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Porphyrin Metabolism
Structure and Properties of Iron Protoporphyrin IX
propionate
methyl
pyrrole ring
vinyl
Derived from protoporphyrin IX
Pattern of side chains defines isomer
Binds metals: Heme- Fe2+ (ferrous)
Hemin- Fe3+ (ferric)
Zinc protoporphyrin (ZnPP)- Zn2+
Extended conjugation across ring system
Photoreactive generation of Reactive Oxygen Species (ROS)
Amino Acid Pools are in Steady State
Majority of amino acids used for de novo protein
synthesis (80%) derives from the degradation of
existing proteins
Only 30 g (6%) used for synthesis of specialized
products
Only 70 g (14%) of total amino acid utilization
is used for energy or stored as glycogen/fatty
acids in the well-fed state (nitrogen balance)
Overview of Heme Synthesis
Heme
Succinyl CoA + Glycine
Protoporphyrin IX
ALA synthase
-aminolevulinic acid
Protoporphyrinogen IX
Coproporphyrinogen III
mitochondrial matrix
cytoplasm
-aminolevulinic acid
Porphobilinogen
Uroporphyrinogen III
Coproporphyrinogen III
Uroporphyrinogen I
Coproporphyrinogen I
Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic
group on enzymes and electron transport chain. By weight, the major locations of
heme synthesis are the liver and the erythroid progenitor cells of the bone marrow.
-Aminolevulinate (ALA) Synthase
is the Committed Step for Heme Biosynthesis
•Rate limiting committed step; requires pyridoxal-5’-phosphate as coenzyme
•Transcriptional regulation is the principal form of control since the enzyme
has a short half life (t1/2 = 1 hr). Heme and hemin repress transcription
•In erythrocytes heme synthesis is coordinated with that of the globin chains, all
of which are stimulated by erythropoietin (Epogen©, Procrit©, and congeners)
•Heme and hemin allosterically inhibit ALA synthase
•Aromatic drugs, xenobiotics, and steroids induce synthesis of ALA synthase
and can exacerbating certain porphyrias (later)
-Aminolevulinate (ALA) Dehydratase
•Asymmetry of the reaction results in acetate and propionate side chains
•The enzyme active site contains a required cysteine, making the enzyme
sensitive to inactivation by lead (Pb2+) and other heavy metals
•Increased urinary excretion of -aminolevulinate is a leading indicator of
heavy metal poisoning
Formation of the Final Ring Requires a
Bi-functional Enzyme
This step occurs by
elimination of the
primary amines as
the methylene adds
across the double
bond of the pyrrole
ring.
Note: Uroporphyrinogen I synthase is alternate name for Hydroxymethylbilane
synthase
Uroporphyrinogen Decarboxylase Remodels
the Acetate Side Chains
Spontaneously oxidizes to the biologically
inactive Coproporphyrin I and III which are
subsequently excreted in the urine
Coproporphyrinogen III Oxidase Catalyzes the Oxidative
Decarboxylation of Specific Propionate Side Chains
Protoporphyrinogen IX Oxidase
This reaction oxidizes the methylene bridge carbons between
the pyrrole rings to methenyl bridge carbons, allowing
extended conjugation through the entire tetrapyrrole ring
system for the first time.
Ferrochelatase
•Inserts Fe2+ into Protoporphyrin IX to yield heme
•The reaction also requires ascorbic acid and cysteine as reducing agents
•Lead (Pb2+) acts as a competitive inhibitor of Fe2+ but does not insert into
protoporphyrin IX
•Iron deficiency leads to insertion of Zn2+ to yield zinc protoporphyrin (ZnPP),
an important clinical indicator of iron deficiency
Porphyrias
Caused by hereditary or acquired defects in heme synthesis
- Accumulation and increased excretion of metabolic
precursors (each unique)
- Most porphyrias show a prevalent autosomal dominant
pattern, except congenital eythropoietic porphyria,
which is recessive
Can be hepatic or erythropoietic, reflecting the two major
locations of heme synthesis
- hepatic can be acute or chronic
Those with tetrapyrrole intermediates show photosensitivity
due to extended conjugated double bonds
- Formation of superoxide radicals
- Skin blisters, itches (pruritis)
- Skin may darken, grow hair (hypertrichosis)
Acquired Porphyrias
Lead poisoning
- inhibition of ferrochelatase and ALA dehydratase
- displaces Zn+2 at enzyme active site
Children
- developmental defects
- drop in IQ
- hyperactivity
- insomnia
- many other health problems
Adults
- severe abdominal pain
- mental confusion
- many other symptoms
Most heme from RBCs (85%) - rest from turnover of
cytochromes, p450s, immature erythrocytes.
RBCs last 120 days, degraded by reticuloendothelial
(RE) system [liver and spleen].
Microsomal heme oxygenase hydroxylates methenyl
bridge carbon and oxidizes Fe2+ to Fe3+. Second
reaction open ring and release methenyl carbon as
CO.
The resulting biliverdin is poorly soluble due to ring
stacking and aggregation.
Serum albumin carries bilirubin in circulation, ligandin
in hepatocytes.
Types of Jaundice
Hemolytic jaundice
- Liver can handle 3000 mg bilirubin/day - normal is 300
- Massive hemolysis causes more than can be processed
- cannot be conjugated
- increased bilirubin excreted into bile, urobilinogen
is increased in blood, urine
- unconjugated bilirubin in blood increases = jaundice
Obstructive jaundice
- Obstruction of the bile duct
- tumor or bile stones
- gastrointestinal pain - nausea
- pale, clay-colored stools
- can lead to liver damage and increased unconjugated
bilirubin
Hepatocellular jaundice
- Liver damage (cirrhosis or hepatitis) cause increased
bilirubin levels in blood due to decreased conjugation
- Conjugated bilirubin not efficiently exported to bile
so diffuses into blood
- Decreased urobilinogen in enterohepatic circulation
so urine is darker and stool is pale, clay-colored
- AST and ALT levels are elevated due to hepatic damage
- Nausea and anorexia
Jaundice in Newborns
Premature babies often accumulate bilirubin due to
late onset of expression of bilirubin glucuronyltransferase
- Maximum expression (adult level) at ~ 4 weeks
- Excess bilirubin can cause toxic encephalopathy
(kernicterus)
- Treated with blue fluorescent light
- converts bilirubin to more polar compound
- can be excreted in bile without conjugation
- Crigler-Najjar syndrome is deficiency in bilirubin
glucuronyltransferase