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HEMOGLOBIN SYNTHESIS
1.
2. HAEME SYNTHESIS ANDHAEME SYNTHESIS AND
CATABOLISMCATABOLISM
BYBY
DR MUHAMMAD MUSTANSARDR MUHAMMAD MUSTANSAR
3. Majority of amino acids used for de novo
protein synthesis (80%) derives from the
degradation of existing proteins
Only 30 g (6%) used for synthesis of specialized
products
Amino Acid Pools are in Steady State
4. Only 70 g (14%) of total amino acid utilization
is used for energy or stored as glycogen/fatty
acids in the well-fed state (nitrogen balance)
5.
6. • Heme is the most important porphyrin
containing compound.
• Heme is a derivative of the porphyrin.
• Porphyrins are cyclic compounds formed by
fusion of 4 pyrrole rings linked by methenyl
(=CH-) bridges.
HEME SYNTHESIS
19. • Metal ions can bind with nitrogen atoms of
pyrrole rings to form complexes.
• Since an atom of iron is present, heme is a
ferroprotoporphyrin.
• The pyrrole rings are named as l, ll, lll, lV and
the bridges as alpha, beta, gamma and delta.
22. Heme structure
Heme is a metaloporphyrine
(cyclic tetrapyrrole)
•Heme contains:
conjugated system of double
bonds → red colour
4 nitrogen (N) atoms
1 iron cation (Fe2+
)
→ bound in the middle of
tetrapyrrole skelet by
coordination covalent
bonds
methine bridge pyrrole
ring
23. • Hb is a spherical molecule consisting of 4
peptide subunits (globins) = quartenary
structure
• Hb of adults (Hb A) is a tetramer consisting of
2 - and 2 β-globins → each globin contains
1 heme group with a central Fe2+
ion (ferrous
ion)
Structure of hemoglobin
28. Biosynthesis of Heme
• Heme can be synthesised by almost all the
tissues in the body.
• Heme is primarily synthesised in the liver and
the erythrocyte-producing cells of bone marrow
(erythroid cells).
• Heme is synthesised in the normoblasts, but not
in the matured ones.
29. • The pathway is partly cytoplasmic and partly
mitochondrial.
Step 1: ALA synthesis
• The synthesis starts with the condensation of
succinyl CoA and glycine in the presence of
pyridoxal phosphate to form delta amino
levulinic acid (ALA).
30. • The enzyme ALA synthase is located in the
mitochondria and is the rate-limiting enzyme
of the pathway.
31.
32. Iron atom is co-ordinately linked with 5 nitrogen
atoms (4 nitrogen of pyrrole rings of
protoporphyrin and 1st
nitrogen atom of a histidine
residue of globin).
34. STRUCTURE OF HEME
Ferrous iron (Fe2+)
Protoporphyrin IX:
contains 4 pyrrole
rings linked
together by
methenyl bridges
35.
36. Heme is the prosthetic group of hemoglobin,
myoglobin, & cytochromes. Heme is an
asymmetric molecule. E.g., note the positions
of methyl side chains around the ring system.
38. •The liver is the main non-RBC source of heme
synthesis
•Heme produced in the liver is used mainly for the
synthesis of the cytochrome P450 class of enzymes that
are involved in detoxification
Regulated at level of ALA synthase: Formation of 5-
ALA is the rate-limiting step in heme synthesis in the
liver
HEME SYNTHESIS: Liver
39. HEME SYNTHESIS: Red blood cells
•85% of total heme synthesis occurs in red blood
cells (RBC)
•Ceases when RBC’s mature
•Heme stimulates protein synthesis in reticulocytes
Synthesis is regulated at the level of the enzymes
ferrochelatase* and porphobilinogen deaminase**
41. The heme ring system is synthesized from glycine &
succinyl-CoA.
Using isotopic tracers, it was initially found that N & C
atoms of heme are derived from glycine and acetate.
It was later determined that the labeled acetate enters
Krebs Cycle as acetyl-CoA, and the labeled carbon
becomes incorporated into succinyl-CoA, the more
immediate precursor of heme.
42. Heme synthesis begins with condensation of glycine &
succinyl-CoA, with decarboxylation, to form d-
aminolevulinic acid (ALA).
43. Pyridoxal phosphate (PLP) serves as coenzyme
for d-Aminolevulinate Synthase (ALA
Synthase), an enzyme evolutionarily related to
transaminases.
44. Condensation with succinyl-CoA takes place
while the amino group of glycine is in Schiff
base linkage to the PLP aldehyde.
CoA & the glycine carboxyl are lost
following the condensation.
45.
46. Uroporphyrinogen I Coproporphyrinogen I
Overview of Heme SynthesisOverview of Heme Synthesis
Succinyl CoA + Glycine
δ-aminolevulinic acid
δ-aminolevulinic acid
Porphobilinogen Uroporphyrinogen III Coproporphyrinogen III
Coproporphyrinogen III
Protoporphyrinogen IX
Protoporphyrin IX
Heme
ALA synthase
cytoplasmmitochondrial matrix
47. Heme synthesis occurs in all cells due to the
requirement for heme as a prosthetic group on
enzymes and electron transport chain. By
weight, the major locations of heme synthesis
are the liver and the erythroid progenitor cells
of the bone marrow.
48.
49. 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.
50. A variant of ALA Synthase expressed only in
developing erythrocytes is regulated instead by
availability of iron in the form of iron-sulfur
clusters.
51. • Acquired: Lead poisoning
• Congenital: Porphyrias
• Deficiency of heme has far-reaching effects
(hemoglobin, cytochromes, etc.)
Disorders of Heme Synthesis
52. • A group of rare disorders caused by deficiencies
of enzymes of the heme biosynthetic pathway
•The majority of the porphyrias are inherited in a
autosomal dominant fashion - thus, affected
individuals have 50% normal levels of the
enzymes, and can still synthesize some heme
PORPHYRIAS
53. • Affected individuals have an accumulation of
heme precursors (porphyrins), which are toxic
at high concentrations
54. • Attacks of the disease are triggered by certain
drugs, chemicals, and foods, and also by
exposure to sun
• Treatment involves administration of hemin,
which provides negative feedback for the
heme biosynthetic pathway, and therefore,
prevents accumulation of heme precursors
55.
56. • Caused by hereditary or acquired defects in heme
synthesis
• - Accumulation and increased excretion of metabolic
• precursors (each unique)
• - Most porphyrias show a prevalent autosomal
dominant pattern, except congenital eythropoietic
porphyria, which is recessive
Porphyrias
57. • Can be hepatic or erythropoietic, reflecting the
two major locations of heme synthesis
• - hepatic can be acute or chronic
58. • Those with tetrapyrrole intermediates show
photosensitivity due to extended conjugated
double bonds
• - Formation of superoxide radicals
• - Skin blisters, itches (pruritis)
• - Skin may darken, grow hair (hypertrichosis)
59. Lead poisoning
- inhibition of ferrochelatase and ALA
dehydratase
- displaces Zn+2 at enzyme active site
Acquired Porphyrias
60. Children
• - developmental defects
• - drop in IQ
• - hyperactivity
• - insomnia
• - many other health problems
61. Adults
• - severe abdominal pain
• - mental confusion
• - many other symptoms
63. Urine from a patient with porphyria cutanea tarda (right)
and from a patient with normal porphyrin excretion (left).
64. Most heme from RBCs (85%) - rest from
turnover of cytochromes, p450s, immature
erythrocytes.
RBCs last 120 days, degraded by
reticuloendothelial (RE) system [liver and
spleen].
65. Microsomal heme oxygenase hydroxylates
methenyl bridge carbon and oxidizes Fe2+ to
Fe3+. Second reaction open ring and release
methenyl carbon as CO.
The resulting biliverdin is poorly soluble due to
ring stacking and aggregation.
Serum albumin carries bilirubin in circulation,
ligandin in hepatocytes.
75. Types of Jaundice
Hemolytic jaundice
- Liver can handle 3000 mg bilirubin/day - normal is 300
- Massive hemolysis causes more than can be processed
- cannot be conjugated
- increased bilirubin excreted into bile, urobilinogen
is increased in blood, urine
- unconjugated bilirubin in blood increases = jaundice
76. Obstructive jaundice
- Obstruction of the bile duct
- tumor or bile stones
- gastrointestinal pain - nausea
- pale, clay-colored stools
- can lead to liver damage and increased
unconjugated bilirubin
77. Hepatocellular jaundice
- Liver damage (cirrhosis or hepatitis) cause
increased
bilirubin levels in blood due to decreased
conjugation
- Conjugated bilirubin not efficiently exported to
bile
so diffuses into blood
78. - Decreased urobilinogen in enterohepatic
circulation so urine is darker and stool is pale,
clay-colored
- AST and ALT levels are elevated due to
hepatic damage
- Nausea and anorexia
79. Jaundice in Newborns
Premature babies often accumulate bilirubin due to
late onset of expression of bilirubin
glucuronyltransferase
- Maximum expression (adult level) at ~ 4 weeks
- Excess bilirubin can cause toxic encephalopathy
(kernicterus)
80. - Treated with blue fluorescent light
- converts bilirubin to more polar compound
- can be excreted in bile without conjugation
- Crigler-Najjar syndrome is deficiency in
bilirubin
glucuronyltransferase
