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Biochem 5.1 Porphyrins and Bile Trans
Biochem 5.1 Porphyrins and Bile Trans
Biochem 5.1 Porphyrins and Bile Trans
Novemeber
7 2015
TRANS OUTLINE
I.
II.
III.
IV.
Heme Synthesis
Heme Catabolism
Fate of Bilirubin
Clinical Notes
I. Heme Synthesis
Biomedical Importance:
Heme: Synthesized from Porphyrins & Iron
Porphyrins Cyclic compounds formed by linkages
of 4 pyrrole rings through methyne bridges.
Heme: Produces Bile Pigments & Iron when degraded
Biosynthesis of Heme:
Occurs in the mitochondria & cytoplasm of RBC
precursors.
Begins with the condensation of Glycine & Succinyl
CoA.
Glycine is activated by Pyridoxal Phosphate.
st
1 Product of Glycine & Succinyl CoA is a-Amino-Bketoadipic acid this product is rapidly
decarboxylated to form a-Aminolevulainate (ALA).
Decarboxylation process of a-Amino-B-ketoapidic
acid is catalyzed by: Aminolevulinate Synthase
(ALAS)
ALA Dehydratase + ALA = Porphobilinogen
ALA Dehydratase is aka: Porphobilinogen Synthase.
ALA Dehydratase is a Zinc containing enzyme
sensitive to inhibition by Lead.
Porphobilinogen Deaminase (aka: hydroxymethylilane
synthase or Urophorphyrinogen 1 Synthase) +
porphobilinogen = Hydroxyl methylbilane or
Urophorphyrinogen 1
Urophorphyrinogen 1 is converted to Uriphorphyrinogen
III by Urophorphyrinogen III Synthase
Urophorphyrinogen III converted to Coporphyrinogen III
by acetate decarboxylation.
This acetate decarboxylation action will convert
acetate to Methyl substituents.
Urophorphyrinogen III conversion to
Coporphyrinogen III is catalyzed by
Urophorphyrinogen Decarboxylase.
Corpophyrinogen III enters the Mitochondria where it is
converted to Protophorphyrinogen III.
Coprophyrinogen Oxidase catalyzes the production
of Porphopyrinogen. (This enzyme only acts on
Coprophyrinogen III).
Protophorphyrinogen III converted to Protophyrin III.
An oxidation process catalyzed by
Protophophyrinogen Oxidase Enzyme.
FINAL STEP OF HEME SYNTHESIS:
Ferrous Iron is incorporated into the Protophyrin.
This reaction is catalyzed by: Ferrochelatase (aka:
Heme Synthase)- a mitochondrial enzyme.
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Degrades heme to :
biliverdin
carbon monoxide
iron
Biliverdin
Bilirubin + NADP
3-
3+
Fe Heme + 3 O2 + 7 e
bliverdin + CO+ Fe
3-
Heme Catabolism
the HMOX1 encoded enzyme is inducible by
heme, heavy metals, and conditions of stress
such as hypoxia
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Sources:
Senescent RBC
Premature RBC Bone Marrow
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biliverdin reductase
genes
BLVRA
1.
BLVRB
NADPH dependent flavin
redcutase
2.
Catabolism of:
-Biliverdin
Catabolism of :
-Bilive-Biliverdin rdin
-Flavins
Eg. Riboflavin
FAD FMN
-MethHG
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-
-
-
Glucuronide
-
Increases polarity and solubility
Glucuronidation
-
Addition of glucuronide
-
Most important of conjugation reaction
-
Reaction does not proceed spontaneously
-
Requires the activated form of glucuronic acid
(glucuronic acid uridine diphosphate)
Glucuronidation and Grey Baby Syndrome
3.
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Uptake by
the Liver
Conjugation
with
Glucorinic
acid
Secretion of
Bilirubin
into the Bile
Bile
RBC will circulate the body for 120 days, when these RBC reached their life span, Old
RBC it will be
phagocytosed by macrophages in spleen and bonemarrow .
RBC now will release to its Hemoglobin molecule
Hemoglobin degraged into globin and heme
Globin is a protein and it will breakdown into AMINO ACIDS and be reuse for
Erythropoiesis
HEME will be broken down to unconjugated bilirubin and Iron
Iron will re-enter the circulation and re- used for Erythropoiesis like the Globin
Unconjugated bilirubin is not recycled and thus needs to be excreted because it is toxic. It
has a yellowish orange color
For the Unconjugated bilirubin to be Lipid soluble when it is in the blood, it requires
protein for it to be carried around. This protein is called Albumin
Albumin will carry the unconjugated bilirubin into the liver for further metabolism
Liver has own macrophage Kupffer cells which break donwn other old/senescent RBC
Unconjugated Bilirubin is lipid soluble
LIVER is the site for conjugation (lipid soluble to water soluble)
Unconjugated Bilirubin will form into conjugated by glucoronic acid
Conjugated Bilirubin will be water soluble for it to be excreted by bile contains which
contains Conjugated Bilirubin and Bile salt
Conjugated Bilirubin and Bile salt will be excreted into small intestine
Conjugated Bilirubin will go to the small intestine through the common bile duct
Conjugated Bilirubin travels in large intestine
Ileum where Conjugated Bilirubin is converted by intestinal bacteria to become
Urobilinogen by removing glucorinic acid
Urobilinogen lipid soluble 10-15 percent bound to albumin and reabsorbed
Stercobilin brown colored pigment
Conjugated Bilirubin excreted
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-
-
-
Types of Hyperbilirubinemia
1. Retention hyperbilirubinemia due to over
production of bilirubin (unconjugated bilirubin)
2. Regurgitation hyperbilirubinemia due to reflux
into the bloodstream secondary to biliary
obstruction (conjugated bilirubin)
Fig.6.Heme Degradation
Clinical Notes
Two types of Clinical problems associated with heme
metabolism:
1. Porphyrias
-
Disorders that arise from defects in the
enzymes of heme biosynthesis
-
Both inherited and acquired
-
Classified as either erythroid or hepatic,
depending upon the principal site
expression of the enzyme defect
-
Cause elevation in serum and urine
Type
Deficient enzyme
Gene
ALADehydratase
Acute
Intermittent
Porphyria
ALA-Dehydratase
ALAD
Gene
locus
9q34
Hydroxymethylbila
ne
synthase
(Porphobilinogen
deaminase
Uroporphyrinogen
III synthase
HMBS
11q23
UROS
10q25-26
Uroporphyrinogen
decarboxylase
UROD
1p34
Uroporphyrinogen
decarboxylase
UROD
3q12
Hereditary
Coproporphia
(HCP)
Variegata
Porphyria (VP)
Coproporhyrinogen
oxidase
CPOX
1q22
Protoporphyrinoge
n oxidase
PPOX
18q21
Erythropietic
(EPP)
X-linked
Protoporphyria
(XLP)
Ferrochelatase
FECH
-Aminolevulinate
synthase 2
ALAS2
Congenital
Erythropoietic
Porphyria
(CEP)
Porphyria
Cutanea Tarda
(PCT), familial
form
Hepatoerythrop
oietic Porphyria
(HEP)
2.
Kernicterus
-
Because
of
its
hydrophobicity,
only
unconjugated bilirubin can cross the bloodbrain barrier into the CNS
-
Encephalopathy due to hyperbilirubinemia
(kernicterus) can occur in only with
unconjugated bilirubin, as found in retention
hyperbilirubinemia
Jaundice
-
Conjugated bilirubin can appear in urine
Choluric jaundice
-
Occurs only in regurgitation hyperbilirubinemia
Acholuric jaundice
-
Occurs only in the presence of an excess of
unconjugated bilirubin
Unconjugated Hyperbilirubinemia
Xp11.21
Bilirubinemias
-
Inherited disorders of bilirubin metabolism
Hyperbilirubunemia and Jaundice
-
Occurs when bilirubin in the blood exceeds
1mg/dL (17.1 mol)
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Conjugated Hyperbilirubinemia
Biliary obstruction
-
Regurgitation into hepatic veins and lymphatics
-
Conjugated bile in blood urine
Dubin-Johnson Syndrome
-
Benign autosomal recessive
-
Mutation in the gene encoding MRP-2 for thee
secretion of conjugated bilirubin into bile
Rotor Syndrome
-
Chronic conjugated hyperbilirubinemia and
normal liver
References
https://www.rarediseasesnetwork.org/porphyrias/patients/lear
nmore/index.htm
th
Harpers Illustrated Biochemistry 30 Edition
Dr. Pacifico Eric E. Calderons Lecture
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