Proteine

(cursul III)
1. hemoproteine
2. proteine extracelulare

Hemoproteine

Mioglobina
Hemoglobina
Citocromii
Peroxidaze
Unele oxidaze

Hem = Protoporfirina IX + Fe2+

Fe

HO

- Localizat intr-o nisa

hidrofoba a
apoproteinei unde e
protejat contra
oxidarii.

Hemoglobina
-proteina intraeritrocitar-

Structura Hemoglobinei
a2

Hem

b1

b2

a1

contacte inter-unitati

DeoxiHb- Fier pentacoordinat, Fe in afara planului hemului

OxiHb- Fier hexacoordinat, Fe in planul hemului

MIOGLOBINA= Depozitarul oxigenului n muchi

Histidina distala

Legarea O2
la mioglobina

Histidina proximala
http://cwx.prenhall.com/horton/medialib/media_portfolio/text_images/FG04_44.JPG

Legarea O2 la hem implic deplasarea Fe2+ n planul hemului i

astfel induce modificri conformaionale n molecula Hb

Starea R

Starea T

Shifts at the
ab interfaces

b chains
further apart

Oxigenarea hemoglobinei
Tranzitia T-R nu e clar definita
2 modele: secvential i concertat

Oxigenarea hemoglobinei
Combinarea
modelului secvential cu
a celui concertat (cele
mai multe molecule
trec din starea T n
starea R cand 2 O2 au
fost legate)

ABC!

Curba de oxigenarea a Mb si Hb
Hiperbola versus
Sigmoida
P50(Mb) = 1 torr
P50(Hb) = 26 torr

*Modificari drastice a pO2 in conditii fiziologice

ABC!

Factori care influeneaz

afinitatea Hb pentru O2

CO2, pH acid, 2,3DPG- scad

afinitatea i deplaseaz
curba la dreapta.
Efectele sunt aditive.

Creterea temperaturii
deplaseaz curba la dreapta.

Efectul Bohr permite eliberarea unei cantiti mai mari

de O2 de pe HbO2 ctre muchi

Influena pH asupra curbei de oxigenare

HEMOGLOBINA la pH (~7.6) in plamini

HEMOGLOBINA la pH (~7.2) tesuturile periferice
MIOGLOBINA in muschi

Factori care influeneaz afinitatea Hb pentru O2:

2, 3-Bisfosfogliceratul
Scade afinitatea, crete p50

Faciliteaza eliberarea de O2
tesuturilor.
OO
OO

O
P
-O

O
O-

2, 3-bisphosphoglycerate

O-

100

saturation with O2

Stabilizeaza deoxiHb
(starea T )

- BPG

50

+ BPG

20

pO2 (mmHg)

100

Legarea 2,3-BPG la Hb: ntre lanurile beta

http://oregonstate.edu/instruction/bb450/stryer/ch10/Slide26.jpg

CURBA DE OXIGENARE
HbF versus HbA

HbF nu leag 2,3DPG

Afinitate mai mare pt

O2 decat HbA

O2 trece de pe HbA pe
HbF

Hemoglobine patologice
MetHb- Hb (Fe3+)
HbS

Hemoglobine patologice- HbS

Anemia cu hematii in forma de secera (HbS)
Deoxigenarea Hb conduce la polimerizarea intracelulara a Hb
Polimerii (HbS)n deformeaz i rigidizeaz eritrocitele.

STAREA OXI

STAREA DEZOXI

Intrebare
Exist hemoglobinopatii n care n urma unei
mutaii punctifome Hys distal este
nlocuit cu un aminoacid mai hidrofil (ex.
n Hb Boston Hys distal este nlocuit cu
Tyr) Explicai posibilele consecine asupra
funciilor biologice ale hemoglobinei care
survin n urma acestei mutaii.

Raspuns
Alterare in hidrofobicitatea cavitatii in care
este hemul, patrunde apa, se oxideaza fierul
la Fe3+, este HbM.
Nu se mai oxigeneaza hemul.
Cianoza tegumnete si mucoase.

Proteine extracelulare

Matricea Extracelulara
Proteine structurale
colagen
elastina

Cell Binding Proteins

Laminine
Fibronectine

Glicozaminoglicani (GAG).

Acid hialuronic
Condroitin sulfati
Heparan sulfati (incluzind heparina)
Keratan sulfati.

Proteoglicani.
GAG se leaga de proteine.
ex. aggrecan in cartilaj.

Colagen

Colagenul
25% din masa tuturor proteinelor din corp
Cel putin 33 de produsi codificati genetic, care
se asambleaza in homo si hetero-trimeri
ABC! Elemente structurale comune tuturor

tipurilor:
Structura tip triplu helix (trimer)
Bogatia in hidroxiprolina si hidroxilisina
Formula moleculara generala este (Gly-X-Y)n; 33%
Gly, X este frecvent Pro (23%), Y este frecvent HOPro sau HO-Lys

Structura colagenului
G

Structura primara (Gly-X-Y)n

GG
GG
GG

GGG
G
G
GG
G
G

Structura secundara este de

tip triplu helix cu pasul de 28 (fiecare lan
are 3.0 reziduuri aminoacidice per pas i pasul
de 9.3 )

De ce pasul este atat de mare comparativ cu -helixul?

TRIPLU
HELIX

Modificari post-translationale
1. Hidroxilarea Lys si Pro

(N.B.hidroxilarea are loc dup sinteza lanurilor

polipeptidice, DAR inainte de formarea triplu helixului)

GGGGGGGGGGGGGG
G
P

= HO-Pro

= HO-Lys

Stabilizeaza triplu helix.

Prolil hidroxilaza (necesit Fe2+
and vitamin C)

Substrat pentru glicozilare

Implicata in crosslinking
Lizil hidroxilaza (necesit Fe2+
and vitamin C)

Sediul hidroxilarii: Reticulul endoplasmic

Modificari post-translationale
2.Glicozilarea HO-Lys
(N.B.glicozilarea are loc inainte de formarea triplu
helixului)

GGGGGGGGGGGGGG
G

= monozaharid
Sediul glicozilarii: reticulul endoplasmic

Capete bogate in Cys

GG
GG
GGG
GGG
GG
GGG
GGGGGGG
GGG
GGGG
G

C C
C
S S
S
H H
H

G
GG
G
G
GG

G
GG
G
GGG

GG
G
G
G
GG

GG
G
G
G
G

G
G
G
G
GGG

GG
G
G
G
G
G

G
GG
G
G
G

G
GG
G
GGG

GG
G

GG G G

G
GG
G
G
G
G

G
GG
G
G
GG

G
GG
G
G
GG

G
GG
G
G
G
G

GG
G
G
G
GGG
G
G G G GG
G
G GG G

S-S
S-S

GG

S-S

GG
G
G
G
G
GGG
GG G G GGGG G
G

G
GG
G
GGG

GG

GG
G
G
G
G
G

GG G

G
GG
G
G
GG

GG
G G
G
G
G
G
G

G
GG
G
GG

G
G
G
G
G G
G GG
G
G
G
GG
G G
G
G
G
G
G

G
G
G
G
G G
G G
G
G
G
GG
G G
G
G
G
G
G

S-S

Modificri post-translationale
3. Punti disulfurice in triplu helix.

GG

Excretie, oxidare si asamblare

CYTOPLASM

G
GG

GGG

GG
GG

G
G

G
G
G
G

GGG

G
GG
GGG

G
GG

GGG

G
GG

GGG

GG
GG
GG

G GG

GG
GG

GGG

GG G G

GGG
GG
GGG
G
G G G GGG G G

G
GG

G GG

GGG

GGG
GGG
GGG
G
GGGG G

GG G

S-S
S-S

G GG

S-S

GG G

G
G

G
G
G
G

GG
GG
G
G
G

G
G
G
G
G
G

G
G
G

G
G

G
G
G
G

GG
G GG

G
G

G
G
GG

G
G
G
GG
GG
G
G
G

G
G
G

GG
G
G
G
G
G

G G

G
G

G
G
G
G

GG

G
G

G
G
G

G
G
G
GG
GG
G
G
G

S-S

Exocytotic
vesicle
G
G

membrane

EXTRACELLULAR
SPACE

Excretie, oxidare si asamblare

CYTOPLASM

G
GG

GGG

GG
GG

G
G

G
G
G
G

GGG

G
GG
GGG

G
GG

GGG

G
GG

GGG

GG
GG
GG

G GG

GG
GG

GGG

GG G G

GGG
GG
GGG
G
G G G GGG G G

G
GG

G GG

GGG

GGG
GGG
GGG
G
GGGG G

GG G

S-S
S-S

G GG

S-S

GG G

G
G

G
G
G
G

GG
GG
G
G
G

G
G
G
G
G
G

G
G
G

G
G

G
G
G
G

GG
G GG

G
G

G
G
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G
G
G
GG
GG
G
G
G

G
G
G

GG
G
G
G
G
G

G G

G
G

G
G
G
G

GG

G
G

G
G
G

G
G
G
GG
GG
G
G
G

S-S

Exocytotic
vesicle
G
G

membrane

EXTRACELLULAR
SPACE

Excretie, oxidare si asamblare

CYTOPLASM

G
GG

GGG

GG
GG

G
G

G
G
G
G

GGG

G
GG
GGG

G
GG

GGG

G
GG

G
GG
GGG

G GG

GG
GG

GGG

GGG

GGG

GGG

GG

GG G G

G
G G G GGG G G

G
GG

G GG

GGG

GGG
GGG
GGG
G
GGGG G

GG G

S-S
S-S

G GG

S-S

GG G

G
G

G
G
G
G

GG
GG
G
G
G

G
G
G
G
G
G

G
G
G

G
G

G
G
G
G

GG
G GG

G
G

G
G
GG

GG
G
G
G
G
G

G
G
G
GG
GG
G
G
G

G
G
G

G G

G
G

G
G
G
G

GG

G
G

G
G
G

G
G
G
GG
GG
G
G
G

S-S

Exocytotic
vesicle

G
G

membrane

EXTRACELLULAR
SPACE

Excretie, oxidare si asamblare

CYTOPLASM

Exocytotic
vesicle

G
GG

GGG

GG
GG

G
G

G
G
G
G

GGG

G
GG
GGG

G
GG

GGG

G
GG

GGG

G
GG
GGG

G GG

GG
GG

GGG

GG G G

GGG
GG
GGG
G
G G G GGG G G

G
GG

G GG

GGG

GGG
GGG
GGG
G
GGGG G

GG G

S-S
S-S

G GG

S-S

GG G

G
G

G
G
G
G

GG
GG
G
G
G

G
G
G
G
G
G

G
G
G

G
G

G
G
G
G

GG
G GG

G
G

G
G
GG

G
G
G
GG
GG
G
G
G

G
G
G

GG
G
G
G
G
G

G G

G
G

G
G
G
G

GG

G
G

G
G
G

G
G
G
GG
GG
G
G
G

EXTRACELLULAR
SPACE

S-S

membrane

G
G

Procesare extracelulara
1. Clivaj capete C- and N-terminale

G
GG

GGG

GG
GG

GG
G
G
G
G
G

GGG

G
GG
GGG

G
GG

GGG

G
GG
GGG

GG

GG
GG

GGG

G
GG
GGG

GG
GG
G
GGG
G
G G G GGG G G

GG G

GG

G GG

G
GG

GGG

GG
GG
G
GG G G GGG G G GGG G

S-S
S-S

GG

S-S

GG G

G
G
G

G
GG

GG
GG
G
G
G

G
G

G
G
G
G
G

G
G
G

G
G

G
G
G
G

GG
G GG

G
G
G
GG
GG
G
G
G

G
G

G
G
GG

GG
G
G
G
G
G

G
G

G
G
G
G

G
G
G

GG
G G

G
G
G
GG
GG
G
G
G

G
G

G
G
G

S-S

EXTRACELLULAR
SPACE
G
G

G
GG

GGG

GG
GG

GG
G
G
G
G
G

GGG

G
GG
GGG

G
GG

GGG

G
GG
GGG

GG
GG

GGG

G
GG

GGG

G
GG

GGG
G

GGG

GG

GG

G
GG
GGG

S-S
G
GGS
G
SGG-

S-S

G
GG

GG

S-S

GGG

GGG

G
GG

G
G G G GGG G G

GG
GG

GG

G
GG
GG

G GG

GG

GG
GG

GG
GG G

GG

GGG

GG

GG G

GG

GG
GG
GG
GG GG
GG
GG
G G G GG G G G G G G
G
GG G
GG G
G G G GGG G G

G
GG

G GG

GGG

S-S
S
S

GG
GG
G
GG G G GGG G G GGG G

S-S

GG

G
G
G

G
GG

GG G

G
G

G
G
G
G
G

G
G

G
G
G
G

GG
GG
G
G
G
G

G
G

G
G
GG

G
G
G
GG
G GG
G
G
G
GG
GG
G
G
G

G
G

GG
G
G
G
G
G

G
G
G

GG

GG
G G

G
G
G
GG
GG
G GG
GG G
GG

GG
GG
G
G
GG
G
G
G
G
G
G
G
GG
G
G
G
G
G
G
GG
G

GG

G
G
G
G
G
G
G

G
G
G
G
G
G

G
G
G
G

G
G
G
G
G

GG
G

G
G
G
GG
G GG
G
G
G
GG
GG
G
G
G

G
G
G
G
G
G

G
G
G
G
G

G
G
G
GG
G G
G
G
G
GG
GG
G
G
G

S-S

N-terminal protease

G
G

GG

G
GG

G
GG
GGG

GGG

G
GG

GGG

GG
GG
GG

GG
GG

GGG

G
GG
GGG

G
GG
GGG

S-S
S
S-

S-S

S-S

GG
GG

GGG

G
GG
GGG

G
GG
GGG

GG

GG G

GG G

GG

GG
GG
G
GG G G GGG G G GGG G

G
G
G

G
G

G
GG
GGG

GG
G
G
G
G
G

GG
GG
GGG

G
GG
GGG

GG

G
GG
GGG

GG
GGG

GG
GG
GG

GG
GG
GGG

GG
GG
GGG

G
GG
GGG

S-S

S-S
S
S-

S-S

GG
GG

GGG

GG
GGG

GG

G
GG
GGG

GG
GGG

G
GG
GG

G
GG
GGG

GG G

GG

GG

GG
GG
GGG

S-S
S
S-

G
GG

GGG

S-SG

GG G

G GG

GG
G G G GGG

GG
GG
G
GG G G GGG G G GGG G

G
GG

GGG

GG
GG
GGG

GG
GGG

GG

G
GG
GGG

GG

GGG

G
GG
GG

GG
GG

GGG

GG
GG
GGG

G
GG
GGG

S-S

S-S
S
S-

S-S

GG
GG

GGG

GG
GGG

GG

G
GG
GGG

GG

GGG

G
GG
GG

GG
GG

GGG

G
GG
GGG

GG
GG
GGG

G
S-S
S-S

S-SGGGGG

GG

GG

GG
GG G G GGG G

G
GG

GGG

GG
GG

GGG

G
GG
GGG

G
GG
GGG

G
GG

GGG

GG
GG
GG

GG
GG

GGG

G
GG

GGG

G
GG
GGG

S-S

S-S
S
S-

S-S

GG
GG

GGG

G
GG
GGG

G
GG
GGG

G
GG

GGG

GG
GG
GG

GG
GG

GGG

G
GG

GGG

G
S-S
S-S

G
GG
GGG

S-GGGSGG

GG G

S-S

GG G

GG

GG

GG G

S-S

GG

GG

GG
GG
G
GGG
G
G G G GGG G G

GG
GG

G GG

G
GG
GGG

GG
GG
G
GGG
G
G G G GGG G G

GG
GG
G
GGG
G
G G G GGG G G

GG
GG
G
GG G G GGG G G GGG G

G
GG
GGG

GG

GG

GG
GGG

GG
GG
GG

GG
GG

GGG

GG

GG
GGG

GG
GG
G
GGG
G
G G G GGG G G

G GG

G GG

G GG

GG
GG
G
GG G G GGG G G GGG G

GG
GG
G
GG G G GGG G G GGG G

GG

S-S
G
GG
GGG
S
S-

GG
GG
G
GG G G GGG G G GGG G

GG

GG

GG G

GG

S-S

GG

GG G

GG

GG G

GG

GG G

GG

GG G

GG G

GG

S-S

GG G

GG

GG G

GG

GG

GG
GG
G
GGG
G
G G G GGG G G

GG
GG
GGG

GG

GG
GG
G
GGG
G
G G G GGG G G

GG
GG
G
GGG
G
G G G GGG G G

G GG

G
GG
GGG

GG
GG
G
GGG
G
G G G GGG G G

G GG

G GG

GG
GG
G
GG G G GGG G G GGG G

G GG

GG

GGG

G
G

GG G

G
GG

G
G

GGG

G
G
G
G
G

GG
GG
G
GG G G GGG G G GGG G

GG
GG
G
GG G G GGG G G GGG G

GG
GG
GGG

G
G
G

GG

G
G
G

G
GG

G
G

GG
GG
GG
G
GG G
G G GG G

G
G
G
G

G
GG

GG
G
G
G
G
G

G
G

GG
GG
G
G
G
G

G
G
G

GG G

G
G
G

GG

G
G

G
GG

GG
G
G
G
G
G

GG

G
G

G
G
G
G
G

G
G

G
G
GG

G
G
G
G

G
G
G

GG
G GG

G
GG

GG
GG
G
G
G
G

GG
G
G
G
G
G

G
G

GG
G GG

G
G

G
G
G
G
G

G
G

G
G

GG
GG
G
G
G

G
G

G
G
G
G

G
G
G
G

G
G
GG

G
G
G

G
G

G
G
G
G
G

G
G

G
G
G
GG
G GG
G
G
G
GG
GG
G
G
G

G
G
GG

G
G
G
G

G
G
G
GG
GG
G
G
G

G
G
G
GG
GG
G
G
G

GG
G G

G
G

GG
G
G
G
G
G

G
G
G
GG
G G
G
G
G
GG
GG
G
G
G

G
G

GG
G
G
G
G
G

G
G

G
G
G

GG
GG
G
G
G
G
G

G
G
GG

G
G
G
GG
G GG
G
G
G
GG
GG
G
G
G

G
G

G
G
G
G

G
G

GG
G
G
G
G
G

GG
G
G
G
G
G

GG
GG
G
G
G
G

G
G

G
G
G

G
G
G
G
G
G
G

G
G

G
G
G
GG
G G
G
G
G
GG
GG
G
G
G

G
GG

G
G

GG
GG
G
G
G
G

GG
G
G
G
G
G

G
G

G
G
G
G

G
G

G
G
G

G
G
G

G
G
G
G
G

G
G
G

G
G

G
G

G
GG

GG
G
G
G
G
G

G
G
G

G
G
G
GG
GG
G
G
G

G
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SPATIU
EXTRACELULAR
G
G
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G
G
G
G
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G
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G
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G
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GG
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G
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membrana

Procesare extracelulara 2.
asamblare in proto-fibrile

Procesare extracelulara 3.
maturarea fibrilelor

G
GG

G
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GGG

GG
GG
GGG

G
GG
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G GG

=Alizina si HO-Alizina. Produse de Lisin OXIDASA Cu-dep

GGG

Crosslinking mai ales la nivelul Lys-OH

G
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G
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G
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G
G
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G
G
G

GG
GG
G
G
G

G
S-S
S-S

membrane

G
G
G

G
GG

ABC!

Sinteza colagenului

Ribozomi-sinteza monomer (lan alfa)

RE- hidroxilare monomer la Lys, Pro
RE-glicozilare monomer la HO-Lys cu glucozil-galactoza
RE- formare punti S-S si asamblare in triplu helix (formare
tropocolagen)
EXPULZARE IN SPATIUL EXTRACELULR (SE)
SE-clivare capete N si C-terminale (proteaze N si Cterminale)
SE- asamblare in protofibrile
SE- maturarea fibrilelor- crosslinking

Subetapele crosslinking
Oxidarea Lys si HO-Lys la aldehide (alizina
si HO-alizina)

Condensarea aldehidelor cu gr. amino (Lys)

Condesarea crotonica a 2 aldehide
Condesarea aldehidei crotonice cu Hys

Boli de colagen
Boala

Simptome majore

Defect biochimic

Facultativ (ce e in cadran)

Osteogenesis
imperfecta

Oase fragile
Malformaii oasoase

Mutatie in colagen tip I

Sindroamele Ehlers Danlos (EDS):

EDS V
Piele subtire si valve
Deficit de lisil oxidaza
cardiace slab dezv., hernii

Boala Menke

oase fragile,
anomalii arteriale

Deficit de absorbtie a Cu
(genetic sau alimentar)

Scorbut
(b. nutritionala)

hemoragii gingivale,
peteii

Deficit de Vitamina C

Scorbut

Osteogenesis Imperfecta

Fibrile de colagen I
(A) normal (B) osteogenesis imperfecta

(Kadler et al. Biochemistry 30:5081-5088, 1991)

Colagenoliza
Degradarea colagenului de proteaze
specifice numite colagenaze.
Digestie secundara de catre gelatinaze
nespecifice si stromelisina.
Turnover-ul este acompaniat de cresterea
excretiei urinare a hidroxiprolinei si
hidroxilisinei.

ABC! (fr structuri)

Elastina

Nu contine HO-Lys
Nu conine glucide
Contine 30% Gly, 10%Pro si putina HO-Pro (nu conine
HO-Lys), multi aa polari
Sintetizata ca proelastina in fibroblasti
Agregate de cite 2,3,4 monomeri uniti prin leg. covalente
rezultate din condensarea unui rest de Lys cu 3 resturi de
alizina (rezulta o grupare de tip desmozina)