Is a hemoprotein (Conjugated protein)
Only found in the cytoplasm of erythrocytes (RBC)
Transports O2 & CO2 between lungs and various
Normal concentration of Hb in the blood:
Adult males 13.5 – 16.5 gm/dl
Adult females 12.0 – 14.8 gm/dl
Structure of hemoglobin
Hb is a spherical molecule consisting of 4 peptide subunits
(globins) = quartenary structure
Hb of adults (Hb A) is a tetramer consisting of 2 α & 2 β-
globins → each globin contains 1 heme group with a
central Fe2+ ion (ferrous ion)
Heme is a
1 iron cation (Fe2+)
Porphyrins are cyclic molecule.
4 pyrrole rings linked by methyenyl
8 side chains (2 on each pyrrol)
These side chains may be…
Methyl (M) or
Vinyl (V) groups
Different porphyrins vary in nature
of side chains.
Depending on substitute groups,
divided into I series & III series
I series (symmetrical arrangement) –
III series (asymmetrical
Properties of iron in heme
• nitrogen (N) atoms of 4 pyrrole
ring can form complex with
metals like Fe++ & Mg ++
• Number of Coordinate bonds
with iron in heme = 6
• 4x pyrrole ring (A,B,C,D)
• 1x link to a protein
• 1x link to an oxygen
In which compounds can we find a heme group?
• Hemoglobin (Hb)
• Myoglobin (Mb)
(decomposition of 2 H2O2
to 2 H2O and O2)
• Tryptophan pyrrolase.
In bone marrow (85% of Hb) & liver (cytochromes)
Cell location: mitochondria/cytoplasm
Substrates: succinyl-CoA + glycine
-aminolevulinic acid (5-aminolevulinic acid, ALA)
Porphobilinogen (PBG) (Pyrrole derivate)
Uroporphyrinogen III (porphyrinogen – heme
protoporphyrin IX (= direct heme precursor)
key regulatory enzyme: ALA synthase
δ-aminolevulinic acid (ALA)
• Synthesis of heme starts in mitochondria.
• Succinyl-CoA and Glycine undergo a condensation → ALA
• Reaction is catalyzed by enzyme ALA synthase
Succinyl CoA Glycine α-Amino-β- ketoadipate
ALA leaves the mitochondria → cytoplasm
2x ALA condense together to form
Reaction is catalyzed by porphobilinogen
synthase (ALA dehydratase)
4x porphobilinogen condense together to form
Reaction is catalyzed by 2 enzymes
Uroporphyrinogen synthase (PBG deaminase)
Uroporphyrinogen III cosynthase
Uroporphyrinogen synthase (PBG deaminase)
• Uroporphyrinogen III is converted in to
Coproporphyrinogen III by decarboxylation.
• 4 acetate residues are decarboxylated into methyl groups.
• This reaction takes place in cytosol.
• Coproporphyrinogen III returns to the mitochondria again
Uroporphyrinogen to Coproporphyrinogen III
• Coproporphyrinogen III is converted in to Protoporphyrinogen-III
by oxidative decaboxylation.
• 2 propionate residues are oxidative decarboxylated into vinyl groups.
• This reaction takes place in mitochondria.
Coproporphyrinogen-III to Protoporphyrinogen-III
• Oxidation of protoporphyrinogen-III produces protoporphyrin III
• Enzyme protoporphyrinogen oxidase catalyses this reaction.
Protoporphyrinogen III to Protoporphyrin III
Fe2+ is incorporated into protoporphyrin-III
Reaction is catalyzed by enzyme ferrochelatase/heme
F o r m a t i o n o f
ALA synthase is a key regulatory enzyme
it is an allosteric enzyme that is inhibited by an end product - heme
Regulation occurs at the level of enzyme synthesis.
Increased levels of heme represses the synthesis of enzyme ALA
The iron atom itself may regulate the heme synthesis.
Several substances induce the synthesis of hepatic
ALA synthase. e.g.. steroid hormones, ethanol, certain
drugs like barbiturates, etc.
Most of the drugs are metabolized in the liver by
cytochrome P450. so, maximum amount of heme is
utilized for the formation of cyto. P450, which in turn
diminishes the intracellular heme conc.
Regulation of Heme biosynthesis
Group of rare genetic disorders
Resulting from deficiency of enzymes in biosynthesis
This results in accumulation & increased excretion of
porphyrin precursors (ALA & PBG).
Porphyria directly affects
Nervous system and
but is possible to only affect one of the two.
This disease is often inherited from a parent, but
environmental factors may initiate the disease.
Autosomal dominant trait (with exception, i.e,
Arises from disruption of the production of heme.
Autosomal dominant pattern inherited form parent
These gene defects cause one or more of the
enzymes involved in the process of converting
porphyrins to heme to be abnormal.
In specific environments, your brain triggers for
your body to make more heme, overwhelming the
enzyme and triggering the disease.
Triggers include: Alcohol, smoking, drugs, and
Abdominal pain or cramping (only in some forms of the
Light sensitivity causing rashes, blistering, and
scarring of the skin (photodermatitis)
Problems with the nervous system and muscles
Muscle pain or muscle weakness or paralysis
Numbness or tingling
Arm or leg pain
Severe electrolyte imbalances