Download Hematology Biochemistry lec.6 Heme synthesis Heme synthesis isn

Hematology
Biochemistry lec.6
Heme synthesis
Heme synthesis isn’t as complicated as it seems, it’s synthesized from 2
simple compounds.
Heme synthesis goes side by side with the globin synthesis, this means that
for a certain amount of heme synthesized, a definite amount of globin is
simultaneously being formed, although they have completely different
biosynthetic machineries.
For heme to stay in its active biological form(the ferrous) ,it needs to bind
the hydrophobic part of the globin ,but in cases of excessive heme
production the globin won’t be enough to keep it in the ferrous state so it
converts to Ferric protoporphyrin or (hemin) that inhibits heme own
synthesis .globin formation also has a regulatory mechanism that we
studied before.
Remember:
 Tetrapyrole rings are connected by methenyl bridges designated
α,β,γ,δ.
 The substituent group in the tetrapyrole ring of heme is the Fe+2 .
 Porphyrin isomers differ in the side chains attached to the pyrrole
rings ,isomer 3 is the one present in heme and it’s also the most
common in nature ,other isomers do exist but aren’t really utilized .
 The side chains of the heme follow a rhythm of
(methyl…vinyl),(methyl…vinyl),(methyl…propionyl) for the 1st 3 rings
but (propionyle …methyl) for the last ring………this arrangement
belongs to isomer 3 .
 Isomer 1 side chains differ.actually it’s synthesized but not used.
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 Heme is not only present in Hb, Mb and cyt . there are enzymes that
are heme proteins like catalase ,tryptophan pyrolase,PG synthase
and others. So heme synthesis occurs in all cells but majorly in the
liver and bone marrow.
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Porphyrinogen
 Is the reduced form of porphyrin
 Not colored
 When oxidized ,it becomes the red colored porphyrin molecule.
Synthesis
Despite the complicated structure of the heme ,it’s made of 2 simple
precursors:
1.glycine: the smallest a.a
2.succinyl coA :a krebs cycle intermediate (mitochondrial)
These 2 precursors condense (8 molecules of each one per heme) by a
synthase that requires the cofactor pyridoxal phosphate ,and the
condensation product is an unstable intermediate that undergoes
decarboxylation to give an acidic molecule called levulinic acid (aka δaminolevulinic acid because the amino group is present on carbon δ and it’s
abbreviated as δALA)
The enzyme that catalyses this step is called δALA synthase:
 It has a short half life
 It’s under regulation in the liver .
 Inhibited by hemin, not only the catalytic site but also the rate of
synthesis (DNA level).so regulation occurs at 2 levels
 Catalysis
 Synthesis
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Cytochrome p450 superfamily contains many enzymes,all of them are
heme proteins ,they function in metabolism (ex. lipids),drug
detoxification and on other pathways. Upon exposure to drugs or
alcohol ingestion more cyt p450 is being synthesized,consequently more
demand on heme synthesis. Such factors are considered +ve effectors in
the heme synthesis pathway.
This 1st step occurs in the the mitochondria.
δALA leaves to the cytoplasm and there it condenses with another δALA
and then they are dehydrated by losing 2 H2O molecules,this 2nd step is
catalyzed by ALA dehydratase to produce the 1st pyrole ring .
The dehydratase enzyme is :
 In the cytosole.
 Multi subunit
 Has an essential sulfhydryl group in its catalytic site sensitive to
inhibition by heavy metals like lead.
 If inhibited by lead ,heme synthesis is defective
 Workers at factories are monitored for lead conc. In their blood.
The product of the dehydratase enzyme is a pyrole derivative called
porphobillinogen -containing acetate and propionate .
4 porphobillinogens join together head to tail by an enzyme called either:
1. porphobillinogen deaminase(removes amine groups) or
2. uroporphyrinogen 1 synthate
The joining product is a tetrapyrole that is linear (straight line) . Then it’s
acted upon by the enzyme uroporphyrinogen 3 cosynthase , responsible for
ring closure and isomerization, to form predominantly isomer 3
(uroporphyrinogen 3) and a tiny amount of isomer 1 (in some genetic
defects the pathway shifts to produce lots of isomer 1 instead).
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Notice the (acetate …propionate) rhythm in uroporphyrinogen 3 except for
the last ring where it’s (propionate …acetate).
uroporphyrinogen 3 loses 4CO2 molecules (one from each acetate that will
ultimately become methyl ) by a decarboxylase to produce
coproporphyrinogen 3.
coproporphyrinogen 3 returns to the mitochondria ,where it becomes
oxidized and it loses CO2 at 2 side chains to form vinyl out of propionate
and this compound is protoporphyrinogen.
Note that all the compounds ending with a (gen) nomenclature are in the
reduced form and colorless ,but when oxidized they retain their colors.
Actually there’s only one enzyme-catalyzed oxidation rxn , which is next
step……. the conversion of protoporphyrinogen to protoporphyrin.
The final step is the addition of Fe+2 to protoporphyrin by ferrochelatase
,this enzyme can also be inhibited by lead .
Note that :
1. δALA dehydratase (2nd step enzyme) and ferrochelatase (the 8th step
enzyme) can be inhibited by lead .
2. all steps occur in the cytoplasm except the 1st one ,and the last 2
(steps 7 and 8).
3. The difference between isomer 1 and isomer 3 formed after step 3
lies in the order of (propionate …acetate) chains on the 4th pyrole
ring of each one .
Please make sure you check fig 21.20 lippincot to understand the order
of the steps or fig 18.3 of the photographed chapters.
Heme (the final product) is hydrophobic although it contains 2 charged
propionates ,those prpionates are exposed on the surface of Hb.
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Porphyria
A widely heterogeneous disorder in which excessive production or
accumulation of any of the intermediates in the 8-step pathway of heme
synthesis might occur.
Most commonly ,porphyria is inherited ,but it can be acquired.
It results in increased excretion of porphyrin(tetrapyrole) or even its
precursors like ALA or PBG(porphobillinogen).
All are inherited as autosomal dominant except for erythropoietic
porphyria (as recessive).
Classified into:
Hepatic or Erythropoietic , and in very rare cases it can be both.
Whenever the defect is concerned with the tetrapyrole ring structure ,the
patient will be photosensitive,any step before its formation(steps 1,2,3) no
photosensitivity is obseved .
Fig 21.8 in lippincot is not required.
Most common cause of acquired porphyria is lead poisoning that affects
enzymes 2 (dehydratase) and 8 (ferrochelatase).as a consequence ALA and
protoporphyrine accumulate…………….low Hb anemia results.
The rest of the enzymes are mainly affected genetically ,esp. those from
step 3 to step 8.
Clinical signs and symptoms of porphyria:
1.acute abdominal pain
2.psychiatric disturbances
3.peripheral neuropathy
4.hepatic damage and photosensitivety
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Photosensitivity :
When the tetrapyrole ring is exposed to sun light it reacts with O2 to form
ROS which in their turn damage lysosomes. Damaged lysosomes release
their contents cause itching ,red lesions,and othe signs of photosensitivity.
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ALA and PBG accumulation inhibits an ATPase in nerves and thus causes
conduction paralysis ,abdominal pain and psychiatric disturbances.
Historically:
George the 3rd,king of England during the American revolution ,was mad
due to porphyria.
Erythropioetic porphyria arises from a deficiency in the enzyme
ferrochelatase and it’s the only recessive form.
Most common genetic porphyria is related to step 5,the conversion of
uroporphyrinogen to coproporphyrinogen .when defective , the alternative
isomer 1 production pathway predominates.
In prophyrias Heme is low , feedback regulation is retarded …..so excessive
production of intermediates result. Part of the management is heme
supplement which downregulates the excessive production.Avoiding
direct exposure to sun light is important. we should also give those patients
antioxidants.
Erythropoietic porphyria occur in deficiencies of :
1.step 4 enzyme
2. Step 8 enzyme
The rest are mostly hepatic porphyrias.
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Dania moamar
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