Download - Heme synthesis and degradation
PORPHYRINSHEME SYNTHESIS AND DEGRADATION
Porphyrins
• Cyclic compounds that bind metal ions
• Chlorphyll (Mg2+)
• Central to solar energy utilization
• Heme (Fe2+)
• Most prevalent metalloporphyrin in humans
• Central to oxygen sensing and utilization
• Cobalamin (Cobalt)
PORPHYRINS
HC
HC
NH
CH
CH
Pyrrole ring
•Porphyrin: Cyclic molecule
formed by linkage of four
pyrrole rings through
methenyl bridges
Porphyrin Side Chains
• M = Methyl (-CH3)
• V = Vinyl (-CH=CH2)
• P = Propionyl (-CH2-CH2-COO-)
• A = Acetyl (-CH2-COO-)
Heme
•One ferrous (Fe2+) atom in the center of the tetrapyrrole ring of Protoporphyrin IX
•Prosthetic group for
• Hemoglobin and Myoglobin
• The Cytochromes
• Catalase and Tryptophan pyrrolase
• Nitric Oxide Synthase
•Turnover of Hemeproteins (Hemoglobin, etc) is coordinated with synthesis and degradation of porphyrins
•Bound iron is recycled
Heme
Protoporphyrin III
prefix or suffix r ing substituents between rings
uro- acetate, propionate - -
copro- methyl, propionate - -
proto- methyl, propionate, vinyl
-porphyrinog e n - - methylene
-porphyrin - - methene
Biosynthesis of Heme
•Synthesized in every human cell
•Liver (15%):
•Bone Marrow (80%)
COOH
CH2
CH2
COSCoA
CH2 NH2
COOH
SUCCINYL CoA
GLYCINE
All Carbon and Nitrogen atoms
provided by 2 building blocks:
COOH
CH2
CH2
COSCoA
CH2 NH2
COOH
SUCCINYL CoA
GLYCINE is
Decarboxylated
IN MITOCHONDRIA
AMINOLEVULINIC ACID SYNTHASE
- CO2
COOH
CH2
CH2
C=O
CH2
NH2
Condense to form:
AMINOLEVULINIC ACID (ALA)
MOVES OUT OF THE MITOCHONDRION
COOH
CH2
CH2
C=O
CH2
NH2
COOH
CH2
CH2
C=O
CH2
NH2
2 Molecules dehydrated by
ALA DEHYDRATASE
-2 H2O
COOH
CH2
CH2
C
C
NH
COOH
CH2
C
C
CH2
NH2
To form Porphobilinogen (PBG)
COOH
CH2
CH2
N
H
COOH
CH2
CH2
NH2
Porphobilinogen (PBG)
Acetate
CH2COO-Propionate
CH2CH2COO-
Porphobilinogen (PBG)
N
HCH2
NH2
A P
HYDROXYMETHYLBILANE SYNTHASE
& UROPORPHYRINOGEN III SYNTHASE
•Four PBG molecules condense
•Ring closure
• Isomerization
NH
NH HN
HN
A B
CD
A
A
P
A
P
P
P
A
Uroporphyrinogen III
NH
NH HN
HN
HOOC-H2C-
HOOC-H2C-
-CH2-CH2-COOH
-CH2-COOH
CH2
CH2
COOH
CH2
CH2
COOH
COOH
CH2
CH2
COOH
CH2
Uroporphyrinogen III
SERIES OF
DECARBOXYLATIONS & OXIDATIONS
• Porphyrinogens:
• Chemically reduced
• Colorless intermediates• Porphyrins:
• Intensely colored
• Fluorescent
• Uroporphyrinogen III
• Coproporphyrinogen III
Moves back into Mitochondrion• Protoporphyrinogen IX
• Protoporphyrin IX
NH
N HN
N
H3C-
H3C-
-CH=CH2
-CH3
CH2
CH2
COOH
CH2
CH2
COOH
CH3
Protoporphyrin IX
CH=CH2
HEME
Fe2+ chelated by Protoporphyrin IX
Assisted by Ferrochelatase
CH3-
REACTIONS FOR
PROTOPORPHYRI
N IX
Regulation of Heme Synthesis
AMINOLEVULINIC ACID SYNTHASE
• Two tissue-specific isozymes
• Coded on separate genes
• In Liver, heme represses synthesis and activity of ALAS
• Heme can be used for treatment of acute porphyric attack
• In RBC heme synthesis regulation is more complex
• Coordinated with globin synthesis
COOH
CH2
CH2
COSCoA
CH2 NH2
COOH
SUCCINYL CoA
GLYCINE
IN MITOCHONDRIA
AMINOLEVULINIC ACID SYNTHASE
RATE-CONTROLLING STEP IN
HEPATIC HEME SYNTHESIS
COOH
CH2
CH2
C=O
CH2
NH2
ALA
Bonkovsky
ASH Education Book
December 2005
Disorders of Heme Synthesis
• Acquired: Lead poisoning
• Congenital: Porphyrias
• Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.)
LEAD TOXICITY
Symptoms Irritibility Poor appetite
Lethargy Abdominal pain (with or
Sleeplessness without vomiting)
Headaches Constipation
Pathophysoiology
Binds to any compound with a sulfhydryl group
Inhibits multiple enzyme reactions including those
involved in heme biosynthesis (ALA dehydratase &
ferrochelatase)
COOH
CH2
CH2
C=O
CH2
NH2
COOH
CH2
CH2
C=O
CH2
NH2
-2 H2O
ALA moves out of the mitochondrion
ALA DEHYDRATASE
Inhibited by Heavy Metal: LEAD POISONING
PBG
N
HCH2
NH2
A P
Lead
Poisoning
Lead Poisoning
ALAD and Ferrochelatase
Are particularly sensitive
to Lead inhibition
Lead
Poisoning
Fe + PPIX
Ferrochelatase
Heme
Disorders of Heme synthesis • Porphyrias are group of inborn errors of metabolism associated with
the biosynthesis of heme.(Greek ‘porphyria’ means purple).
• These are characterised by increased production and production
and excretion of porphyrins and/or their precursors (ALA + PBG).
• Many of the porphyrias are inherited as autosomal dominant traits.
• Porphyrias may be broadly grouped into 3 types:
a. Hepatic porphyrias
b. Erythropoietic porphyrias
c. porphyrias with both erythropoietic and hepatic abnormalities.
PORPHYRIAS A group of rare disorders caused by deficiencies of enzymes of the
heme biosynthetic pathway
The majority of the porphyrias are inherited in a autosomal dominant
fashion - thus, affected individuals have 50% normal levels of the
enzymes, and can still synthesize some heme
Affected individuals have an accumulation of heme precursors
(porphyrins), which are toxic at high concentrations
Attacks of the disease are triggered by certain drugs, chemicals, and
foods, and also by exposure to sun
Treatment involves administration of hemin, which provides
negative feedback for the heme biosynthetic pathway, and therefore,
prevents accumulation of heme precursors
ACUTE INTERMITTENT PORPHYRIA
Hepatic, autosomal dominant
Caused by a deficiency in porphobilinogen
deaminase, which is involved in the conversion of
porphobilinogen (PBG) to uroporphyrinogen III
PBG, uroprophryin, and 5-ALA accumulate in the
plasma and the urine
Patients have neuropyschiatric symptoms and
abdominal pain (neurovisceral)
PORPHYRIA CUTANEA TARDA
Most common porphyria
Hepatic, autosomal dominant
Disease is caused by a deficiency in uroporphyrinogen
decarboxylase, which is involved in the conversion of
uroporphyrinogen III to coproporphyrinogen III
Uroporphyrinogen accumulates in urine
Patients are photosensitive (cutaneous photosensitivity)
Accumulation of porphyrinogens results in their
conversion to porphyrins by light
Porphyrins react with molecular oxygen to form
oxygen radicals
Oxygen radicals can cause severe damage to the
skin
BLOOD CELLS
LIVER
Bilirubin diglucuronide(water-soluble)
2 UDP-glucuronic acid
via bile duct to intestines
Urobilinogenformed by bacteria KIDNEY
CO
Biliverdin
Heme oxygenase
O2
Bilirubin (water-insoluble)
NADP+
NADPH
Biliverdinreductase
Heme
Globin
Hemoglobin
reabsorbedinto blood
Bilirubin (water-insoluble)
via blood to the liver
INTESTINE
Disorder of Hb catabolism•Disease or conditions that interfere with bilirubin
metabolism may cause a rise in its serum concentration of bilirubin
Total bilirubin
0.1 to 1mg/dlConjugated
0.1 to 0.4mg/dlUnconjugated
0.2 to 0.7mg/dl
NORMALLEVELS
Hyperbilirubinaemia• When serum bilirubin exceeds 1mg/dl – HYPERBILIRUBINAEMIA
• >2.2 to 5mg/dl - JAUNDICE
Yellowish discoloration of skin and sclera due to deposition of bilirubin in the tissues. The
condition is called jaundice or icterus
INCREASED HAEMOLYSIS
↑breakdownof Hb
JAUNDICE
LIVER DAMAGE
↓Excretion of bilirubin
JAUNDICE
BILE DUCT OBSTRUCTION
↓Excretion of bilirubin
JAUNDICE
CAUSES OF JAUNDICE
JAUNDICES
NORMAL METABOLISM OF BILE
PIGMENTS
CELLS OF RES
Indirect
bilirubin
NADP+
NADPH2
Biliverdin
reductase
Biliverdin
Iron
Globin
Verdoglobin
NADP+
Hemoxi-
genase
NADPH2
Hemoglobin ERYTHROCYTES
K
I
D
N
E
Y
S
Stercobilinogen
URINE
Stercobilin
Indirect
bilirubin 1,7-
20,5 mkmol/l
albumin
albumin
Indirect bilirubin
UDP-glucoronil-
transferase
Direct
bilirubin 0.8-
4.3 mkmol/l
B
L
O
O
D
L
I
V
E
R
Bilirubin mono-
glucoronid, 20 %
Bilirubin di-glucoronid,
80 %
Dipyrols
-glucoro-
nidase
Glucoronic
acid
Direct
bilirubin
B
I
L
E
I
N
T
E
S
T
I
N
E
Mesobilirubin
Mesobilirubin
(urobilinogen)
Stercobilinogen
Stercobilin
STOOL
METABOLISM OF BILE PIGMENTS IN HEMOLYTIC
JAUNDICE
CELLS OF RES
Indirect
bilirubinIndirect
bilirubin
albumin
albumin
Indirect
bilirubin
Biliverdin
reductase
UDP-glucoronil-
transferase
Direct
bilirubin
NADP+
NADPH2
Biliverdin
Iron
Globin
Verdoglobin
NADP+
NADPH2
Hemoglobin
Hemoxi-
genase
B
L
O
O
D
L
I
V
E
R
Bilirubin mono-
glucoronid, 20 %
Bilirubin diglucoronid,
80 %
-glucoro-
nidase
Glucoronic
acid
Direct
bilirubin
B
I
L
E
ERYTHROCYTES
K
I
D
N
E
Y
S
I
N
T
E
S
T
I
N
E
STOOL
Stool hypercholic
URINEUrine dark
Mesobilirubin
Mesobilinogen
(urobilinogen)
Stercobilinogen
Stercobilin
Stercobilinogen
StercobilinUrobilin
METABOLISM OF BILE PIGMENTS IN HEPATIC
JAUNDICE
CELLS OF RES
Indirect
bilirubin
Indirect
bilirubin
albumin
albumin
Indirect
bilirubin
Biliverdin
reductase
UDP-glucoronil-
transferase
Direct
bilirubin
NADP+
NADPH2
Biliverdin
Iron
Globin
Verdoglobin
NADP+
NADPH2
Hemoglobin
Hemoxi-
genase
B
L
O
O
D
L
I
V
E
R
Bilirubin mono-
glucoronid, 20 %
Bilirubin diglucoronid,
80 %
-glucoro-
nidase
Glucoronic
acid
Direct
bilirubin
B
I
L
E
ERYTHROCYTES
K
I
D
N
E
Y
S
Urobilinogen I
N
T
E
S
T
I
N
E
STOOL
Stool hypocholic
URINEUrine dark
Stercobi-
linogen
StercobilinBilirubinUrobilin
Mesobilirubin
Mesobilinogen
(urobilinogen)
Stercobilinogen
Stercobilin
METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE
JAUNDICE
CELLS OF RESIndirect
bilirubinIndirect
bilirubin
albumin
albumin
Indirect
bilirubin
Biliverdin
reductase
UDP-glucoronil-
transferase
Direct
bilirubin
NADP+
NADPH2
Biliverdin
Iron
Globin
Verdoglobin
NADP+
NADPH2
Hemoglobin
Hemoxi-
genase
B
L
O
O
D
L
I
V
E
R
Bilirubin mono-
glucoronid, 20 %
Bilirubin diglucoronid,
80 %
Bile
acids
-glucoro-
nidase
Glucoronic
acid
Direct
bilirubin
B
I
L
E
Direct
bilirubin
ERYTHROCYTES
K
I
D
N
E
Y
S
Direct bilirubinI
N
T
E
S
T
I
N
E
STOOL
Stool acholic, steatorhea
URINE Direct bilirubin Bile acids
Urine dark, foaming