Biokimia Hemato

8/16/2019 Biokimia Hemato

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Bagian Biokimia Fakultas Kedokteran

Universitas Hasanuddin Makassar

Dr. Marhaen Hardjo, M.Biomed,PhD

ru ur, ungs anMetabolisme Eritrosit Dan

Lekosit



The Structure andFunctionof Blood



Composition of Blood

Blood is responsible for… Transporting gases !o"#gen $ carbon

dio"ide% Transporting &aste products Transporting nutrients

Helping remove to"ins from the bod#




Blood makes up '()* of our

total bod# &eight

+ormal adult blood volume is , -

Blood is made up of cellular

material in a .uid called plasma




Blood is a circulating tissueconsisting of three t#pes of cells

/ 0ed Blood Cells 1r#throc#tes2 3hite Blood Cells -eukoc#tes

4 5latelets Thromboc#tes

• The cells listed above are suspended ina li6uid kno&n as plasma



Formation of Blood

Hematopoiesis the formation and development of blood cells

7n adults the cellular elements are produced in the bone marro&

Some 3BCs are produced in the l#mphatic tissue and bonemarro&

Blood cells need certain nutrients to form properl#

1"amples include…87ron8

Folic acid89itamin B/2

:ll blood cells formed comefrom a hematopoietic stem cell

These cells can become an#

blood cell




The blood is made up of cellsthat are suspended in li6uidcalled plasma

5lasma makes up ,,* of the blood

5lasma is made of ;<* &ater and/<* proteins= lipids= carboh#drates=amino acids= antibodies= hormones=

electrol#tes= &aste= salts= and ions Blood cells make up the remaining

>,* of the blood

0ed blood cells make up ;;* of the blood cells

3hite blood cells and platelets make up the other /*




• 1ach t#pe of blood cell performs a di?erent function

•

0ed blood cells !1r#throc#tes%

• 3hite blood cells !-eukoc#tes%

• 5latelets !Thromboc#tes%



Composition of Blood@0ed Blood Cells

• 0ed Blood Cells

8 :K:@ 1r#throc#tes or 0BCs

8

Most abundant cell in the blood!> million ( ' million per microliter of blood%

8 Formed in the bone marro&

8Main function is transporting

o"#gen and carbon dio"ide

8 Mature forms do +AT have a nucleus

8 Shaped as biconcave disks

8 ') micrometers in diameter

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Composition of Blood@0ed Blood Cells

• 0ed Blood Cells8 Stain pinktan

8 Center of cell is lighter

Dcentral area of pallorE

8 -ife span of about /2< da#s

8 Hemoglobin !iron protein%is

found in the 0BC

8 Hemoglobin carries o"#gen from the

lungs to the rest of the bod# and carbon

dio"ide binds to the 0BC and is taken to

the lungs to be e"haled

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Metabolisme Sel arahMerah

Sel darah merah #ang masih mudamempun#ai metabolisme #ang sangat

aktif karena organel seln#a masih lengkap Sel darah merah de&asa tidak lagi

mempun#ai aktivitas metabolisme seperti

sel muda tersebut Tetapi Sel darah merah de&asa masih

memerlukan energi untuk menGalankanfungsin#a

//



2 Genis metabolisme pada

sel darah merah de&asa@

likolisis

Fosfoglukonat !HM5shunt%

/2



13

Glucose

Glucose-6-P

Pyruvate

Hexokinase

PentosePhosphateShunt

glycolysis

Overvie !arboh"dratesOvervie !arboh"drates

MetabolismeMetabolisme

Glc-1- phosphat

glycogen



14

Pyruvatecytosol

Acetyl CoA mitochondria(aerobic)

KrebsKrebs

cyclecycleReducingequivalen

xidativePhos!horylat(A"P)

A#$% AC$&'

A"" AC$&'



15

#likolisis#likolisis

Galur metabolisme 1mbdenMe#erhof

Galur oksidasi glukosa menGadipiruvat I

energi !:T5% I +:H

berlangsung dalam sitosol

Galur sumber energi terutama bagisel darah merah de&asa #ang tidak lagipun#a mitokondria



16

PENGERTIAN

GLIKOLISIS

@.PEMECAHAN GLUKOSA=OKSIDASI GLUKOSA

@.C6H12O6 CO2 + H2O + 38 ATP

@. EMBDEN MEYERHOFF: GLUKOSAPIRU!AT

8 ATP " AEROB#.HANYA 2 ATP BILA ANAEROB

@. PIRU!AT ASETIL K$A : 2NADH=6ATP

@. KREB%S: 2&12=2' ATP TOTAL 38 ATP

BILA ANAEROB: 2 ATP + LAKTAT























27

$asib Piruvat$asib Piruvat

5iruvat dapat mengalami proses@

/ :erobik !ada oksigen%=

piruvat dioksidasi untuk menghasilkan

CA2 dan H2A melalui daur KrebJs

2 :naerobik !tanpa oksigen%=

manusia piruvat laktat

ragi piruvat etanol



28

C

C

CH3

O−

O

O

C

HC

CH3

O−

OH

O

NADH + H+ NAD

+

Lactate Dehydrogenase

pyruvate lactate



29



30

Pengaturan #likolisisPengaturan #likolisis

he"okinase or

glucokinase

phosphofructokinase

p#ruvate kinase



31

Pengaturan PertamaPengaturan Pertama

#likolisis%#likolisis%

HeksokinaseHeksokinase Mengkatalisis semua heksosa

Terdapat hampir dalam semua sel=

kecuali hepar dan selL pankreas Tidak dipengaruhi oleh

puasa= diet= insulin= diabetesmelitus

ihambat oleh lukosa'fosfat



32

Pengaturan PertamaPengaturan Pertama

#likolisis%#likolisis%

#lukokinase#lukokinase Mengkatalisis han#a glukosa saGa

Terdapat dalam sel hepar saGa

ipengaruhi oleh

puasa= diet= insulin= diabetesmelitus

Tidak dihambat oleh lukosa'fosfat



33

Pengaturan #likolisisPengaturan #likolisis

&tama%&tama%

Fos'o'ruktokinase 1nNim ini membatasi mengatur

kecepatan Galur glikolitik

iaktifkan oleh peningkatan :M5dalam sitosol

:M5 meningkat karena :T5 dihidrolisisoleh reaksi #ang memerlukan energi



34

Piruvat (inase diatur didalam hepar

1nNim ini mengubah kelebihan glukosamenjadi )iruvat= selanGutn#adimetabolisme menGadi a*et"l+!o agar

bisa disimpan sebagai 'att" a*ids untukcadangan energi Gangka panGang

Pengaturan oleh Piruvat KinasePengaturan oleh Piruvat Kinase



35

Hasil Bersih #likolisis erobHasil Bersih #likolisis erob

#lukosa - $D- - Pi - DP

Piruvat - $DH - /H- - 0P -H.O



36

Hasil Bersih #likolisisHasil Bersih #likolisis

naerobnaerob

#lukosa - DP - Pi

la*tate - 0P



37

HMP+ShuntHMP+Shunt

isebut Guga Galur pentosa fosfat heksosa monofosfat

Oalur ini menghasilkan +:5H danribosa di luar mitokondria

+:5H diperlukan untuk biosintesis

asam lemak=kolesterol= dan steroid lain 0ibosa untuk biosintesis asam nukleat



38

(e)entingan lain(e)entingan lain

HM5shunt berlangsung dalam Garingan

hepar= lemak= korteks adrenal= tiroid=eritrosit= kelenGar mammae sedanglaktasi

+:5H Guga penting dalam

detoksiPkasi obat olehmonooksigenase=

reduksi glutation



39

HMP+shunt terdiri dari 'ase%HMP+shunt terdiri dari 'ase%

/ Aksidatif !irreversible%

glukosa 'fosfat Q ribulosa ,fosfat

2 +onoksidatif !reversible%ribulosa ,fosfat Q ribosa ,fosfat

1alur HMP Shunt

1alur HMP+Shunt



40

1alur HMP+Shunt 1alur HMP+Shunt



41

HMP+shunt terdiri dari 'ase%HMP+shunt terdiri dari 'ase%

/ Aksidatif !irreversible%

glukosa 'fosfat Q ribulosa ,fosfat

2 +onoksidatif !reversible%ribulosa ,fosfat Q ribosa ,fosfat

1alur HMP+Shunt

1alur HMP+Shunt



42

1alur HMP+Shunt 1alur HMP+Shunt



43

Hasil BersihHasil Bersih

4 glukosa 'fosfat I ' +:5I

4 CA2

I ' +:5H I 'HI

I2 fruktosa 'fosfat I gliseraldehida

4fosfat



44

De2siensi glukosa 3+'os'atDe2siensi glukosa 3+'os'at

dehidrogenase 4#3PD5dehidrogenase 4#3PD5

1ritrosit matang sudah tidakmengandung mitokondria=

Sehingga sangat tergantung pada '5 +:5H diperlukan untuk mereduksi

glutation teroksidasi Q glutation

tereduksi !SH% Q !SS%

SH penting untuk meredam H2A2



45

De2siensi glukosa 3+'os'atDe2siensi glukosa 3+'os'at

dehidrogenase 4#3PD5dehidrogenase 4#3PD5

Hidrogen peroksida !H2A2%

men#ebabkan Hb Q metHb= karenaFe2I Q Fe4I

:kibatn#a terbentuk badanHeinN #angakan menimbulkan anemia hemolitik

5en#akit ini makin memburuk bilapenderita memakan obat malariaprimaguin atau kacang fava



Composition of Blood@3hite Blood Cells• 3hite blood cells

8 :K:@ -eukoc#tes or 3BCs

8 -argest siNed blood cells

8 -o&est numbers in the blood!>=,<< ( //=<<< per microliter%


and some in l#mph glands

8

5rimar# cells of the immune s#stem8 Fights disease and foreign invaders

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Composition of Blood@3hite Blood Cells• 3hite blood cells

8 Contain nuclei &ith +:=

the shape depends on t#pe of cell

8 Certain 3BCs produce antibodies

8

-ife span is from 2> hours to several #ears8 SiNe is )2< micrometers in diameter

8 There are Pve di?erent t#pes of 3BCs

/ +eutrophils

2 1osinophils

4 Basophils> -#mphoc#tes

, Monoc#tes

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Composition of Blood@5latelets

• 5latelets

8 :K:@ Thromboc#tes or 5-Ts


8 Fragments from the c#toplasm of megakar#oc#tes

8 Smallest of the blood cells

8 /> micrometers in diameter

8 Shape can be round= oval= or appear spik#

8 -ife span of around )/2 da#s



Composition of Blood@5latelets• 5latelets

8 7nvolved in the clotting process

8 Seal &ounds and prevent blood loss

8 Help repair damaged vessels

8 /,<=<<< ( ><<=<<< per microliter of blood

8 5latelets stain bluish &ith reddish or purple granules



Metabolism of

leukoc#te



i?erentiation of the bone marro& stemcells

myeloid

progenitor

tem !ell

lymp"oid

progenitor

m#!rop"#gedendriti! !ell

pl#telet

ne$trop"il eoinop"il %#op"il

mono!yte

m#t$re

lymp"o!yte

eryt"ro%l#t

eryt"ro!yte

pl#m#

!ell

meg#&#ryo!yte



5 Phago*"ti* *ells%5 Phago*"ti* *ells%

+eutrophils ( most abundant

1osinophils

Monoc#tes

Macrophages ( rise b# di?erentiation of monoc#tes intissues



egradation of the ingestedparticle@

/% :ctivation of +:5H o"idase

2% 5roduction of +A b# nitric o"ide s#nthase

4% Fusion of phagosome &ith l#sosomes of the phagoc#tic cell

that contain bactericidal substances and h#drol#tic enN#mes!often &ith acidic pHopt%



/% +:5Ho"idase

5rotein comple" of neutrophils= eosinophils= monoc#tes=macrophages

+:5H I 2 A2 R +:5I I HI I 2 A2

2 A2 I 2 HI R A2 I H2A2

H2A2 can damage bacteria directl# or after conversion to AH @

H2A2 I MI R AH I AH I M2I !M metal%

$pero'ide #nion



!yto!"rome %558

#!ti(e NAD)H*o'id#e

:ctivation@ b# association of the components localiNed inc#tosol &ith c#tochrome b,,) in the membrane electronsfrom c#tosolic +:5H are ( via F: and c#tochrome (transferred to o"#gen



pl#m#

mem%r#ne

+$ion

,it"

lyoome

p"#goome



M#elopero"idase

5resent in granules of neutrophils and monoc#tes= but notmacrophages

SigniPcant portion of H2A2 !produced b# dismutation of A2 generated

b# +:5H o"idase% is used b# m#elopero"idase to o"idiNe Cl to HClA

HClA is highl# reactive= able to o"idiNe biomolecules it also providesto"ic chlorine gas@

HClA I HI I Cl R Cl2 I H2A

HClA also reacts &ith A2 #ielding AH@

HClA I A2 R A2 I AH I Cl



Chronic granulomatous disease

Caused b# a dePcienc# of one of the +:5H o"idase subunits

Supero"ide and the other reactive o"#gen species are notproduced

Severe infections that are ver# hard to treat ( eg@ Burkholdaria cepacea causes pneumonia Aspergillus causes intractable pneumonia= septicaemia can

lead to death

Treatment@ antibiotics= antifungal agents



2% +itric o"ide production Mainl# b# inducible nitric o"ide s#nthase !i+AS% of macrophages &hich

is induced b# c#tokines !7+F= T+F% or bacterial lipopol#saccharide@

+A can kill bacteria directl# !eg b# inhibition of the respirator#chain% or indirectl#@ b# reaction &ith A2

= generating pero"#nitrite

A+AA &hich attacks FeS proteins and essential (SH groups=

inactivates enN#mes…

Arg !itr$lline



+:5H o"idase is e?ective mainl# in degradation ofe"tracellular pathogens !Salmonella, Staphylococcus,Streptococcus pyogenes%…neutrophils

6

+A serves mainl# to kill the intracellular parasites !Listeria=Brucella= Candida albicans%…macrophages



4% ranules !l#sosomes% ofneutrophils

Contain bactericidal substances and h#drolases that= afterfusion &ith phagosome= destro# the engulfed particles@ m#elopero"idase l#soN#me ( cleaves gl#cosidic bonds in peptidogl#can of the

bacterial !primaril# I% cell &alls

defensins ( cationic peptides !:rg% &ith Mr of 4=,' ka

interact &ith anionic lipids of bacterial membrane and makepores in it can also inhibit s#nthesis of +: and proteins

h#drolases= eg elastase ( serine protease@ can damagebacteria and cleave virulence factors= but also cause harmto host tissues !cleaves the proteins of e"tracellular matri"=

too%





1osinophils

Main task@ defence against multicellular parasites

ispla# all the abovementioned mechanisms &ith slightdi?erences@

0AS production pero"idase of eosinophils ( similar to m#elopero"idase= but

prefers Br as a substrate !instead of Cl%= thus generatingHBrA !instead of HClA%

basic protein of eosinophils disrupting the parasite cellmembranes



B5 Baso)hils and mastB5 Baso)hils and mast

*ells*ells :ctivated b# antigens allergens interacting &ith 7g1 bound to the surface 7g1 receptors of basophils !mast cells% Upon activation= content of their granules is released ( substances that are harmful to parasite and induce reactions that should lead to its

removal ho&ever= the# can also be responsible for allergic s#mptoms@

h#drolases

histamine

heparin

S#nthesis of eicosanoids is activated leukotrienes are potent bronchoconstrictors= stimulate chemota"is and leukoc#te activation

!ytopl#mi! gr#n$le



Histamine

5roduced b# histidine decarbo"#lation@

Causes vasodilation and bronchoconstriction ⇒ helps toeliminate parasites !cough= peristalsis= enhanced production ofmucus%



:top#

7g1 recogniNing allergens !from pollen= food…% are produced andbind to 7g1 receptors of basophils !mast cells% +e"t e"posure to

the allergen can lead to release of histamine and heparin ands#nthesis of eicosanoids

-ocal s#mptoms occur@ allergic rhinitis= asthma= conGunctivitis

7f the allergen enters bloodstream= it can cause a massivedegranulation of basophils !mast cells% ⇒ increase in vascularpermeabilit#= decrease in blood pressure ⇒ pulmonar# oedema=ischemia… anaph#lactic shock

Treatment@ antihistamines ( block histamine receptors



!5 L"m)ho*"tes!5 L"m)ho*"tes

Have speciPc receptors recogniNing one particular antigen@ Bcell receptors !BC0% and T cell receptors !TC0%= respectivel#

B0C is a membranebound immunoglobulin= TC0 is ver# similarto 7g

B cells !after proliferation and di?erentiation into plasma cells%secrete large amounts of antibodies !soluble immunoglobulins%



Soluble immunoglobulins

2 heav# chains !H% interconnectedb# disulPde bonds

2 light chains !-%= each connected

to one of the H chains !b# disulPdebond%

H chain@ >, domains= ,<V, ka- chain@ 2 domains= 2, ka

+terminal domains of H and -

chains are variable !9H resp 9-%=the others are constant !CH resp

C-%= ie the same in one t#pe of 7g

9ariable domains of H a - chains

form the antigenbinding site

VHVL

CH1

CL

CH2

CH3

-!

-#%



T#pes of immunoglobulins!7g%

There are 2 isot#pes of -@ W= X There are , isot#pes of H@

α= = Y= Z= [ :ccording to these isot#pes of

H= , t#pes of immunoglobulinscan be distinguished@ 7g: !2 subt#pes%

7g !> subt#pes% 7g 7g1 7gM

7gM can form pentamer= 7g:

can form dimer or trimer

155 &D#

900 &D#.imil#r/ gD g



D5 PlateletsD5 Platelets +o nucleus ⇒ man# of their metabolites come from

megakar#oc#tes

Form blood clots= act as vasoconstrictors

5articipate in defence against infections= eg@ the# suppress thegro&th of Plasmodium falciparum !infectious agent that causesmalaria%

enerate A2 and H2A2 that ma# s#nergiNe &ith pro

aggregator# stimuli

Contain thrombo"an : s#nthase that catal#Nes conversion ofprostaglandin H2 to thrombo"an :2@

A2 promote pl#telet #ggre*

g#tion #nd (#o!ontri!tion



5latelets also release t&o ver# important factors that canin.uence not onl# platelets but also other cell t#pes@

5latelet:ctivating Factor !5:F% 5lateleterived ro&th Factor !5F%



5latelet:ctivating Factor

Mainl# Gu"tacrine and paracrine signalling via 5C0

5romotes platelet aggregation

7nduces activation of leukoc#tes= adhesion= chemota"is= c#tokineproduction= causes vasodilation and bronchoconstriction

Mediates interpla# bet&een thrombotic and in.ammator# cascades

BUT@ it is also suspected of contributing to allerg#= anaph#lactic shock…

7t is produced also b# endothelial cells= monoc#tes= granuloc#tes…

p"op"olipid



5lateleterived ro&th Factor

imeric protein= 4 isoforms

0eceptors@ t#rosine kinases ( e"pressed on Pbroblasts= glia=

smooth muscle cells= leukoc#tes… 1?ects@

proliferation chemota"is

c#toskeletal rearrangements di?erentiation of certain t#pes of cells !eg in C+S% ⇒ participates in &ound healing= capillar# formation=

embr#onic and postnatal development BUT@ probabl# also pla#s a role in pathogenesis !some tumours%



!"tokines!"tokines

5roteins secreted b# leukoc#tes and other cells !but there are

also membrane c#tokines% that in.uence !via receptors% the cellsof the immune s#stem

C#tokine signalling@ autocrine ( a c#tokine in.uences the same cell that produces

it paracrine ( a c#tokine in.uences the nearb# cells endocrine ( a c#tokine in.uences distant cells !after transport

b# the bloodstream%



T#pes of c#tokines

7nterleukins ( eg 7-'@ produced b# macrophages= neutrophils= stimulates l#mphoc#tes= secretion of 7g= s#nthesis of acute phase reactants

Chemokines ( induce chemota"is

7nterferons ( eg 7+Fα@ produced b# l#mphoc#tes= monoc#tes= andmacrophages= participates in antiviral defense !induces s#nthesis ofenN#mes that block viral replication%

Transforming gro&th factors ( eg TFL@ produced b# Tl#mphoc#tes= macrophages= and platelets= displa#s antiin.ammator#e?ects

Tumor necrosis factors ( eg T+FL@ able to induce apoptosis

-eukoc#te inPltration into tissues



-eukoc#te inPltration into tissues diapedesis !e"travasation%@

-eukoc#tes are slo&ed do&n b# the interaction of their mucins &ithselectines on the surface of endothelial cells !1C%

C#tokines on the surface of 1C interact &ith the receptors of leukoc#tes : strong adhesion mediated b# the interaction of integrins &ith

molecules on the surface of 1C R migration of leukoc#tes into the tissue

directed b# c#tokins released b# in.ammator# cells or 1C

Taken from:

Halliwell, Gutteridge,

Oxford University Press, 1999



7egulation7egulation

Man# functions of leukoc#tes are regulated b# monomeric T5

binding proteins= eg 0ac= 0ho@ activation of +:H5 o"idase chemota"is phagoc#tosis

fusion of phagosome &ith granules

0ho and 0ac are able to modulate the assembl# of actinPlaments= &hich pla#s a role in the processes listed above

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HemoglobinHemoglobin

Stru*ture 8 Fun*tionStru*ture 8 Fun*tion

Objectives of theObjectives of the



Objectives of theObjectives of the

LectureLecture

9+ &nderstanding the main structural structural &functional functional details o' hemoglobin as one o' thehemo)roteins.

+ :denti'" t")est")es 8 relative *on*entrations o'normal adult hemoglobin ith re'eren*e toHB9*HB9* ith its *lini*al a))li*ation.

;+ 7e*ogni<e some o' the main geneti* 8bio*hemi*al as)e*ts o' methemoglobinopathiesmethemoglobinopathies ith some im)li*ations on *lini*al 'eatures4ith 'o*using on thalassemiasthalassemias5.



Hemoglobin is a globularHemoglobin is a globular

hemoproteinhemoprotein

Heme)roteins are a group of specialiNed proteins that containhemeheme as a tightl# bound prosthetic group

HemeHeme is a comple" of )roto)or)h"rin :6)roto)or)h"rin :6 and 'errous iron'errous iron4Fe-5 .4Fe-5 .

The ironiron is held in the center of the heme molecule b# bonds tothe four nitrogens of the porph#rin ring

The heme Fe-heme Fe- can form t&o additional bonds= one on eachside of the planar porph#rin ring

7n m#oglobin and hemoglobin= one of these positions iscoordinated to the side chain of a histidine residuehistidine residue of the globinmolecule= &hereas the other position is available to bind o"#geno"#gen



Globin of hemoglobin is a globularGlobin of hemoglobin is a globular

protein with a quaternary structure protein with a quaternary structure



Structure of hemeStructure of hemeHemeHeme is a comple" of protoporph#rin 7^protoporph#rin 7^ and ferrousferrous

iron !Fe2I%iron !Fe2I%

The ironiron is held in the center of the heme moleculeb# bonds of the four nitrogens of the protoporphrin

ring

Heme F2I can form t&o additional bonds= one on eachside ofthe porph#rin ring Ane of these positions iscoordinated to the

Side chain of histidinehistidine residue of the globin molecule=&hereasthe other position is available to bind o"#geno"#gen





Structure & function ofStructure & function of

hemoglobinhemoglobin

HemoglobinHemoglobin is found e"clusivel# in 0BCs

7ts main function is to transport o"#gen from lungs to the

tissues $ carbon dio"ide $ h#drogen protons from tissuesto lungs

Hemoglobin Hemoglobin is the maGor hemoglobin in adults= iscomposed of four pol#peptide chains= 2 alpha !α% $ 2

beta !β% chains= held together b# noncovalent interactions

1ach subunit1ach subunit has stretches of αhelical structure $ aheme binding pocket




hemoglobinhemoglobin (cont.



=uaternar" stru*ture o' hemoglobin=uaternar" stru*ture o' hemoglobin%% The hemoglobin tetramer can be envisioned as being composed of t&o identical

dimers= 4>?59 and 4>?5= in &hich the numbers refer to dimers one and t&o

The t&o pol#peptide chains &ithin each dimer are tightl#tightl# held together=

primaril# b# hydrophobic interactions

7n contrast= the t&o dimers are able to move &ith respect to each other= beingheld together primaril# b# polar bonds.

The &eaker&eaker interactions bet&een these mobile dimers result in the t&o dimersoccup#ing di?erent relative positions in deo@"hemoglobindeo@"hemoglobin as compared &itho@"hemoglobino@"hemoglobin


hemoglobinhemoglobin (cont.



o@"genation 8 deo@"genation o'o@"genation 8 deo@"genation o'

hemoglobinhemoglobin

!o"#hemoglobin $ deo"#hemoglobin%

O@"hemoglobinO@"hemoglobin0ela"ed structure

Deo@"hemoglobinDeo@"hemoglobin Taut structure



ypes of adult hemoglobinypes of adult hemoglobin

3 –6%

HB@ the maGor hemoglobin in humansHB@ Prst appears /2 &eeks after birth a minor component of normal

adult HBHBF@ normall# s#nthesiNed onl# during fetal developmentHB9! @ has glucose residues attached to βglobin chains ( increasedamounts in M



Hemoglobin !"c #H$!"c%Hemoglobin !"c #H$!"c%

Hb!"c could be used as a monitor for the control of theblood glucose level during the last months for diabetic

patients

Some of hemoglobin : isgl#cos#lated1"tent of gl#cos#lation depends onthe plasma concentration of aparticular he"ose !as glucose%

The most abundant form ofgl#cos#lated hemoglobin is HB9*HB9*&hich has a glucose residuesattached to βglobin chains inhemoglobin 0BCs

7ncreased amounts of HB9*HB9* arefound in 0BCs of patients &ith

diabetes mellitus !M%



HemoglobinopathiesHemoglobinopathies

HemoglobinopathiesHemoglobinopathies are members of a famil# of geneticdisorders caused

b#@

/ 5roduction of a structurally abnormalstructurally abnormal hemoglobinmolecule

!_ualitative hemoglobinopathies%

Or @ 2 S#nthesis of insu'cient quantitiesinsu'cient quantities of normal

hemoglobin !_uantitative hemoglobinopathies%

Or( )* bothboth !rare%!rare%



halassemiashalassemias

halassemiashalassemias are hereditar# hemol#tic diseases in &hich

an imbalance occurs in the s#nthesis of globin chains

The# are most common single gene disorderssingle gene disorders inhumans

+ormally +ormall y = s#nthesis of α and β globin chains arecoordinated= so that each αglobin chain has a βglobinchain partner

This leads to the formation of α2β2 !Hb:%

,n thalassemias,n thalassemias= the s#nthesis of either the α or βglobin chain is defective



halassemiahalassemia can be caused b# a variet# of mutations= including@

/ !ntire gene deletions!ntire gene deletions ( "hole gene is absent "hole gene is absent

Ar@ 2 Substitutions or deletions of one or more nucleotides inSubstitutions or deletions of one or more nucleotides inthe #$Athe #$A

-ach thalassemia can be classied as either -ach thalassemia can be classied as either @

/ : disorder in &hich no globinno globin chains are produced

! o

+ oro

thalassemia% Or @ 2 Some βchains are s#nthesiNed= but at a redu*ed ratea redu*ed rate

! -+ or -+ thalassemia%

halassemiashalassemias (cont.



// β β *thalassemias*thalassemias@@ S#nthesis of *globin*globin chains are decreased or absent= &hereas

αglobinchain s#nthesis is normal

αglobin chains cannot form stable tetramers= and thereforeprecipitate

causing )remature death o' 7B!s)remature death o' 7B!s :ccumulation of .γ. !HbF%=

γ/ !Hb Barts% $ +*hain )re*i)itateoccurs

These factors end result in development of *hroni**hroni* anemiaanemia !hemol#tic%




Some genetic aspects of thalassemia(Some genetic aspects of thalassemia(

There are onl# t&o copies of the β globin gene in each cell !one oneach

chromosome //%

So= individuals &ith ββ globin gene defectsglobin gene defects have either @ / *thalassemia minor #

*thalassemia trait%(if the# have onl# oneone defective βglobin gene

%& * thalassemia major #/ooley anemia%(if bothboth genes are defective




Mutation in bothboth +globin genes

+thalassemia

majorma jor

utation in oneone o' +globin genes

+thalassemiaminorminor




Some clinical aspects ofSome clinical aspects ofthalassemiasthalassemias''

/ :s βglobin gene is not e"pressed until late fetal gestation= the ph#sical manifestations of * thalassemias appear onl# after birth

2 7ndividuals &ith * thalassemias minor = make some βchains= andusuall#

re6uire no speciPc treatment

4 7nfants born &ith * thalassemias major seem health# at birth= but

become severel# anemic during the Prst or second #ears of life The# re6uire regular transfusions of blood

7n these cases= bone marro& replacement therap# is recommended




%& α *thalassemia(

S#nthesis of α&globin chains is decreased or absent.

1ach individuals genome contains four copies of theαglobin !t&o

on each chromosome /'%= there are several levels ofαglobin chain

dePciencies




0")es% :' one o' the 'our genes is de'e*tivethe individual is termed a silent *arrier o' + thalassemia as no ph#sical manifestations

of thedisease occur :' to +globin genes are de'e*tive=

the individual is designated as having +thalassemia trait :' three +globin genes are de'e*tivethe individual has hemoglobin H !HbH% disease &hich is a mildl# to moderatel# hemol#ticanemiaS#nthesis of una?ected γ and then β globin chains continues= resulting in the accumulation

ofγ tetramer in the ne&born !γ/= Hb Barts% or βtetramers ! /= HbH%

The subunits do not sho& hemeheme interactions So= the# have ver# high o"#genanities Thus=

the# are essentiall# useless as o"#gen carriers to tissues :' 'our +globin genes are de'e*tive=h"dro)s 'etalis $ fetal death !death at birth%= occurs as αglobin chains are re6uired for thes#nthesis of HbF





0")es o' +thalassemias



ssignmentsssignments

MethemoglobinMethemoglobin

Si*kle *ell anemia 4#eneti*,Si*kle *ell anemia 4#eneti*,

Bio*hemi*al 8 !lini*al s)e*ts5Bio*hemi*al 8 !lini*al s)e*ts5



B:OS:$0ES:S HEMO#LOB:$4PO7F:7:$5

Struktur Por2rinStruktur Por2rin



102

5orPrin adalah sen#a&a siklik #g

dibentuk oleh > cincin pirol Masingmasing cincin dihubungkan oleh

> Gembatan metenil !HC%

Sifat khas porPrin adalah atomnitrogenn#a mampu mengikat ionlogam

Contoh heme pada Hb mengikat Fe

kloroPl pada tumbuhan hiGau mengikat

Mg

Struktur Por2rinStruktur Por2rin

4!4! HH $$ 55



103

4!4!CCHH9/9/$$//55

Bebera)a Hemo)roteinBebera)a Hemo)rotein



104

Protein Fungsi

+ Hemoglobin mengangkut oksigen di dalamdarah

+ Mioglobin men"im)an oksigen di dalam otot

+ Sitokrom c keterlibatan )ada rantai trans)orelektron

+ Sitokrom

P/C hidroksilasi @enobiotikobat+

obatan+ (atalase degradasi hidrogen )eroksida

4HO5

+ 0ri)to'an

)irolase oksidasi tri)to'an

Sintesis Heme di MitokondriaSintesis Heme di Mitokondria



105

),* sintesis heme terGadi dalam sel

pembentuk eritrosit pada sumsumtulang

Heme disintesis dari suksinil Ko: I

glisin 5iridoksal fosfat diperlukan untuk

mengaktifkan glisin

Hasil kondensasi tsb ialah asam αaminoβketoadipat

Kondensasi diatas dikatalisis oleh

:minolevulinatsintase !:-:sintase%




106


:sam αaminoβketoadipat dengancepat mengadakan dekarboksilasi untukmembentuk δaminolevulinat !:-:%

0eaksi ini dikatalisis oleh :-:sintase

:-:sintase adalah enNim pengendali

laGu reaksi biosintesis porPrin di hepar




107

Sintesis Heme di SitosolSintesis Heme di Sitosol



108

ua molekul :-: berkondensasi melaluikerGa enNim :-:dehidratase

5roduk

/ molporfobilinogen !5B%

2 mol H2A

:-:dehidratase mengandung seng !]n%

1nNim ini dapat diinhibisi oleh timbal!5b%= sebagaimana terGadi padakeracunan 5b

Si i di Si lSi t i H di Sit l



109





110

Sintesis Heme di SitosolS es s e e d S oso

Kondensasi > mol5B menghasilkantetrapirol linier= #aitu hidroksimetilbilana

0eaksi ini dikatalisis oleh uroporPrinogen/sintase !5B deaminase%

Hidroksimetilbilana mengalami siklisasispontan membentuk uroporPrinogen 7 atau=

MenGadi uroporPrinogen 777 #ang dikatalisis

oleh uroporPrinogen 777 kosintase



111




112

S es s e e d S oso

UroporPrinogen 777 dikatalisis olehenNim uroporPrinogen dekarboksilasemenGadi koproporPrinogen 777

5ada penderita porPria=uroporPrinogen dekarboksilase Gugabisa mengubah UroporPrinogen 7 Gadi

koproporPrinogen 7 KoproporPrinogen 777 selanGutn#a

memasuki mitokondria




113




114

KoproporPrinogen 777 selanGutn#amemasuki mitokondria

KoproporPrinogen oksidasemengkatalisis dekarboksilasi sen#a&atsb menGadi protoporPrinogen 777 !7^%

1nNim ini han#a mampu bekerGauntuk koproporPrinogen 777




115




116

5rotoporPrinogen 777 akan dioksidasioleh protoporPrinogen oksidasemenGadi protoporPrin 777 !7^%

Terakhir= pen#atuan ion Fe2I !ferro%pada protoporPrin 777 #ang dikatalisis

oleh ferokelataseheme sintase agarmenGadi heme




117




118

Sintesis HemeSintesis Heme



119

Pengaturan Sintesis HemePengaturan Sintesis Heme



120

g

1nNim regulator adalah :-:sintase

Heme bertindak sebagai regulator

negatif !umpan balik negatif% sintesisenNim :-: sintase

Oika heme meningkat= maka sintesis:-:sintase akan menurun

Bebera)a Faktor angBebera)a Faktor angMem)engaruhiMem)engaruhi



121

) gSintesis HemeSintesis Heme

/ Metabolisme obatan di sitokrom 5>,< akan ban#ak menghabiskan heme

intrasel= akibatn#a sintesis heme akanmeningkat

2 lukosa $ hematin dapat mencegahsintesis :-:sintase

Si'at Por2rinSi'at Por2rin



122

Berbagai porPrinogen tidak ber&arna

Sedangkan semua porPrin ber&arna=karena adan#a ikatan rangkap #angmen#atukan cincin pirol

5orPrin #g terlarut dalam asam mineralkuat atau pelarut organik disinari dgnU9= maka akan mengeluarkan caha#a.uorecen merah

Sifat porPrin ini digunakan untukmenegakkan diagnosis porPria denganmenggunakan spektrofotometer

Por2rin )ada Sel (ankerPor2rin )ada Sel (anker



123

Sel kanker tertentu mengambil lebih

ban#ak porPrin daripada sel normal Sifat fotodinamik porPrin dimanfaatkan

untuk fototerapi kanker

Metode terapi

5enderita tumor diberi hematoporPrin=

kemudian tumor tsb disinari dengan laser

argon #ang akan memicu porPrin menGadi

sitotoksik

Por2riaPor2ria



124

Merupakan gangguan genetikbiosintesis heme

Umumn#a autosomal dominan= kecualiporPria eritropoitik kongenital

eGala

n#eri abdomen

gangguan neuropsikiatri fotosensitiPtas kulit

bila berat prototipe manusia srigala

Dasar Biokimia Por2riaDasar Biokimia Por2ria



125

+#eri abdomen $ neuropsikiatrimungkin akibat :-: dapatmenghambat enNim :T5ase di

Garingan saraf atau=

:-: mungkin diambil oleh Garingan

otak sehingga melumpuhkan hantaranimpuls saraf




126

FotosensitiPtas disebabkan olehakumulasi porPrinogen #g mudahteroksidasi di kulit

Bila terpaGan caha#a DtampakE!><<nm%= maka porPrin akan terpicuuntuk bereaksi dengan oksigenmolekular membentuk radikal oksigen

0adikal oksigen dapat merusak lisosom$ organel lain mengeluarkan enNimpengurai #ang merusak kulit


M t i D$



127

Mutasi D$

bnormalitas en<im )ada sintesis heme

kumulasi L 8 PB# atau kumulasi)or2rinogen

)enurunan heme dlm sel 8 di kulit 8 jaringantubuh

!airan tubuh

0anda 8 gejala Oksidasi s)ontan)or2rinogen

neuro)sikiatrik menjadi )or2rin

Fotosensiti2tas

0era)i Por2ria0era)i Por2ria Han#a simptomatik



128

Han#a simptomatik

0epresor :-:sintase glukosa

hematin !bentuk hidroksida dariheme%

βkaroten untuk fotosensitiPtas

preparat tabir sur#a Kontraindikasi

preparat anestesi

alkohol

griseofulvin $ barbiturat

0i)e Por2ria0i

)e Por2ria

9 nemia sideroblastik terangkai+6



129

9. nemia sideroblastik terangkai+64eritro)oitik5

+ de2siensi L+sintase+ gejala% anemia

+ Lab% hitung eritrosit 8 hemoglobin menurun

. De2siensi L+dehidratase 4he)atik5

+ gejala% n"eri abdomen, neuro)sikiatrik

+ Lab% L urine )ositi'

;. Por2ria akut intermiten 4he)atik5

+ de2siensi uro)or2rinogen+9+sintase

+ gejala% n"eri abdomen, neuro)sikiatrik

+ Lab% PB# 8 uro)or2rin urine )ositi'

0i)e Por2ria0i

)e Por2ria/. Eritro)oitik kongenital 4eritro)oitik5



130

+ de2siensi uro)or2rinogen+:::+sintase

+ gejala% tan)a 'otosensiti2tas

+ Lab% uro)or2rin urine )ositi' 8 PB# urine negati'

. Por2ria kutanea tarda 4he)atik5

+ de2siensi uro)or2rinogen dekarboksilase

+ gejala% 'otosensiti2tas+ Lab% uro)or2rin urine )ositi' 8 PB# urine negati'

3. (o)ro)or2ria herediter 4he)atik5

+ de2siensi ko)ro)or2rinogen oksidase+ gejala% 'otosensiti2tas, n"eri abdomen,neuro)sik

+ Lab% PB# 8 uro)or2rin urine )ositi'

)roto)or2rin 'eses )ositi'

0i)e Por2ria0i

)e Por2ria



131

G. Por2ria variegata 4he)atik5

+ de2siensi )roto)or2rinogen oksidase+ gejala% 'otosensiti2tas, n"eri abdomen,

neuro)sikiatrik

+ Lab% PB# urine )ositi'

)roto)or2rin 'eses )ositi'

. Proto)or2ria 4eritro)oitik5

+ de2siensi 'errokelatase+ gejala% 'otosensiti2tas

+ Lab% )roto)or2rin 'eses )ositi'

)roto)or2rin sel darah merah )ositi'

(e)ustakaan(e)ustakaan



Marks= B= Marks= := Smith CM /;;' Basic medicalbiochemistry' a clinical approach alam@ BU 5endit=penerGemah Biokimia Kedokteran asar@ Sebuah5endekatan Klinis 1ds O Su#ono= 9 Sadikin= -7Mandera Oakarta@ 1C= 2<<<

Murra#= 0K 2<<4 5orPrin dan pigmen empedu alam@:ndr# Hartono= penerGemah arper)s Biochemistry. 2,th

ed 1ds 0K Murra#= K ranner= 5: Ma#es= 930od&ell Mcra&Hill Companies= +e& ork@ 4>2 ;

Cohen= 0O Carboh#drate metabolism55T.med.uI.edubio*hemr*ohenr*ohen.html. CCG

. HardGasasmita= 5 *khtisar' biokimia dasar B Balai

5enerbit FKU7 Oakarta /;;4

http://www.med.ufl.edu/biochem/rcohen/rcohen.html.%202007




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Biokimia Hemato