Heme Synthesis, Heme Degradation, Porphyrias, Jaundice

1. PORPHYRIN METABOLISM
Conversion of amino acids to specialized products, chapter 21, 277

2. A. Structure of porphyrins
• Porphyrins are cyclic molecules formed by the linkage of four pyrrole
rings through methenyl bridges. Some structural features are:
• 1. Side chains:
• Different porphyrins vary in the nature of side chains that are attached to
each of the pyrrole rings.
• uroporphyrin> acetate and propionate (A & P)
• Coproporphyrin > methyl and propionate (M & P)
• Protoporphyrin > vinyl, methyl & propionate (V, M & P)

3. • 2. Distribution of side chains :
• side chains’ order can be different on the pyrrole rings of porphyrins
• Rings are named from A-D
• Type III porphyrins contain an asymmetric substitution on ring D
• Only Type III porphyrins are physiologically important in humans
• 3. Porphyrinogens :

4. B. Biosynthesis of heme
• Occurs in liver (rate-variable) and erythroid tissues (rate>
constant)
• The initial and the last three steps occur in mitochondria
while the rest of the reactions occur in cytosol
• 1. Formation of δ-aminolevulinic acid:
• Alanine and succinyl CoA condense to form d-
Aminolevulinic acid
• Catalyzed by ALAS I/II (I> in all tissues; II> erythroid
specific only)
• Porphyrins production exceeds the availability of
apoproteins> heme accumulates> converted to hemin by
oxidation of Fe2+ to Fe3+; hemin inhibits activity of ALAS
• Administration of any of a large no. of drugs inc. ALAS
activity as drug metabolism is carried out by CYP-
monooxygenase system which contain hemeproteins

5. • 2. Formation of porphobilinogen:
• 2 molecules of ALA condense to form porphobilinogen by the action of Zn
containing dehrdatase (porphobilinogen synthase)
• May be inhibited by heavy metals such as lead as seen in lead poisining

6. • 3. Formation of uroporphyrinogen:
• 4 porphobilinogen condense to form linear tetrapyrrole hydroxymethylbilane
which is converted into uroporphyrinogen III by uroporphyrinogen III
synthase

7. • 4. formation of coproporphyrinogen
• Decarboxylation of acetate groups of uroporphyrinogen III generate
coproporphyrinigen III

8. • 5. Formation of protoporphyrin IX:
• Coproporphyrinogen III enters mitochondria and its two P-side chains are
decarboxylated to vinyl groups by the action of coproporphyrinogen III oxidase.
Protoporphyrinogen IX is produced which is oxidized to protoporphyrin IX by
protoporphyrinogen oxidase

9. • Fe2+ is introduced to protoporphyrin IX to produce Heme; can be spontaneous or
can also be with the help of ferro chelatase.
• Ferro chelatase is also inhibited by lead

10. PORPHYRIAS
• Rare, inherited (occasionally acquired) disorder due to deficiency of specific
enzymes in heme synthesis, resulting in accumulation and excessive excretion of
specific porphyrins and intermediates in urine
• Red-blue color appears in urine due to pigment porphyrins
• Hepatic porphyria> enzyme deficiency in liver; erythropoietic porphyria> enzyme
deficiency in erythropoietic cells
• enzyme def. prior to tetrapyrrole formation causes abdominal and
neuropsychiatric signs
• Enzyme def. leading to accumulation of tetrapyrrole intermeds. Causes light
sensitivity
• Photosensitivity due to> oxidation of colorless tetrapyrrole intermeds.> produce
colored porphyrins which in the presence of light form ROS> ROS damage cell
membranes

11. HEPATIC PORPHYRIAS
• Chronic
• Due to def. of uroporphyrinogen decarboxylase; accumulation of
uroporphyrinogen III
• Light sensitivity; red to brown (natural light) and pink to red (fluorescent light)
color urine is formed
• ACUTE
• Due to deficiency of ALA-dehydratase; accumulation of ALA
• Abdominal pain; neuropsychiatric disturbances; anxiety
• Drug therapy> barbiturates or alcohol>> which induces CYP system heme-
proteins synthesis>> increases ALAS1 production to boost up heme synthesis for
drug oxidation

12. ERYTHROPOIETIC PORPHYRIAS
• Chronic; congenital and protoporphyria
• Skin rashes; blisters in early childhood
• Increased δ-aminolevulinic acid synthase activity:
• In any type of porphyria heme is not synthesized. This signals more production of
ALAS1 to cause heme synthesis but this synthesis proceeds as far as the step
where there is a genetic defect and heme is again not synthesized. This in turn
stimulates more ALAS1 synthesis and more accumulation of intermediates
(intermeds.) which is a severe pathological condition.
• So treatment of porphyria includes
• injections of hemin and glucose so that ALAS1 synthesis remains normal/or maybe
depressed (due to the fact that there is now more heme in body and no more heme
synthesis is required)
• Drugs for treatment of GIT disturbances
• Beta carotene as an antioxidant etc.

13. DEGRADATION OF HEME
• 85% of heme for degradation comes
from RBCs which have lived for 120
days; remainder comes from other
heme containing proteins
• Degradation is carried out by
reticuloendothelial system
particularly in liver and spleen
• 1. Formation of bilirubin:
• Heme oxygenase in macrophages
oxidizes heme into BILIVERDIN, CO
and Fe2+ in the presence of NADPH +
H+ and O2
• BILIVERDIN reduced to BILIRUBIN by
biliverdin reductase
• Biliverdin is green pigment while
bilirubin is red-orange pigment. These
colored compounds constitute bile
pigments
• CO is anti-inflammatory; and bilirubin
is mild antioxidant.

14. • 2. Uptake of bilirubin by the liver
• Bilirubin is only slightly soluble in
plasma therefor is transported in blood
by Albumin
• Salicylates and sulphonamides can
displace bilirubin from albumin,
causing bilirubin to be free which
enters CNS and maybe damaging
• Albumin-bilirubin complex reaching
liver dissociates, bilirubin enters liver
and binds to a protein called ligandin

15. • 3. Formation of bilirubin diglucuronide
• To inc. Solubility of bilirubin in liver 2
molecules of glucuronic acids are added
using UDP- glucuronic acid as
glucuronate donor
• Reaction catalysed by Bilirubin UDP-
glucuronosyltransferase [conjugation
reaction forming conjugated bilirubin
(CB)]
• 4. Secretion of bilirubin into bile :
• CB is actively transported from liver into
bile canaliculi and then into bile
• Energy dependent and rate limiting
step; deficiency of transporting protein>
Dubin-Johnson Syndrome

16. • 5. Formation of urobilins in the intestine:
• CB is hydrolyzed and reduced by the gut bacteria producing urobilinogen (ub), a
colorless compound
• Ub is oxidized by intestinal bacteria to STERCOBILIN which gives feces brown
color
• Some Ub is reabsorbed from intestine and enters blood. Blood transports Ub to
liver and kidney
• In liver, Ub is resecreted into bile; reconverted into stercobilin and removed in feces. This is
known as enterohepatic circulation.
• In kidneys, Ub is converted into yellow urobilin and is excreted in urine giving urine its
characteristic yellow color

17. CATABOLISM OF HEME

18. JAUNDICE
• Also known as icterus; refers to the yellow color of skin, nail beds and sclerae of eyes
due to Bilirubin deposition as a result of elevated Bilirubin plasma levels.
• A symptom not a disease
• Normal bilirubin levels> 1mg/dL; jaundice at 2-3mg/dL
• A. Hemolytic jaundice: bilirubin is produced by the macrophages and conjugation of
bilirubin occurs in liver to produce conjugated bilirubin (CB) which is passed to bile. (as
described in previous section)
• In case of extensive hemolysis, large no. of RBCs are degraded> more Heme is degraded
into Bilirubin>these high levels of bilirubin exceed the conjugating capacity of liver> the
result is that unconjugated bilirubin (UCB) levels rise in blood plasma>> jaundice
• B. Hepatocellular jaundice:
• Damage to liver cells> liver capacity of conjugating Bilirubin is dec.> plasma levels of
UCB are elevated>> jaundice
• 2ndly hepatic damage dec. enterohepatic circulation of Ub as a result more Ub is
delivered to the kidneys>> more Urobilin is produced and Urine Darkens
• Also liver damage dec. the amount of CB in intestine>> stercobilin production is dec.
and stool becomes pale, clay colored.
• Another scenario is that Bilirubin is effectively conjugated to CB but this CB is not
secreted into bile, a condition referred to as intrahepatic cholestasis this causes CB to
diffuse into blood leading to conjugated hyperbilirubinemia.

19. • C. Obstructive jaundice: obstruction in bile duct due either to
bile stone or tumor>> CB is not secreted into bile duct>>
extrahepatic cholestasis>> CB levels rise in plasma >> conjugated
hyperbilirubinemia
• CB is excreted in urine then which darkens upon standing
• D. Jaundice in newborns (neonatal jaundice) :
• Usually in preterm babies but can also be found in full term
babies
• Due to low levels of bilirubin Uridine-glucuronosyl-transferase
(UGT) that catalyzes the conjugation of bilirubin in liver.
• UGT in infants reaches adult levels in about 4 weeks after birth.
• Scenario : low UGT> raises plasma levels of UCB>> high UCB
levels exceed the binding capacity of Albumin and UCB enters
brain by crossing BBB>> result is toxic encephalopathy and
jaundice
• Treatment is phototherapy> newborn is subjected to flourescent
light>> which converts UCB to water soluble isomers>> these can
be excreted into bile without conjugation.