2. ObjectivesObjectives
• Understand the structure of HemeUnderstand the structure of Heme
• Identify the rate limiting stepIdentify the rate limiting step
• Describe the site of effect of certain drugs on hemeDescribe the site of effect of certain drugs on heme
biosynthesis and its clinical importancebiosynthesis and its clinical importance
• Identify how blocking in one of the enzyme involved inIdentify how blocking in one of the enzyme involved in
heme biosynthesis will affect the mode of presentation ofheme biosynthesis will affect the mode of presentation of
the diseasethe disease
• Identify the most common type of porphyrias & its causeIdentify the most common type of porphyrias & its cause
4. Objectives
By the end of this lecture the student should
be able to:
Understand the porphyrias
Describe the site of effect of certain drugs on heme
biosynthesis and its clinical importance
Identify how blocking in one of the enzyme involved in
heme biosynthesis will affect the mode of presentation
of the disease.
Identify the most common type of porphyrias & its
cause
6. Structure of heme prosthetic group
Protoporphyrin ring w/ iron =Protoporphyrin ring w/ iron =
hemeheme
Four Pyrrole groups [A to D]Four Pyrrole groups [A to D]
linked by methane bridgeslinked by methane bridges
FeFe+2+2
coordinated by prophyrin Ncoordinated by prophyrin N
atoms and a N from Histidineatoms and a N from Histidine
(blue)(blue)
A molecule of OA molecule of O22 acts as 6acts as 6thth
ligandligand
7. 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
8. Properties of iron in heme
• Coordination number of
iron in heme = 6
6 bonds:
• 4x pyrrole ring (A,B,C,D)
• 1x link to a protein
• 1x link to an oxygen
9. Heme biosynthesis - repetition
• in bone marrow (85% of Hb) and liver (cytochromes)
• cell location: mitochondria / cytoplasm / mitochondria
• substrates: succinyl-CoA + glycine
• important intermediates:
δ-aminolevulinic acid (= 5-aminolevulinic acid, ALA)
porphobilinogen (PBG = pyrrole derivate)
uroporphyrinogen III (= porphyrinogen – heme
precursor)
protoporphyrin IX (= direct heme precursor)
● key regulatory enzyme: ALA synthase
10. Regulation of heme biosynthesis
ALA synthase is a key regulatory enzyme
● it is an allosteric enzyme that is inhibited by an end product - heme
(feedback inhibition)
● requires pyridoxal phosphate as a coenzyme
● certain drugs and steroid hormones can increase heme synthesis
Porphobilinogen synthase is inhibited by lead ions Pb2+
in case of lead
poisoning.
Ferrochelatase (heme synthase) can be also inhibited by Pb2+
. Its
activity is influenced by availability of Fe2+
and ascorbic acid.
11. Porphyrias - disturbances of heme synthesis
• are hereditary or acquired disturbances of heme
synthesis
• in all cases there is an identifiable abnormality of
the enzymes which synthesize heme
• this leads to accumulation of intermediates of the
pathway and a deficiency of heme → excretion of
heme precursors in feces or urine, giving them a dark
red color
● accumulation of porphyrinogens in the skin can lead to
photosensitivity
• the neurological symptoms
12. Disorders of Heme Synthesis
Acquired: Lead poisoning
Congenital: Porphyrias
13. LEAD TOXICITY Mechanism
• Binds to any compound with a sulfhydryl group
• Inhibits multiple enzyme reactions including
those involved in heme biosynthesis (ALA
synthase & ferrochelatase)
• One symptom of lead toxicity is increases in 5-
ALA without concomitant increases in PBG
14.
15. Porphyria Cutanea TardaPorphyria Cutanea Tarda
Chronic hepatic porphyria
The most common type of porphyria
a deficiency in uroporphyrinogen decarboxylaseuroporphyrinogen decarboxylase
Clinical expression of the enzyme deficiency is influenced by
various factors, such as exposure to sunlight, the presence of
hepatitis B or C
Clinical onset is during the fourth or fifth decade of life.
Porphyrin accumulation leads to cutaneous symptomscutaneous symptoms and urineurine
that is red to brown in natural light and pink to red in fluorescent
light
17. Symptoms of Cutaneous Forms
Occur most commonly with
exposure to sunlight
Mainly skin symptoms that occur
Due to excess poryphorins that
accumulate in surface of skin
Symptoms:
Fluid filled blisters
Changes in pigmentation
Breakdown (necrosis) of the skin
when exposed to sunlight
Overall skin can become scarred,
brown, blotchy and fragile
18. Treatment for Cutaneous Forms
Avoiding sunlight
Attention to skin care
Beta-carotene
supplements
Function to neutralize the
effects of reactive
protoporphyrins
19. Acute Hepatic PorphyriasAcute Hepatic Porphyrias
e.g. Acute Intermittent Porphyria
Porphyrias leading to accumulation of ALA and
porphobilinogen cause abdominal pain and
neuropsychiatric disturbances, ranging from anxiety to
delirium.
Symptoms of the acute hepatic porphyrias are often
precipitated by administration of drugs such as barbiturates
and ethanol.
20. Porphyrias
(A) Acute intermittent Porphyria:
An acute disease caused by a deficiency in
hydroxymethylbilane synthase.
Porphobilinogen and δ-aminolevulinic acid
accumulate in the urine.
Urine darkens on expoure to light and air.
Patients are not photosenstive
21. Porphyrias :
Acute hepatic Porphyrias
(2) Hereditary coproPorphyria:
An acute disease caused by a deficiency in
coproPorphyrinogen oxidase
CoproPorphyrinogen lll and other
intermediates prior to the block
accumulate in the urine.
Patients are photosenstive.
22. Porphyrias :
Acute hepatic Porphyrias
(3) Varigate Porphyria:
An acute disease caused by a deficiency in
protoporphyrinogen oxidase .
ProtoPorphyrinogen lX and other
intermediates prior to the block
accumulate in the urine.
Patients are photo-senstive.
24. (1) Erythropoietic Porphyrias:
The disease caused by a deficiency in
ferrochelates.
ProtoPorphyrin accumulate in the
erythrocytes, bone marrow and plasma
Patients are photosenstive.
25. (2) Congenital erythropoietic Porphyrias:
The disease caused by a deficiency in
uroporphyrinogen lll synthase.
Uroporphyrinogen l & coproPorphyrinogen l
accumulate in urine
Patients are photosenstive.
28. ALA Synthetase
Most important rate
limiting enzyme
Deficiency may cause
Sideroblastic
anemia
Bone marrow
produces ringed
sideroblast?
Respond to pyridoxine
treatment
32. Acute intermittent porphyria (AIP)
2nd
most common form of porphyria
Caused by deficiency of PGB deaminase
Metabolite porphobilinogen accumulates in cytoplasm
raised concentration of urinary porphyrins
Porphobilinogen (PGB)
PGB deaminase
Hydroxymethylbilane
34. Congenital erythropoietic porphyria (CEP)
Deficiency of Uroporphyrinogen III synthase
Severe photosensitivity
Hydroxymethylbilane Uroporphyrinogen III
Uroporphyrinogen III synthase
36. Porphyria cutanae tarda (PCT)
Most common porphyria
Classified as such when Uroporphyrinogen
decarboxylase activity <20%
Inherited or obtained through Hepatitis C, alcohol,
Uroporphyrinogen III
Uroporphyrinogen
decarboxylase
Coproporphyrinogen
III
Explain what happens with accumulation of porphobilogen
Porphyria cutanae tarda (PCT) is the most common porphyria. It is classified as a hepatic disorder and occurs when a deficiency in Uroporphyrinogen decarboxylase (enzyme) ‘s activity is reduced to less than 20%.
PCT can be inherited or acquired from other means such as hepatitis C, drug or alcohol use, or poisons such as halogenated hydrocarbons.
It can be diagnosed through recognition of symptoms or through testing of urine for porphyrins or heme precursors (like in this case, uroporphyrinogen)
the high amount of iron in the blood is a characteristic in PCT patients (iron overload); caused by a disturbance of iron metabolism.
hepcidin; hormone that regulates iron metabolism; inhibits iron absorption, iron release from storage and iron recycling by erythrocytes. Reactive oxygen species decrease hepcidin expression lack of regulation of iron levels accumulation of iron
Treatment for this disease can be through several methods;
low dose of antimalarials to remove excess porphyrins from liver by increasing the excretion rate. This can less buildup of heme precursors toxic side effects
low dose of chloroquine (is chloroquine an antimalarial?)
phlebotomy (withdrawal of blood to reduce iron concentration) can alleviate symptoms
try to avoid causes of PCT,consumption of alcohol or use of drugs or exposure of poisons
Extra porphyria info
PCT, the most common porphyria,hepatic disorder
Uroporphyrinogen decarboxylase activity &lt;20%
Low dose chloroquine treatment
buildup of uroporphyrinogen in the urine, which can be helpful in the diagnosis of this disorder.
PGB level is normal…
can increase the demand for heme and the enzymes required to make heme. The combination of this increased demand and reduced activity of uroporphyrinogen decarboxylase disrupts heme production and allows byproducts of the process to accumulate in the body, triggering the signs and symptoms of porphyria cutanea tarda
Major role of iron in pathogenesis of PCT; reduction of hepatic iron through phlebotomyfull recovery from PCT.
Iron overload is common in PCT patients
Recently, uroporphomethene, an oxidized form of uroporphyrinogen, the substrate of URO-decarboxylase, was shown to be the enzyme inhibitor
Of note, the oxidation of uroporphyrinogen to the inhibitor is iron dependent in the liver, emphasizing the importance of iron overload as a causative factor and therapeutic target
Hepcidin; hormone that regulates iron homeostasis in humans. Prevents iron increase by inhibiting iron absorption, iron release from storage, and iron recycling by erythrocytes.
Increase in Reactive Oxygen species down decreases hepcidin expression.
People with PCT have high ferritin levels (biomarkert of iron stores and infflamation) increased hepcidinincreased iron stores (accumulation in tissue of iron)
patients diagnosed with PCT avoid alcohol consumption, iron supplements, excess exposure to sunlight (especially in the summer), as well as estrogen and chlorinated cyclic hydrocarbons, all of which can potentially exacerbate the disorder. Additionally, the management of excess iron (due to the commonality of hemochromatosis in PCT patients) can be achieved through phlebotomy, whereby blood is systematically drained from the patient. Low doses of antimalarials can be used. They remove excess porphyrins from the liver by increasing the excretion rate.
---------------------------
Inhibitor of the enzyme is the oxidized form of uroporphyrinogen ,uroporphomethene. The process of oxidation is dependent on iron in the liver.
Removal of the four carboxyl groups present in the cyclic uroporphyrinogen molecule
Purple discolorations: conjugated structure of porphyrins, alternating single and double bonds
Photosensitivity: