The document discusses porphyrin metabolism, focusing on heme synthesis, regulation, and catabolism. It details the pathways for heme synthesis, regulatory mechanisms in liver and erythroid cells, and the processes leading to bilirubin formation and excretion. It also covers disorders related to heme metabolism, including porphyrias and jaundice, highlighting their causes and symptoms.

1. PORPHYRIN METABOLISM
BY JYOTI ARORA

2. STRUCTURE
• Porphyrins are cyclic compounds that bind to metallic
ions (usually Fe2+ or Fe3+)
• Porphyrin + metal = metalloporphyrin
• The most prevalent metallopophyrin in human is heme,
which consists of one Fe2+ coordinated in the center of
tetrapyrrol ring through methyl bridges. The porphyrin
in heme, with its particular arrangement of four methyl,
two propionate, and the two vinyl substituents, is
known as protoporphyrin IX.
• Heme is the prosthetic group for hemoglobin,
myoglobin, the cytochromes, catalase and tryptophan
pyrrolase.

3. Protoporphyrin III
prefix or suffix ring substituents between rings
uro- acetate, propionate --
copro- methyl, propionate --
proto- methyl, propionate, vinyl
-porphyrinogen -- methylene
-porphyrin -- methene

4. Uroporphyrinogen I Coproporphyrinogen I
Overviewof Heme Synthesis
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.
Succinyl CoA + Glycine
-aminolevulinic acid
-aminolevulinic acid
Porphobilinogen Uroporphyrinogen III Coproporphyrinogen III
Coproporphyrinogen III
Protoporphyrinogen IX
Protoporphyrin IX
Heme
ALA synthase
cytoplasm
mitochondrial matrix

5. SYNTHESIS
• The porphyrins are constructed from four molecules of the monopyrolle
derivative porphobilinogen, which itself is derived from two molecules of δ-
aminolevulinate.
• There are two major pathways to δ-aminolevulinate:
 in higher eukaryotes, glycine reacts with succinyl-CoA in the first step to yield
α-amino-β-ketoadipate, which is then decarboxylated to δ-aminolevulinate.
 In plants, algae, and most bacteria, δ-aminolevulinate is formed from
glutamate.The glutamate is first esterified to glutamyl-tRNAGlu ; reduction by
NADPH converts the glutamate to glutamate 1-semialdehyde, which is
cleaved from tRNA. An aminotransferase converts the glutamate 1-
semialdehyde to δ-aminolevulinate.

7. Synthesis contd.
• In all organisms, two molecules of δ-aminolevulinate condense to
form porphobilinogen and then the condensation of four molecules
of porphobilinogen results in the formation of uroporphybilinogen lll.
• uroporphybilinogen lll is converted to heme by a series of
decarboxylation and oxidation reactions
• The introducing of Fe+2 into protoporphyrin spontaneously, but the
rate is enhanced by ferrochelatase ( an enzyme inhibited by lead.

9. REGULATION OF HEME BIOSYNTHESIS
• The two major sites of heme biosynthesis are erythroid cells, which synthesize
~85% of the body’s heme groups, and the liver, which synthesizes ~ 80% of the
remainder.
• An important function of heme in liver is as the prosthetic groups of the
cytochromes P450, a family of oxidative enzymes involved in detoxification,
whose members are required throughout a liver cell’s lifetime in amounts that
vary with conditions.
• In contrast, erythroid cells, in which heme is, of course, a hemoglobin
component, engage in heme synthesis only on differentiation, when they
synthesize hemoglobin in vast quantities.This is a onetime synthesis; the heme
must last the erythrocyte’s lifetime (normally 120 days) since heme and
hemoglobin synthesis stop on red cell maturation (protein synthesis stops on the
loss of nuclei and ribosomes).
• The different ways in which heme biosynthesis is regulated in liver and in
erythroid cells reflect these different demands: In liver, heme biosynthesis must
really be “controlled,” whereas in erythroid cells, the process is more like
breaking a dam.

10. Regulation contd.
IN LIVER :
• The main control target in heme biosynthesis is ALA synthase, the
enzyme catalyzing the pathway’s first committed step. Heme, or its
Fe(III) oxidation product hemin, controls this enzyme’s activity
through three mechanisms:
(1) feedback inhibition,
(2) inhibition of the transport of ALA synthase (ALAS) from its site of
synthesis in the cytosol to its reaction site in the mitochondrion, and
(3) repression of ALAS synthesis.
IN ERYTHROCYTES
• In erythroid cells, heme exerts quite a different effect on its
biosynthesis. Heme induces, rather than represses, protein synthesis
in reticulocytes (immature erythrocytes).

11. Regulation contd.
• Moreover, the rate-determining step of heme biosynthesis in
erythroid cells may not be the ALA synthase reaction.
• Experiments on various systems of differentiating erythroid cells
implicate ferrochelatase and porphobilinogen deaminase in the
control of heme biosynthesis in these cells. There are also indications
that cellular uptake of iron may be rate limiting.
• Iron is transported in the plasma complexed with the iron transport
protein transferrin. The rate at which the iron–transferrin complex
enters most cells, including those of liver, is controlled by receptor-
mediated endocytosis. However, lipid-soluble iron complexes that
diffuse directly into reticulocytes stimulate in vitro heme biosynthesis.

12. CATABOLISM OF HEME
• When hemoglobin is destroyed in the body, globin is degraded to its constituent
amino acids, which are reused, and the iron of heme enters the iron pool, also for
reuse. The iron-free porphyrin portion of heme is also degraded, mainly in the
reticuloendothelial cells of the liver, spleen, and bone marrow.
• The catabolism of heme from all of the heme proteins appears to be carried out
in the microsomal fractions of cells by a complex enzyme system called heme
oxygenase. By the time the heme derived from heme proteins reaches the
oxygenase system, the iron has usually been oxidized to the ferric form,
constituting hemin.
• the hemin is reduced to heme with NADPH, and, with the aid of more NADPH,
oxygen is added to the α-methyne bridge between pyrroles I and II of the
porphyrin. The ferrous iron is again oxidized to the ferric form. With the further
addition of oxygen, ferric ion is released, carbon monoxide is produced, and an
equimolar quantity of biliverdin results from the splitting of the tetrapyrrole ring.

13. Catabolism contd.
• In birds and amphibia, the green biliverdin IX is excreted; in
mammals, a soluble enzyme called biliverdin reductase reduces the
methylene bridge between pyrrole III and pyrrole IV to a methylene
group to produce bilirubin, a yellow pigment
• Bilirubin formed in peripheral tissues is transported to the liver by
plasma albumin. The further metabolism of bilirubin occurs primarily
in the liver. It can be divided into three processes:
(1) uptake of bilirubin by liver parenchymal cells,
(2) conjugation of bilirubin with glucuronate in the endoplasmic
reticulum, and
(3) secretion of conjugated bilirubin into the bile. Each of these
processes will be considered separately.

14. THE LIVER TAKES UP BILIRUBIN
• Bilirubin is only sparingly soluble in water, but its
solubility in plasma is increased by noncovalent
binding to albumin. Bilirubin in excess of this
quantity can be bound only loosely and thus can
easily be detached and diffuse into tissues.
• In the liver, the bilirubin is removed from albumin
and taken up at the sinusoidal surface of the
hepatocytes by a carrier-mediated saturable
system. This facilitated transport system has a very
large capacity, so that even under pathologic
conditions the system does not appear to be rate-
limiting in the metabolism of bilirubin.
Catabolism contd.

15. Conjugation of Bilirubin with Glucuronic Acid Occurs in the
Liver
• Bilirubin is nonpolar and would persist in cells (eg, bound to lipids) if
not rendered water-soluble. Hepatocytes convert bilirubin to a polar
form, which is readily excreted in the bile, by adding glucuronic acid
molecules to it. This process is called conjugation and can employ
polar molecules other than glucuronic acid (eg, sulfate).
• The conjugation of bilirubin is catalyzed by a specific
glucuronosyltransferase. The enzyme is mainly located in the
endoplasmic reticulum, uses UDP-glucuronic acid as the glucuronosyl
donor, and is referred to as bilirubin-UGT. Bilirubin monoglucuronide
is an intermediate and is subsequently converted to the diglucuronide
Catabolism contd.

16. Bilirubin Is Secreted into Bile
• Secretion of conjugated bilirubin into the bile occurs by an active transport
mechanism, which is probably rate-limiting for the entire process of
hepatic bilirubin metabolism.
• The protein involved is MRP-2 (multidrug-resistance-like protein 2), also
called multispecific organic anion transporter (MOAT). It is located in the
plasma membrane of the bile canalicular membrane and handles a number
of organic anions.
ConjugatedBilirubinIs Reduced to Urobilinogenby Intestinal Bacteria
• As the conjugated bilirubin reaches the terminal ileum and the large
intestine, the glucuronides are removed by specific bacterial enzymes (β-
glucuronidases), and the pigment is subsequently reduced by the fecal flora
to a group of colorless tetrapyrrolic compounds called urobilinogens. In the
terminal ileum and large intestine, a small fraction of the urobilinogens is
reabsorbed and reexcreted through the liver to constitute the
enterohepatic urobilinogen cycle.
Catabolism contd.

19. DISORDERS IN HEME METABOLISM
PORPHYRIA
Porphyria are rare inherited defects in heme
synthesis. An inherited defect in an enzyme of heme
synthesis results in accumulation of one or more of
porphyrin precursors depending on location of
block of the heme synthesis pathway. These
precursors increase in blood & appear in urine of
patients. Most porphyrias show a prevalent
autosomal dominant pattern, except congenital
eythropoietic porphyria, which is recessive.
The most common form of porphyria is acute
intermittent porphyria.

20. Disorders: porphyria contd.
• One of the rarer porphyrias results in an accumulation of
uroporphyrinogen I, an abnormal isomer of a protoporphyrin
precursor. This compound stains the urine red, causes the teeth to
fluoresce strongly in ultraviolet light, and makes the skin abnormally
sensitive to sunlight. Many individuals with this porphyria are anemic
because insufficient heme is synthesized. This genetic condition may
have given rise to the vampire myths of folk legend.

22.  JAUNDICE
• When bilirubin in the blood exceeds 1 mg/dL (17.1 μmol/L),
hyperbilirubinemia exists. Hyperbilirubinemia may be due to the
production of more bilirubin than the normal liver can excrete, or it
may result from the failure of a damaged liver to excrete bilirubin
produced in normal amounts. In the absence of hepatic damage,
obstruction of the excretory ducts of the liver—by preventing the
excretion of bilirubin—will also cause hyperbilirubinemia. In all these
situations, bilirubin accumulates in the blood, and when it reaches a
certain concentration (approximately 2–2.5 mg/dL), it diffuses into
the tissues, which then become yellow. That condition is called
jaundice or icterus.
Disorders contd.

23. Elevated Amounts of Unconjugated Bilirubin in Blood
Occur in a Number of Conditions
• Hemolytic anemias
• Neonatal “Physiologic Jaundice”
• Type I Crigler–Najjar syndrome
• Crigler–Najjar Syndrome, Type II.
• Gilbert Syndrome
• Toxic Hyperbilirubinemia
Disorders: jaundice contd.

24. Obstruction in the Biliary Tree Is the Most Common
Cause of Conjugated Hyperbilirubinemia
• Obstruction of the Biliary Tree
• Dubin–Johnson Syndrome
• Rotor Syndrome
Some Conjugated Bilirubin Can Bind Covalently to
Albumin
Disorders: jaundice contd.

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