Download Heme

Section 8.
Amino Acid
Metabolism
Porphyrins, heme, bile pigments
11/22/04
Heme
• In addition to the heme in hemogloblin and
myoglobin, molecules with the porphyrin
ring structure include cytochromes, and in
plants, the chlorophylls.
• Heme is synthesized in most cells.
Reticulocytes make ~ 4 x 1012 hemes per
second.
• In all cases, the precursors are glycine and
succinyl CoA.
1
Heme Structure
• The core
protoporphyrin
ring structure is
constant.
• The sidechains
vary in other
porphyrins.
• The protein
structure
determines the
properties of the
prosthetic group.
2
(p270)
Protoporphyrin IX Structure
O
O
O
O
NH N
N HN
Stryer 4th
3
• Fe(II) displaces the two protons in the center.
B12 Coenzyme
Structure
• Not heme, but
similiar.
• Compared to a
protoporphyrin
ring, the corrin ring
has smaller space
in center to fit
Co(II), smaller than
Fe(II).
• Vitamin B12,
cobalamin, may
have Co(III) with
5’-deoxyadenosine
substituted by CN
or CH3.
4
Stryer 4th
Succinyl CoA Biosynthesis
Valine
Methionine
CH3
H2C
ADP
+ Pi
O
propionyl CoA
carboxylase
propionyl CoA
O
O
H
O
SCoA
Isoleucine
-
HCO3
+ ATP
CH3
O
SCoA
O
B12
methylmalonyl
CoA mutase
methylmalonyl CoA
O
SCoA
succinyl CoA
• One heme precursor, succinyl CoA. can be made
from propionyl CoA, or from -ketoglutarate in the
Krebs cycle.
• Propionyl CoA can be made from amino acids, or
from the oxidation of odd-numbered fatty acids.
• After propionyl CoA is carboxylated, the conversion
of methylmalonyl CoA to succinyl CoA requires
vitamin B12.
5
Heme Biosynthesis: Part 1
O
A
CoA + CO2 +
O
P
O
O
O
SCoA
succinyl CoA
+
O
+
H3N
O
glycine
O
O
O
PLP
-ALA
synthetase
O
+
NH3
-ALA
dehydrase
+
H 3N
NH
porphobilinogen
-aminolevulinate
(-ALA)
-ALA synthetase
catalyzes the committed
+
H
N
3
step.
• Reactions occur in the
mitochondrial matrix.
• 8 succinyl CoA & 8 glycine.
•
6
O
porphobilinogen
deaminase
A
P
NH
P A
A
NH
P
NH
A
P
NH
a tetrahydropyrrole
P A
P A
A
P A
P
+
H3N
NH
NH
NH
NH
Uroporphyrinogen III
Synthetase and Cosynthetase
O
O
O
O
O
Heme Biosynthesis:
Part 2
O
O
O
O
O
O
O
O
+
Fe(II) 2 H
O
O
O
NH N
O
NH N
N HN
O
O
ferrochelatase
N
N
N
N
Fe
N HN
O
O
O
O
O
uroporphyrinogen III
protoporphyrin IX
HEME
• Notice that one of the pyrrole rings was “rotated” by the
uroporphyrinogen cosynthetase making the cyclic
uroporphyrinogen III asymmetric (look at the A-P distribution).
7 • The multiple arrows are several decarboxylations.
Ferrochelatase Mechanism
• Ferrochelatase (FC) binds Fe(II),
displacing 2 H+ on the enzyme.
• Next it “domes” the protoporphyrin IX.
• Fe(II) is inserted, exchanging 2 H+.
• It appears that distortion of the
protoporphyrin planar structure occurs
after the metal binds to FC.
• From Blackwood etal, Biochemistry 37:779 (1998).
8
Stoichiometry
8 glycine + 8 succinyl CoA + Fe(II)
1 heme
• This ignores the conversion of some of
the acetate and propionate groups to
methyl and vinyl groups.
9
Control Mechanisms
O
O
• -ALA synthetase catalyzes the
CH2
H2C
committed step.
O
• Heme inhibits the activities of
H2C
-ALA synthetase, -ALA
+
NH3
dehydrase and ferrochelatase.
• Heme also binds a nuclear receptor, which
reduces the transcription of the mRNA for ALA synthetase.
• Heme inhibits transport of -ALA synthetase
into the mitochondria.
10
Diseases Related to Heme Synthesis
O
O
O
O
O
O
O
O
O
O
O
O
O
O
NH N
O
O
O
NH N
O
N HN
N HN
O
O
O
O
O
O
O
O
O
Asymmetric
O
O
O
Symmetric
O
O
• Congenital erythropoietic porphyria is due to deficient
uroporphyrinogen III cosynthetase activity in red blood cell
precursors.
• The symmetric product uroporphyrinogen is not degraded.
• Short rbc lifetime, photosensitive skin, red enamel (UV light).
• Deficient ferrochelatase causes erythropoietic protoporphyria,
11
which has similar but milder symptoms.
Acute Intermittent Porphyria
• Due to deficient uroporphyrinogen
synthetase activity in the liver, coupled
to elevated -ALA synthetase activity.
• The result is high [-ALA] and
[porphobilinogen].
• Symptoms are abdominal pain, dark
urine, neurological aberrations.
• King George III ? Vincent Van Gogh ?
12
O
O
O
Heme Degradation
O
H2O
O2
+ NADPH
N
N
Fe
N N
+ NADP+
V M
M
Fe(III)
P
+ CO
heme oxygenase
O
N
NH
NH
O
NH
biliverdin
NADPH
biliverdin
reductase
• Heme is degraded in the liver.
• The final product, bilirubin
diglucuronide, is transported in O
bile from the liver to the gall
bladder and excreted.
• It, and several related structures,
are bile pigments.
M
• Notice energy is used to reduce
biliverdin to a waste product.
O
V M
M
13
V
M M
P
NADP+
P
NH
NH
V
M M
P
NH
O
NH
bilirubin
2 UDP-glucuronate
2 UDP
V M
NH
NH
V
M M
PG PG
NH
bilirubin diglucuronide
NH
O
Hb Heme Life Cycle
• Synthesized in red blood cell precursors.
• Spends about 120 days in the bloodstream.
• Identified as “old” by the spleen, which disrupts the
rbc membrane, freeing the Hb.
• Transported to the liver as a haptoglobin-hemoglobin
complex.
• Degraded in the liver to amino acids, Fe(III) and
bilirubin diglucuronide.
• The iron is transported to other cells, bound to
transferrin, for reuse.
• Bilirubin diglucuronide excreted by gall bladder.
14
Bile
• About 500 ml per day of bile is made by the liver,
which excretes it and transfers it to the gall bladder.
• The gall bladder concentrates bile and excretes it
into the intestinal lumen.
• The three main dissolved constituents are
glycocholate (~80%), phospholipids (~15%) and
cholesterol (~5%).
• Glycocholate, a fat-solubilizing detergent, is
reabsorbed by the intestinal epithelium.
• The other constituents, such bile pigments, are
minor.
15
Gallstone
Formation
0
100
Percent
Phospholipid
Percent
Cholesterol
50
50
* 80% bile salt
15% phospholipid
5% cholesterol
0
100
16
*
100
50
0
Percent Bile Salt
• At typical total concentrations in bile, the solubility of the
constituents is limited (Percent is percent of total solid).
• The hatched area includes the combinations of
cholesterol, phospholipid and bile salt that are soluble.
• Precipitation can lead to gallstones, which are painful if
they block the bile duct.
Neonatal Jaundice
O
O
O
NH
O
NH
O
NH
NH
O
bilirubin
• The immature liver cannot add glucuronate to bilirubin.
• Bilirubin circulates in the blood instead of being transported
to the gall bladder.
• Bilirubin can cross the immature blood brain barrier and
causes brain damage.
• Two therapies are successful :
– Visible light irradiation.
– Sn-substituted protoporphyrin.
17 • Sn-protoporphyrin inhibits heme oxygenase.
Next topic: One-carbon metabolism,
purine metabolism