legame co c 1958 - moodle@units · fattore intrinseco (intestino) transcobalamina (sangue) -sheet...
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a
b
Dorothy Hodgkin, premio Nobel
per la Chimica nel 1964 per la
struttura ai raggi X
1958 Legame Co-C
Anello corrinico
5′-desossiadenosilcobalamina
catena amidica
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2
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a
b
7 catene amidiche laterali,
9 centri chirali
1580 Da
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Distorsione nelle cobalamine
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Co(III) d6
Co(II) d7
Co(I) d8
supernucleofilo
C. N. = 6 C. N. = 5
C. N. = 4
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C
H
R1
R2
C
H
H
R3 C
H
R1
H
C
R2
H
R3
shift-1,2
Enzima R1 R2 R3
Diolo
deidratasi
CH3 OH OH
Etanolamina
deaminasi
H NH2 OH
Glutammato
mutasi
H CH(NH2)COO
H
COOH
Glicerolo
deidratasi
CH2OH OH OH
Reazioni catalizzate dal coenzima B12 mutasi
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H
HH
COOH
CO-S-CoA
H
CO-S-CoA
HH
COOH
H
H
MMCM
metilmalonil succinil
MetilMalonil-Coenzima A-Mutasi (metabolismo degli amminoacidi nel fegato)
Coenzima A
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CoIII
CH2A CoII + CH2A
C
H
C
R
+ CH2A C C
R
+ CH3A
(B12r)
C C
R
C
R
C
CH3A + C
R
C CH2A + C
R
C
H
CoIII
CH2ACH2ACoII +
(coenzima B12)
(coenzima B12)
(B12r)
shift-1,2
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La rottura del legame Co-C è 1012 volte più veloce nell’enzima
completo rispetto al coenzima B12
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Metilcobalamina: cofattore della Metionina Sintasi
S-adenosil-L-metionina
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Metionina Sintasi
cisteina
N5-metiltetraidrofolato
Cap-Cob
metilcobalamina
S-adenosil-L-metionina
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Metilcobalamina in Cap-Cob: base-off/His-on
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Variazioni conformazionali della metionina sintasi
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Modelli
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Uptake e Trasporto della Cobalamina
(duodenum)
TC - Cbl
plasmaTC(liver, etc.)
lysosome
Cbl-OH
GS-Cbl mitocondrion
TC-Cbl
Cbl (II) Cbl (I) CH3-Cbl
Homocys
Met FH4
CH3 -FH4
reductase
synthase
Cbl (I)
reductase
Ado-
transferaseAdo-Cbl
L-Methylmalonyl-CoA
Succinyl-CoA
mutase
R TC-Cbl
HC
Cbl in food
HC-Cbl
(gastric fluid)
IF
IF-Cbl
RDA1-5 g/day
(duodenum)
TC - CblTC - Cbl
plasmaplasmaTC(liver, etc.)
lysosome
Cbl-OH
GS-Cbl mitocondrion
TC-Cbl
Cbl (II) Cbl (I) CH3-Cbl
Homocys
Met FH4
CH3 -FH4
reductase
synthase
Cbl (I)
reductase
Ado-
transferaseAdo-Cbl
L-Methylmalonyl-CoA
Succinyl-CoA
mutase
R TC-Cbl
HC
Cbl in food
HC-Cbl
(gastric fluid)(gastric fluid)
IF
IF-Cbl
RDA1-5 g/day
Aptocorrina
(stomaco)
fattore intrinseco
(intestino) Transcobalamina
(sangue)
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β-sheet domain
α-helix domain
Cobalamin
β-sheet domain
α-helix domain
Cobalamin
β-sheet domain
α-helix domain
Cobalamin
β-sheet domain
α-helix domain
Cobalamin
Struttura TC+Cobalamina (2006)
a b
Coordinazione base-on/His-on (su b)
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Complesso IF-Cbl (2007)
Coordinazione base-on
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Confronto IF-Cbl e TC-Cbl
IF = rosso
TC = blu
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Addotto IF-Cbl con CUB5-8
recettori della cubilina
IF b domain
Ca2+ IF a domain
Cbl
CUB8
CUB7
CUB5
CUB6