Transcript Document

PHM142 UNIT 9A
Mitochondrial Diseases and the Brain
Instructions and materials:
Read ONLY sections in paper by Chaturvedi and Beal, 2013
(included in lecture material) highlighted in yellow, plus
Figures 1 and 3 and Table 1 in this paper.
Be prepared to discuss these topics in class.
1
PHM142 UNIT 9B
Mitochondrial Function and hepatic
detoxification of
a) monoamines, alcohol, toluene
b) heme & bilirubin
2
a) Detoxification of monoamines catalysed by
mitochondrial outer membrane MAO
e.g.,
dopamine
norepinephrine
tyramine
phenethylamine
octylamine
serotonin
outer
membrane
MONOAMINE OXIDASE
R-CHNH2
Flavin-containing amine oxidase
R-CH=NH (imine)
O2
H2O2
NAD+
NADH
R-CHO
aldehyde
dehydrogenase
inner
membrane
NH3
ATP,
HCO3urea
cycle
UREA
R-COOH
b-oxidation
CO2
3
Amine specificity for the two isoforms (A & B) in humans
MAO A preferentially metabolizes serotonin.
MAO B preferentially metabolizes phenethylamine, dopamine.
MAO inhibitor + dietary amines or proprietary drugs
MAOB inhibitor deprenyl (selegiline) similar to phenethylamine and increases brain
dopamine levels. This is used to treat Parkinson’s disease.
But “Hypertensive crisis” is a hyperadrenergic state induced by MAO inhibitors +
pressor amines (e.g., tyramine in cheese,beer,wine or soya sauce) or proprietary drugs
(e.g., L-DOPA, ephedrine, etc).
Cheese
Cheese
Tyramine (mg/g)
Tyramine (mg/g)
Cheddar cheese, old
1530
English Stilton
1157
Beer
2-11
Blue
998
Sherry Wine
3
Mozzarella
158
Chianti Wine
25
Feta
76
Processed cheese slice
nil
Perry, 1996. http://www.vh.org/adult/provider/psychiatry/CPS/19.html
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b) Detoxification of alcohols by matrix ALDH2
Covalently binds
to protein-NH2
(ADH)
ETHANOL
cytosolic alcohol
dehydrogenase
NADH
Methyl
pyrazole
acetaldehyde
ANTABUSE
(disulfiram)
or cyanamide
NAD+
NAD+
aldehyde
dehydrogenase
(ALDH)
NADH
acetate
ADH
Chromosome # 4
Caucasians
99% normal
ALDH
9, 12, 17
90% normal
Japanese
40% deficient
90% atypicial
ATP
CoASH
CO2
TCA
cycle
acetylCoA
Suscept. to alcoholism
Appearance social drinking
10% (>)
< 10%
-flushing
5
c) Benzoic acidosis induced by toluene glue sniffing
Toluene
Benzaldehyde
Benzyl alcohol
ADH
Cyt P-450
CH3
CH2OH
ER
CHO
CYTOSOL
ALDH1/
ALDH2
MITOCHONDRIA
COOH
URINE
CONHCH2COOH
Benzoic acid
ATP
CoA
Hippuric acid
Benzoyl-CoA
synthetase
Benzoyl-CoA
glycine
Teratogen Update: Toluene teratology. 55, 145-51, (1997)
5
Cytochrome Heme Synthesis - Overall picture
7
Heme synthesis
• Heme required for synthesis of mitochondrial
cytochromes and endoplasmic reticular P450s.
• Heme required for bone marrow synthesis of
hemoglobin and muscle myoglobin
• STEP 1 for heme synthesis is the synthesis of
aminolevulinic acid (ALA) from succinyl CoA of
the citric acid cycle and glycine
8
Heme biosynthesis in bone marrow (hemoglobin)
and liver (cytochromes)
ALA SYNTH ESIS AND TO XICITY
M i t o c ho n d r i a l
M at r i x
H+
NH
COO
2
COO
CH2
+
CH2
C
S
CH2
COO
CO2 + CoA
R. L. S .
AL A s y n t h e t a s e
COO
CH2
p y r i d o x a l1
CH2
C
CoA
C
NH3
AL A s y n t h e t a s e i n d u c e d b y
1 ) He m e d e f i c i e n c y d u e t
s y nt h e s i s / i nd u c t i o n e . g . ,
Su l f o n am i d es :
Th e r
u r i n e po r p h yr i n s
2 ) E RYT HROP OI E T I N
( f o r m e d b y ki d n e ys )
of l i f e of pat i e nt s o
3 ) Ac u t e i n t e r m i t t e n t p o
d e h y d r a t a s eor dlead
e f i ci e n
4 ) L E AD
HE M E BI OS YNT HE S I S
S T EP I I
( CYT OS OL)
H2
Fe e d b a c k i n hi b i t i o n
Gl y c i n e
O
b y he m e
O
AL A a c c u m u l a t e s
( a l s o i nd u c e s h e m e
a ) Ac u t e i n t e r m i t t e n t p
S u c c i n y l Co A
o x y g e n a s e )  Am i n o l e v u l i n a tb e) L e a d
( ALA)
CO2 + CoA
ci t r i c
AL A t o x i c i t y
aci d
- k e t o g l u t a r a t e
1)
Br a i n
c ycl e
d e hy d r o ge n a s e
Ne u r o p s y c h i a t r i c
com pl ex
a c ut e po r p h yr i a ,
Fe, O2
+
NH4
,
O
2
2
)
L
i ver nec r os i s /
s u c c i n a t e - k e t o g l u t a r a t e
ROS
p a r t i c ul a r l y i f
T
h
e
r
a
p
y
T h e r e f o r e ANAP L E ROT I C
DNA s t r a n d b r e a k s
1)
HE M E a r g i n a t e
r e a c t i o n r e qu i r e d t o r e p l a c e
COO
2
)
Hi g h c a r b o h y d r a t e
s u c c i n y l Co A i n c i t r i c a c i d
CH2
c ycl e .
g l u c o s e - 6 - PNADPH
DNA ADDUCTS
CH2
LI VER CANCER
O
GS H r e d u c t a s
H2O2
C C
GS H p e r o x i d a
H
O
Ar c h Bi o c h e m Bi o p h y s .
373,
368- 74,
( 4,5-dioxovaleric
2 0 0 0)
acid (DOVA)
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Erythropoietin synthesised by kidney induces hemoglobin synthesis
in bone marrow (replaces blood transfusion!)
10
Heme Biosynthesis - STEP 2 in the cytosol (4 enzymes 2-5)
COOH
LI VER/ BONE M ARROW cyt osol
Po r p hy r i a
Cu t a ne a 5
Ta r d a
COOH
COOH
HOOC
Cu t a ne ou s P or ph yr i a
HN
NH
co pr op or phy r i no ge n
no n- e n z y m a t i c
* Ac ut e Por ph yr i a
HN
NH
Hy dr ox ym et hy l b i l ane
HOOC
COOH
COOH
COOH
HOOC
CYP1 A2
COOH
COOH
HOOC
Ur op or ph yr i no ge n I
HN
NH
P
A
Sy m m et r i c al
HO
A
P
NH
HN
N
HN
HN
NH
HOOC
COOH
HOOC
3
COOH
U r o p o r p h y r i n o COOH
ge n I I I
s y nt ha s e
4
Ac ut e
ph os ph ob i l i no ge n
I n t e r m i t t e nt
Co ng e n i t a l
de a m i na s e
Po r p hy r i a *
Er yt hr op oi e t i c
Po r p hy r i a
NH
HOOC
A
A
COOH
P
COOH
HOOC
NH
HN
NH
HN
CYP1 A2
P
Ur op or ph yr i n
(UROPORPHYRIA)
HOOC
COOH
NH2
HOOC
COOH
HOOC
Po r p ho bi l i n og e n
( P BG)
2
Ur op or ph or y r i no ge n
Po r p hy r i a
de c a r bo xy l a s e
Cu t a ne a 5
Ta r d a
COOH
ALA De hy dr a t a s e
De f i ci en cy
PBG
Po r p hr yi a *
SYNTHASE
r. l. s
po l y m or phi s m
-4CO2
COOH
NH
HN
COOH
NH
STEP 1
1
STEP 3
HN
O
H2N
AL A
COOH
COOH
Co pr op or phy r i no ge n I I I
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Heme Biosynthesis - STEP 3 - mitochondrial final steps (3 enzymes)
A
c
*
u
C
S
t
e
u
t
P
a
n
T E P
o
r
e
hCOOH y
p
o
u
r
s
i
P
2
a
o
NH
HN
NH
HN
rCOOH p
P
r
o
t
o
p
p
o
r 6 e
r
p
r
i
CO2
p
r
d
o
m
i
o
i
p
t
o
a
r
r
p
y
h
n
i
t
t
e
o
r
c
m
a
p
o
r
p
o
COOH
COOH
o
y
O2
C
C
H e
h
C o
r
o
o
r
p
o
r
h V ya
P
o
p
p
rr
r
h
ii
p
y
ae
h
r
i
g
y
h
x
n
a
r
t
i
y
h
y
i
o
r
d
g
e
a
*
8
7
N
N
Fe2+
Fe
F
e
NH
r
r
o
c
i
r
COOH
COOH
H
E
h
M
.
.
m
l
e
l
a
t
.
s
.
P
o
t
a
o
s
p
o
i
r
h
y
r
HN
NH
.
p
e
O2
m
.
C OOH
COOH
E
r
HN
N
HN
NH
P
N
N
N
C OOH
C OOH
r
o
t
o
p
o
r
p
Ph
ry
or
ti
on
p
oI
MITOCHONDRIA
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OXIDATIVE DEGRADATION OF
HEME TO BILIRUBIN
(a brain neurotoxin in babies)
13
Detoxification function of the liver
a) heme toxin oxidation to bilirubin
b) detoxification of bilirubin
by glucuronidation or albumin
albumin
LIVER
CO
phagosome
Heme
oxygenase
14
Degradation of heme
STAGE 1
Hemoglobin of old
erythrocyte trapped
in spleen
HEME
O2 + NADPH
Heme oxygenase (ER)
H2O + NADP+
exhaled
Fe3+
CO
Bone marrow
transferrin
M
O
V
M
C
H
N
H
P
P
C
H
N
M
C
H
N
H
V
M
O
N
H
Excreted by Reptiles
and birds
Biliverdin
H2O soluble
NADPH + H+
Biliverdin Reductase
Modified from
Fig. 28-31 Stryer
4th Ed.
NADP+
M
O
M
V
N
H
C
H
Fat soluble
P
P
N
H
C
H2
M
M
N
H
C
H
V
N
H
O
BILIRUBIN (Neurotoxin to babies)
ANTIOXIDANT
NEONATAL
JAUNDICE
Bilirubin accumulates in
newborns.
(destroy with sunlight).
Plasma Serum Albumin Complex
LIVER
15
STAGE II - ligandin in hepatocyte surface membrane traps bilirubin
from plasma and helps transport it into the liver where it is glucuronidated
Albumin
- bilirubin
(a GSH transferase)
16
COO
COO
COO
M
M
V
M
M
V
O
H
+
O
N
H
C
H
C
H2
N
H
C
H
N
H
OH
UDP
H
Bilirubin
OH
UDP-glucuronate
UDP
Endoplasmic reticulum
UDP-glucuronosyl
transferase (UGT 1A1*)
COO
O
H
H
*mutated gene
in Gilbert’s disease
(carried by 15% of
population)
H
OH
O
OH
H
OH
M
O
H
OH
O
N
H
H
C
COO
M
V
N
H
O
C
H
M
M
N
H
C
H2
N
H
C
H
V
N
H
O
BILIRUBIN MONOGLUCURONIDE
UDP gluc. + UGT 1A1
BILIRUBIN DIGLUCURONIDE
(Soluble bilirubin diglucuronide secreted
into the bile)
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