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![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](https://image.slidesharecdn.com/26porphyria-150903110923-lva1-app6892/85/26-porphyria-6-320.jpg)
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26 porphyria
The document discusses enzymes and porphyrias. It begins by defining enzymes as proteins with catalytic properties. It then provides objectives about understanding heme structure, identifying rate-limiting steps and effects of drugs in heme biosynthesis. The rest of the document details heme synthesis, the pathway of porphyrin synthesis, different types of porphyrias caused by deficiencies in specific enzymes in this pathway, and their associated symptoms. It highlights that porphyrias can be acquired from lead toxicity or inherited congenital disorders.
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26 porphyria
- 1. ENZYMES A protein withcatalytic properties due to its power of specific activation © 2007 Paul Billiet ODWS
- 2. ObjectivesObjectives • Understand thestructure 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
- 3. Abnormalities in synthesisheme (porphyrias)
- 4. Objectives By theend 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
- 5.
- 6. Structure of hemeprosthetic 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 isa 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 ironin 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 hemebiosynthesis 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 - disturbancesof 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 HemeSynthesis 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
- 15. Porphyria Cutanea TardaPorphyriaCutanea 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
- 16. (1) Porphyria cutaneatarda:
- 17. Symptoms of CutaneousForms 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 CutaneousForms Avoiding sunlight Attention to skin care Beta-carotene supplements Function to neutralize the effects of reactive protoporphyrins
- 19. Acute Hepatic PorphyriasAcuteHepatic 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 intermittentPorphyria: 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 hepaticPorphyrias (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 hepaticPorphyrias (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.
- 23.
- 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 erythropoieticPorphyrias: The disease caused by a deficiency in uroporphyrinogen lll synthase. Uroporphyrinogen l & coproPorphyrinogen l accumulate in urine Patients are photosenstive.
- 26.
- 27.
- 28. ALA Synthetase Most importantrate limiting enzyme Deficiency may cause Sideroblastic anemia Bone marrow produces ringed sideroblast? Respond to pyridoxine treatment
- 29.
- 30. ALA dehydratase deficiency Autosomal recessive Very rare Aminolevulinic Acid Porphobilinogen ALA dehydratase
- 31.
- 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
- 33.
- 34. Congenital erythropoietic porphyria(CEP) Deficiency of Uroporphyrinogen III synthase Severe photosensitivity Hydroxymethylbilane Uroporphyrinogen III Uroporphyrinogen III synthase
- 35.
- 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
- 37.
- 38. Hereditary coproporphyria: Deficiencyof Coproporphyrinogen III Oxidase Autosomal dominant No cure exists
- 39.
- 40. Variegate porphyria Deficiencyin protoporphyrinogen IX-oxidase Autosomal dominant
- 41.
- 42. Erthropoietic Protoporhyria Caused bydeficiency of Ferrochelatase Autosomal dominant Photosensitivity- can be managed by limiting exposure
- 44.
Editor's Notes
- #29 Error in metabolism
- #33 Explain what happens with accumulation of porphobilogen
- #37 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: