liver by carrier-mediate
transport into parenchymal
cells
• In the cells bilirubin binds to
Ligandin and protein Y
• Conjugation of bilirubin to
make it polar is achieved by
addition of mainly
glucuronide. Others include
xylose, sulfate and ribose
• Conjugation with
glucuronide is catalysed by
glucuronyltransferase
(glucuronyl-UDP)
• Two glucuronic acid is
conjugated to bilirubin
(bilirubin diglucuronide)
• Conjugated bilirubin is
secreted into the bile by an
active transport mediated
by multidrug resistance like
protein 2 (MRP-2)

18. • Bile gets secreted into the intestine
• At the terminal ileumand large intestine
bacterial glucuronidases remove the
glucuronides to form
• The free bilirubin is reduced in the intestine
to the colourless urobilinogen
• Urobilinogen/stercobilinogen is oxidized to
the coloured urobilin/stercobilin (excreted in
feaces- imparts red brown colour to stool)
• Some of the urobilinogen is taken up by the
blood back to the liver to be re-excreted back
into the bile (enterohepatic urobilinogen
cycle)
• Urobilinogen excreted by the liver. Oxidized
to urobilin (gives urine its unique straw
colour

19. Hyperbilirubinaemia
• Increases levels of
bilirubin (conjugated or
unconjugated)
• Could be due to increased
bilirubin production or
decreased bilirubin
secretion
• Classified as pre hepatic,
intra-hepatic and post
hepatic

20. Neonatal Jaundice
• Common, particularly in premature infants
• Transient (resolves in the first 10 days)
• Due to immaturity of the enzymes involved in bilirubin conjugation
• High levels of unconjugated bilirubin are toxic to the newborn – due to its
hydrophobicity it can cross the blood-brain barrier and cause a type of mental
retardation known as kernicterus
• If bilirubin levels are judged to be too high, then phototherapy with UV light is used to
convert it to a water soluble, non-toxic form
• If necessary, exchange blood transfusion is used to remove excess bilirubin
• Phenobarbital is oftentimes administered to Mom prior to an induced labor of a
premature infant – crosses the placenta and induces the synthesis of UDP glucuronyl
transferase
• Jaundice within the first 24 hrs of life or which takes longer then 10 days to resolve is
usually pathological and needs to be further investigated