Metabolism of - PowerPoint Presentation

1. Metabolism of heme

2. Competency-B16.11Describe the functions of heme in the body and the process involved in heme and porphyrin metabolism

3. B16.11-SLO1. Enumerate the various heme proteins and their functions.2. Discuss the biosynthesis and catabolic pathways of heme and its regulation.3. Define porphyrin and classify porphyria.4. Discuss the disorders of heme metabolism.

4. hemeHeme is a derivative of the porphyrin. Porphyrins are cyclic compounds formed by fusion of 4 pyrrole rings linked by methenyl bridges.pyrrole rings

5. most common porphyrin in humans is heme - one ferrous goup in tetrapyrole ring Heme - prosthetic group of hemoglobin, myoglobin,cytochromes,catalase,peroxidase&Tryptophan Pyrrolase cyclic compounds that bind metals - usually iron - Fe+2 = ferrous

6. Heme- proteins(Metalloproteins)1.HaemoglobinIron porphyrin linked with globin. Tetramer,made up of four subunits. Quaternary structure of Protein.Reversibly combine with oxygen & transports oxygen.2.MyoglobinMonomer, Structure is similar to Hb.Present in muscles. Tertiary structure of Protein.Storage of oxygen.

7. Heme protein(Metalloproteins)3.CytochromesIron porphyrin conjugated to protein.Components of respiratory chain in mitochondria & transport electron.Cyto- P450 , takes part in microsomal hydroxylation.4.Catalase-Iron porphyrin containing enzyme,present in animals.-It acts on hydrogen peroxide.

8. Heme proteins(Metalloproteins)5. Peroxidase-Iron porphyrin containing enzyme.-Present mainly in plants.-It acts on hydrogen peroxide.6. Tryptophan PyrrolaseIron porphyrin containing enzyme.It acts on tryptophan.

9. Synthesis of heme - Substrates mainly include succinyl-CoA, glycine, Fe2+ . -Heme can be synthesized by almost all the tissues -Major sites of synthes is liver and bone marrow - cytochrome p450 in liver - hemoglobin in bone marrow - heme production equal to globin synthesis in bone - marrow. - variable in liver dependent on heme pool balance Ins

10. ALA Synthase is the committed step of the heme synthesis pathway, & is usually rate-limiting for the overall pathway.Regulation occurs through control of gene transcription. Heme functions as a feedback inhibitor, repressing transcription of the ALA Synthase gene in most cells.

11. Step 1In mitochondrion+HSCoA + CO2 ALA synthase（pyridoxal phosphate）① Heme synthesis begins with condensation of glycine & succinyl-CoA, with decarboxylation, to form d-aminolevulinic acid (ALA).

12. Pyridoxal phosphate (PLP) serves as coenzyme for d-Aminolevulinate Synthase (ALA Synthase).Condensation with succinyl-CoA takes place while the amino group of glycine is in Schiff base linkage to the PLP aldehyde.

13. ALA dehydratase2H2OporphobilinogenStep 2★ The succeeding few reactions occur in the cytoplasm.one ALA condenses with another molecule of ALA to form porphobilinogen(PBG).★ the condensation involves removal of 2 molecules of water and the enzyme is ALA dehydratase .

14. the enzyme contains zinc and is very sensitive to lead and other heavy metals. Inhibition of Porphobilinogen Synthase by Pb++ results in elevated blood ALA. High ALA is thought to cause some of the neurological effects of lead poisoning, although Pb++ also may directly affect the nervous system. ALA is toxic to the brain, perhaps due to: Similar ALA & neurotransmitter GABA (g-aminobutyric acid) structures. ALA autoxidation generates reactive oxygen species (oxygen radicals).

15. The porphyrin ring is formed by condensation of 4 molecules of porphobilinogen. Porphobilinogen Deaminase catalyzes successive PBG condensations, initiated in each case by elimination of the amino group. Porphobilinogen (PBG) is the first pathway intermediate that includes a pyrrole ring.

16. PBG units are added to the dipyrromethane until a linear hexapyrrole has been formed.

17. Uroporphyrinogen III Synthase converts the linear tetrapyrrole hydroxymethylbilane to the macrocyclic uroporphyrinogen III.

18. uroporphyrinogen III converted to coproporphyrinonogen III - transported back into mitochondria converted to protoporphyrinogen IX, then to protoporphyrin IX

19. Fe++ is added to protoporphyrin IX via Ferrocheletase. heme is formed by incorporation of iron (Fe+2) - partly spontaneous - ferrochelatase enhances rate - also inhibited by lead

20. URO COPROPROTO

21. Major sites of heme synthesis liver and bone marrow (erythroblasts). Matured red blood cells have no mitochondria, so can’t synthesize heme.3. The substrates mainly include succinyl-CoA, glycine, Fe2+ .3. First and last 3 reactions take place in mitochondria, others in cytoplasmSummary

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23. ① It is regulated by repression mechanism. Heme inhibits the synthesis of ALA synthesis by acting as a corepressor. The feedback regulatory effect is a typical example of end-product inhibition.1. ALA synthaseMajor site of regulation is at the level of ALA synthase. Regulation of heme synthesis

24. ② ALA synthase is also allosterically inhibited by hematin. When there is excss of free heme without globin chains to bind with, the Fe++ is oxidized to Fe+++ forming hematin. Hematin will inhibit ALA synthase to prevent excessive unwanted production of heme. Hematin will also inhibit the translocation of ALA synthase from the cytoplasm into the mitochondria where its substrate, succinyl CoA is formed. thus heme synthesis is inhibited till there are sufficient globin chains to bind with.

25. Lack of Vit B6 will decrease the synthesis of ALA. Drugs like INH (isonicotinic acid hydrazide) that decrease the availability of pyridoxal phosphate may also affect heme synthesis.

26. 2. Heme synthesis may be inhibited by heavy metals. the steps catalyzed by ALA dehydratase and ferrochelatase are inhibited by lead.3. Erythropoietin, EPO - Kidneys also secrete a hormone called erythropoietin. - Function of erythropoietin is to stimulate the production of RBC. The kidney produces 85~95% of the body's erythropoietin.During kidney disease or failure, not enough erythropoietin is produced to maintain normal red blood cell levels. This leads to anemia.

27. PorphyriaPorphyria is a name given to a group of metabolic disorders. These disorders cause the individual to accumulate "porphyrins" or "porphyrin precursors" in their body. which in turn causes an abundance of the porphyrins. In porphyria, the cells do not convert porphyrins to heme in a normal manner.

28. Porphyrias are genetic diseases in which activity of one of the enzymes involved in heme synthesis is decreased (e.g., PBG Synthase, Porphobilinogen Deaminase, etc…). Porphyrias Symptoms vary depending on ★ the enzyme ★ the severity of the deficiency ★ whether heme synthesis is affected primarily in liver or in developing erythrocytes.

29. Biochemical causes of major sign and symptoms of porphyria

30. 2. Photosensitivity is another common symptom. ◆formation of superoxide radicals. ◆ Skin damage may result from exposure to light. This is attributable to elevated levels of light-absorbing pathway intermediates and their degradation products.

31. 3. porphyrins build up in the body and are excreted in the urine and stool in excessive amounts. When present in very high levels, they cause the urine to have a port wine color.

32. Porphyriascaused by hereditary or acquired defects in heme synthesis — genetic diseases: the enzymes of heme synthesis — Liver dysfunction, lead posioningcan be grouped into erythropoietic porphyria and hepatic porphyria - hepatic can be acute or chronic

33. Occasional episodes of severe neurological symptoms ◆had acute bouts of abdominal pain and mental confusion Permanent nerve damage and even death can result, if not treated promptly. common symptom of Porphyrias

34. - -Acute Intermittent porphyria is a result of a deficiency of one of the enzymes(Uroporphyrinogen I synthase) in the heme biosynthesis pathway. -These deficiencies result in an accumulation of the precursors of porphyrins in the liver (delta-aminolevulinic acid, ALA and porphobilinogen, PBG).- variagate porphyria(Protoporphyrinogen oxidase) -Hereditary coproporphyria(Coproporphyrinogen oxidase), an accumulation of porphyrins resulting in cutaneous manifestations. Acute hepatic porphyrias.

35. -When an acute attack is confirmed, urgent treatment with an injection of human hemin .- Management includes the prevention of attacks (by avoiding causal factors) and the protection of skin from the light in cases of cutaneous manifestations

36. Porphyria cutanea tarda- a chronic porphyria- liver and erythroid tissues deficiencey in uroporphyrinogen decarboxylase- often no symptoms until 4th or 5th decadeclinical expression determined by many factors: - hepatic iron overload - exposure to sunlight - hepatitis B or C symptoms include: - cutaneous rashes, blisters - urine that is red to brown in natural light, or pink to red in UV light

37. Erythropoietic porphyrias- congenital erythropoietic porphyria (uroporphyrinogen III synthase)- erythropoietic protoporphyria (ferrochelatase)symptoms include: - skin rashes and blisters early in childhood - cholestatic liver cirrhosis and progressive liver failureTreatment for Porphyrias- Medical support for vomiting and pain- Hemin, decreases ALA synthase synthesis- Avoidance of sunlight and precipitating drugs, factors

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39. Acquired Porphyrias- Hexochlorobenzene used as a fungicide in Turkey in 1950s - thousands of children ate bread from treated wheat- they acquired porphyria cutanea tarda due to inhibition of uroporphyrinogen decarboxylase- due to hypertrichosis - referred to locally as the “monkey children”

40. Acquired Porphyriaslead poisoninginhibition of ferrochelatase, ALA dehydratase displaces Zn+2 at enzyme active sitechildren - developmental defects - drop in IQ - hyperactivity - insomnia - many other health problemsadults - severe abdominal pain - mental confusion - many other symptoms

41. FATE OF RED BLOOD CELLS Life span in blood stream is 60-120 days  RBCs are phagocytosed and/or lysedNormally, lysis occurs extravascularly in the reticuloendothelial system subsequent to RBC phagocytosis Lysis can also occur intravascularly (in blood stream)

42. Extravascular Pathway for RBC Destruction(Liver, Bone marrow, & Spleen)HemoglobinGlobinAmino acidsAmino acid poolHemeBilirubinFe2+ExcretedPhagocytosis & Lysis

43. NORMAL BILIRUBIN METABOLISM Uptake of bilirubin by the liver is mediated by a carrier protein (receptor) On the smooth ER, bilirubin is conjugated with glucoronic acid Glucoronic acid is the major conjugate - catalyzed by UDP glucuronyl tranferase“Conjugated” bilirubin is water soluble and is secreted by the hepatocytes into the biliary canaliculi Converted to stercobilinogen (urobilinogen) (colorless) by bacteria in the gut Oxidized to stercobilin which is colored Excreted in feces Some stercobilin may be re-adsorbed by the gut and re-excreted by either the liver or kidney

44. Prehepatic (hemolytic) jaundiceResults from excess production of bilirubin (beyond the livers ability to conjugate it) following hemolysisExcess RBC lysis is commonly the result of autoimmune disease; hemolytic disease of the newborn (Rh- or ABO- incompatibility); structurally abnormal RBCs (Sickle cell disease).High plasma concentrations of unconjugated bilirubin (normal concentration ~0.5 mg/dL)

45. Intrahepatic jaundiceImpaired uptake, conjugation, or secretion of bilirubinReflects a generalized liver (hepatocyte) dysfunction In this case, hyperbilirubinemia is usually accompanied by other abnormalities in biochemical markers of liver function

46. Posthepatic jaundiceCaused by an obstruction of the biliary treePlasma bilirubin is conjugated, and other biliary metabolites, such as bile acids accumulate in the plasma Characterized by pale colored stools (absence of fecal bilirubin or urobilin), and dark urine (increased conjugated bilirubin)In a complete obstruction, urobilin is absent from the urine

47. Neonatal Jaundice Common, particularly in premature infantsTransient (resolves in the first 10 days)Due to immaturity of the enzymes involved in bilirubin conjugationHigh levels of unconjugated bilirubin are toxic to the newborn – due to its hydrophobicity it can cross the blood-brain barrier and cause a type of mental retardation known as kernicterusIf bilirubin levels are judged to be too high, then phototherapy with UV light is used to convert it to a water soluble, non-toxic form

48. If necessary, exchange blood transfusion is used to remove excess bilirubinPhenobarbital is often administered to Mom prior to an induced labor of a premature infant – crosses the placenta and induces the synthesis of UDP glucuronyl transferaseJaundice within the first 24 hrs of life or which takes longer then 10 days to resolve is usually pathological and needs to be further investigated

49. Causes of Hyperbilirubinemia

50. Benign liver disorder ½ of the affected individuals inherited it  Characterized by mild, fluctuating increases in unconjugated bilirubin caused by decreased ability of the liver to conjugate bilirubinOnset of symptoms in teens, early 20’s or 30’s Can be treated with small doses of phenobarbital to stimulate UDP glucuronyl transferase activity Gilbert’s Syndrome

51. Autosomal recessive Extremely rare < 200 cases worldwide Characterized by a complete absence or marked reduction in bilirubin conjugation Present with a severe unconjugated hyperbilirubinemia that usually presents at birth Condition is fatal when the enzyme is completely absent Treated by phototherapy (10-12 hrs/day) and liver transplant by age 5Crigler-Najjar Syndrome

52.  Characterized by impaired biliary secretion of conjugated bilirubin Present with a conjugated hyperbilirubinemia that is usually mildDubin-Johnson and Rotor’s Syndromes