Haemoglobin Synthesis.pdf

Haemoglobin Synthesis

1. BY
DR EBOT WALTER OJONG
HEMOGLOBIN SYNTHESIS

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3. INTRODUCTION
Hemoglobinisanoxygen-bindingproteinfoundin
erythrocytesthattransportsoxygenfromthelungstotissues.
Eachhemoglobinmoleculeisatetramermadeoffour
polypeptideglobinchains.
Hemoglobin(averagemolecularweight64,000)consistsof
heme(ironandprotoporphyrin)andglobin(twopolypeptide
chains).
Haem&globinproducedattwodifferentsitesinthecells.
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4. INTRODUCTION
Theironmoleculeineachhememoietycanbind
andunbindoxygen,allowingforoxygentransport
inthebody.
Themostcommontypeofhemoglobinintheadult
isHbA,whichcomprisestwoalpha-globinandtwo
beta-globinsubunits.
Differentglobingenesencodeeachtypeofglobin
subunit.
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5. INTRODUCTION
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6. INTRODUCTION
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7. INTRODUCTION
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8. INTRODUCTION
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9. INTRODUCTION
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10. INTRODUCTION
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11. INTRODUCTION
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12. INTRODUCTION
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13. INTRODUCTION
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14. MECHANISM OF ACTION OF HAEMOGLOBIN BUFFER SYSTEM
(KHb/H Hband KHbO
2/HHbO
2)
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15. INTRODUCTION
Porphyrinsareaclassofwater-soluble,
nitrogenousbiologicalpigments(biochromes),
derivativesofwhichincludethehemoproteins.
Aclassofpigments(includinghaemand
chlorophyll)whosemoleculecontainaflatringof
fourlinkedheterocyclicgroups,withacentral
metalatom.
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16. STRUCTURE OF PORPHYRINS
Porphyrinsare cyclic compounds (complex cyclic
compounds).
Each porphyrinmolecule is made up of four
pyrrolerings.
Each pyrrolering is a five membered close
structure containing four carbon atoms and one
nitrogen.
The rings are linked by methylene (=HC-) bridge.
Porphyrinsare found in hemeand chlorophyll.
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17. STRUCTURE OF PORPHYRINS
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21. SYNTHESIS OF PORPHYRINS (SHEMIN CYCLE)
Shemincycle(alsocalledglycine-succinatecycle).
Aseriesofmetabolicstepsinwhichglycineis
condensedwithsuccinyl-CoAandisthenoxidised
toCO
2andH
2Owithregenerationofthesuccinyl–
coA;importantinthesynthesisofd-
aminolevulinicacidandinthemetabolismofred
bloodcells.
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22. SYNTHESIS OF PORPHYRINS (SHEMIN CYCLE)
Thecommittedstepforporphyrinbiosynthesisisthe
formationofδ-aminolevulinicacid(δ-ALA,5-ALAor
dALA)bythereactionoftheaminoacidglycinewith
succinyl-CoAfromthecitricacidcycle.
TwomoleculesofdALAarethencombinedby
porphobilinogensynthasetogiveporphobilinogen
(PBG),whichcontainsapyrrolering.
FourPBGsarethencombinedthroughdeamination
intohydroxymethylbilane(HMB),whichishydrolysed
toformthecirculartetrapyrroleuroporphyrinogenIII.
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23. SYNTHESIS OF PORPHYRINS (SHEMIN CYCLE)
Thismoleculeundergoesanumberoffurther
modifications.
Intermediatesareusedindifferentspeciesto
formparticularsubstances,but,inhumans,the
mainend-productprotoporphyrinIXiscombined
withirontoformheme.
Porphyriasariseasaresultofdeficiencyof
enzymesinthebiosyntheticpathway
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24. SYNTHESIS OF PORPHYRINS (SHEMIN CYCLE)
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26. SYNTHESIS OF
HEMOGLOBIN
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27. SYNTHESIS OF HEMOGLOIN
•Synthesisofhemoglobinactuallystartsinthe
proerythroblasticstage.
•However,hemoglobinappearsintheintermediate
noroblasticstage.
•Productionofhemoglobincontinuesuntilthe
stageofreticulocyte(65%aterythroblaststage
and35%atreticulocytestage).
•Thehemeportionofthehemoglobinissynthesized
inthemitochondriaandtheglobinpartis
synthesizedintheribosomes(cytosol).
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28. SYNTHESIS OF HEMOGLOIN
Thetwomaincomponentsofhemoglobin
synthesisareglobinproductionandheme
synthesis.
Globinchainproductionoccursinthecytosol
(polyribosomes)oferythrocytesandoccursby
genetictranscriptionandtranslation.
Manystudieshaveshownthatthepresenceof
hemeinducesglobingenetranscription.
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29. SYNTHESIS OF HEMOGLOIN
Genesforthealphachainareonchromosome16,
andgenesforthebetachainareonchromosome
11.
Hemesynthesisoccursinboththecytosolandthe
mitochondriaoferythrocytes.
ItbeginswithglycineandsuccinylcoenzymeAand
endswiththeproductionofaprotoporphyrinIX
ring.
ThebindingoftheprotoporphyrintoaFe
2+
ion
formsthefinalhememolecule.
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30. SYNTHESIS OF HEMOGLOIN
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31. SYNTHESIS OF HEMOGLOIN
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32. SYNTHESIS OF HEMOGLOIN
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33. HEME
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34. INTRODUCTION
Hemeisanironcontainingporphyrin
Hemeistheprostheticgroupofseveralproteinsandenzymeslike:
I.Hemoglobin:Importantforoxygentransport
II.Myoglobin:Actsasastorageofoxygeninthetissues
III.Cytochromes:Playsimportantroleintheelectrontransportchain
IV.CytochromeP450:Importantfordetoxificationofdrugsintheliver
V.Catalase:Antioxidantenzyme
VI.Peroxidase:Antioxidantenzyme
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35. STRUCTURE OF HEME
Hemeisformedfromfourpyroleringsjoined
togetherwiththehelpofmethenylbridges
Thepyroleringscanbenumberedinroman
numbersI,ii,iii,iv
Themethenylbridgescanbenumberedasalpha,
beta,gammaanddelta
TypeIIIporphyrinringsarecommonlyseenin
humnas
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36. STRUCTURE OF HEME
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38. SITE OF HEME SYNTHESIS
Ittakesplaceinallcells(except
matureRBCs).
Toamajorextenthemesynthesis
takesplaceintheliverandbone
marrow.
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39. MAIN PATHWAY OF HEME SYNTHESIS
Thefirststepinthesynthesisof
hemeoccursinthemitochodriaand
itistheratelimitingstep.
Thereiscondensationofglycinewith
succinyl-CoA(fromtheTCAcycle)
catalysedbyALAsynthase(rate
limitingenzyme).
DeficiencyofPLPleadstoanaemia.
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40. MAIN PATHWAY OF HEME SYNTHESIS
Thenextstepoccursinthecytosol.
ALAdehydrataseandferrochelatasearelead
sensitiveenzymes(inhibitedbylead).
Delta–ALAisdetectedintheurineofpatients
suspectedofhavingleadpoisoning.
Coproporphyronogen-IIIentersthemitochondrion
whereitisoxidativelydecarboxylatedto
protoporphyrinogen-IX.
Hemeinhibitsthefirststepofthispathwayby
feedbackinhibition.
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41. MAIN PATHWAY OF HEME SYNTHESIS
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42. REGULATION OF HEME SYNTHESIS
Hemesynthesisismainlyregulatedbytheratelimitingstep
enzyme,ALAsynthase.
Thisenzymeisallostericallyregulatedwiththehelpofheme
HemeinhibitsthetransportofALAsynthasefromthecytoplasm
intothemitochondrialmatrix
HemedecreasesthetranslationofALASynthase
ItrepressesALAsynthasegene
ALAsynthaseIenzymeinthehepatocytesisinducedbydrugslike
barbiturates,phenytoinetc.
AvailabilityofPLPisimportantforhemesynthesisasdeficiencywill
leadtomicrocytichypochromicanaemia
ALAsynthaseIactivityisincreasedduringfastingandstarvation
ALAsynthaseIIisregulatedentirelybytheavailabilityofiron
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43. REGULATION OF HEME SYNTHESIS
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44. REGULATION OF HEME SYNTHESIS
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45. REGULATION OF HEME SYNTHESIS
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46. REGULATION OF HEME SYNTHESIS
CarbohydratedietandinfusionofglucosereducesALAsynthase
activitybecauseitworksbyPPARalpha.
ALAsynthaseexistsintwoforms,typeIandtypeII.TypeIALA
synthaseispresentinallcellsofthebodybuttypeIIispresentin
erythroidprecursorcells.ThegeneforALAsynthaseIIisonX
chromosome
Erythroidcellscontribute85%ofhemesynthesis
Theother15%hemesynthesistakesplaceinothertissuesbut
chieflyintheliver.
Steroidsandbarbiturateswillleadtothestimulationof
cytochromeP450.Thiswillleadtostimulationofhemesynthesis.
Thecompartmentalisationofenzymesalsoplaysanimportantrole
intheregulationofhemebiosynthesis.
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47. REGULATION OF HEME SYNTHESIS
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48. SYNTHESIS OF GLOBIN
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49. SYNTHESIS OF GLOBIN
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Thealphaandbetaglobinchainsaremadeviatheprocessof
proteinsynthesis.Theinformationaboutthesepolypeptide
chainsispresentintheDNAoftheredbloodcells.
Thesynthesisoftheproteinpartofhemoglobininvolvestwo
steps;
Copyingoftheinformationpresentinthegeneintheformof
messengerRNA.ThemRNAcopiesofthegenearemadeby
RNApolymerase2inaprocesscalledtranscription.Oncethe
mRNAmoleculehasundergonepost-transcriptionalchanges,
itmovesoutofthenucleusintothecytoplasmofthecell.
Here,itisacteduponbytheproteinmanufacturing
machineryofthecell.

50. SYNTHESIS OF GLOBIN
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Thesecondstepinvolvestranslatingtheinformation
presentinthemRNAtothesequenceofaminoacidsin
thepolypeptidechains.ThecodonsonthemRNAare
readbythetRNAonthesurfaceoftheribosomesand
complementaryaminoacidsareaddedmakinga
polypeptidechain.Onceaterminationcodonisreached,
thepolypeptidechainisreleasedfromthetranslation
complex.
Thegenesforalpha-globinchainsarepresenton
chromosome16whilethoseforbeta-globinchainsare
presentonchromosome11.Therearetwoalphagenes
onchromosome16whileonlyonebetageneispresent
onchromosome11.

51. SYNTHESIS OF GLOBIN
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52. SYNTHESIS OF GLOBIN
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53. SYNTHESIS OF GLOBIN
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•Thealphaandbetachainsformedbytheabove
processundergofurtherstructuralmodifications.
•Normally,differenttypesofhemoglobinsare
presentduringembryoniclife,fetallife,infancy,
andadulthood.
•Globinsynthesis,startsat3rdweekofgestation

54. SYNTHESIS OF GLOBIN
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55. SYNTHESIS OF GLOBIN
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56. FACTORS REQUIRED FOR THE SYNTHESIS OF
HEMOGLOBIN
Firstclassproteinsi.e.proteinsofhighbiological
valuearenecessaryforHbsynthesis.e.g.Histidine,
Phynylalanine,Leucineetc.
Vitamins:VitB12,VitCarehelpfulinsynthesis.
Folicacid,riboflavin,nicotinicacid,pantothenic
acidplayimportantrole.VitB12andFolicacidare
calledmaturationfactorsandarerequiredfor
multiplicationandmaturationofRBC.
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57. FACTORS REQUIRED FOR THE SYNTHESIS OF
HEMOGLOBIN
EndocrineSecretions:Thyroidhormonesare
requiredforsynthesis.
Thyroxineisimportant.
Ironisrequiredinferrousstateforsynthesisofthe
haemofHbanddeficiencyofFecauses
microcyticandhypocromicanemia.
CopperisrequiredforbiosynthesisofHb.
CobaltandManganeseisrequiredinverysmall
quantities.
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58. FACTORS WHICH AFFECT HEMOGLOBIN LEVELS
Age
Sex
Diurnalvariation
Altitude
Exercise
Excitement
Adrenaline
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