ENZYMESA protein with catalytic properties due to its power of specific activation
© 2007 Paul Billiet ODWS
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 heme Describe 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 in Identify how blocking in one of the enzyme involved in
heme biosynthesis will affect the mode of presentation of heme biosynthesis will affect the mode of presentation of the diseasethe disease
• Identify the most common type of porphyrias & its cause Identify the most common type of porphyrias & its cause
Abnormalities in synthesis heme (porphyrias)
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
HEMOGLOBIN SYNTHESIS
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 coordinated by prophyrin N atoms and a N from Histidine N atoms and a N from Histidine (blue)(blue)
A molecule of OA molecule of O22 acts as 6 acts as 6thth ligandligand
Heme structureHeme 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
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
Heme biosynthesis - repetition• in bone marrow (85% of Hb) and liver (cytochromes)• cell location: mitochondria / cytoplasm / mitochondria• substrates: succinyl-CoA + glycine• important intermediates:
-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
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.
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
Disorders of Heme Synthesis
Acquired: Lead poisoning
Congenital: Porphyrias
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
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
(1) Porphyria cutanea tarda:
Symptoms of Cutaneous Forms Occur most commonly with
exposure to sunlight Mainly skin symptoms that occurDue to excess poryphorins that
accumulate in surface of skinSymptoms:
Fluid filled blisters Changes in pigmentation Breakdown (necrosis) of the skin when exposed to sunlight Overall skin can become scarred, brown, blotchy and fragile
Treatment for Cutaneous Forms
Avoiding sunlight Attention to skin care Beta-carotene
supplements Function to neutralize the
effects of reactive protoporphyrins
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.
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
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.
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.
Porphyrias Erythropoietic Porphyrias
(1) Erythropoietic Porphyrias: The disease caused by a deficiency in
ferrochelates.
ProtoPorphyrin accumulate in the erythrocytes, bone marrow and plasma
Patients are photosenstive.
(2) Congenital erythropoietic Porphyrias:
The disease caused by a deficiency in uroporphyrinogen lll synthase.
Uroporphyrinogen l & coproPorphyrinogen l accumulate in urine
Patients are photosenstive.
Overall Pathway
Overall pathway
ALA Synthetase Most important rate
limiting enzymeDeficiency may cause Sideroblastic anemia Bone marrow
produces ringed sideroblast?
Respond to pyridoxine treatment
Overall pathway
ALA dehydratase deficiency
Autosomal recessive Very rare
Aminolevulinic Acid
Porphobilinogen
ALA dehydratase
Overall pathway
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
Overall pathway
Congenital erythropoietic porphyria (CEP)
Deficiency of Uroporphyrinogen III synthase Severe photosensitivity
Hydroxymethylbilane Uroporphyrinogen III
Uroporphyrinogen III synthase
Overall pathway
Porphyria cutanae tarda (PCT)
Most common porphyriaClassified as such when Uroporphyrinogen
decarboxylase activity <20%Inherited or obtained through Hepatitis C, alcohol,
Uroporphyrinogen III
Uroporphyrinogen decarboxylase
Coproporphyrinogen III
Overall pathway
Hereditary coproporphyria:
Deficiency of Coproporphyrinogen III Oxidase Autosomal dominant No cure exists
Overall pathway
Variegate porphyria
Deficiency in protoporphyrinogen IX-oxidase Autosomal dominant
Overall pathway
Erthropoietic Protoporhyria
Caused by deficiency of FerrochelataseAutosomal dominant Photosensitivity- can be managed by limiting exposure
Thank You!
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