Heme Metabolism PDF
Heme Metabolism PDF
Heme Metabolism PDF
Biochemistry-1(PHL-284)
Heme Metabolism
Heme is a member of a family of compounds called porphyrins.
Many important proteins contain heme as a prosthetic group.
Heme proteins
Hemoglobin (oxygen transport)
Myoglobin (oxygen transport)
Cytochromes (electron transport)
Catalase (H2O2 utilization)
Structure of Prophyrins
The base structure is porphin
Made up of 4 pyrrole rings
Linked by 4 methyne (=CH-) groups
Porphyrins are substituted at positions 1-8
Properties of porphyrins
Color: dark red/purple
Fluorescent
Properties of porphyrinogens
Colorless
Not fluorescent
Easily auto-oxidized to porphyrins
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Names of Porphyrins:
The names of the porphyrins of interest consist of a word and a
number, e.g., uroporphyrin III. The word denotes the kinds of
substituents found on the ring, and the number denotes how they
are arranged.
There are three important words:
uroporphyrin contains A and P only
coproporphyrin contains M and P only (A has been
changed to M)
protoporphyrin contains M and P and V (some P has been
changed to V)
There are two important numbered series, I and III.
Series II and IV do not occur in natural systems.
In series I the substituents repeat in a regular manner, e.g.,
APAPAPAP (starting with ring I).
In series III the order of substituents in ring IV is reversed:
APAPAPPA.
If three kinds of groups are present, as in the protoporphyrins, its
immediate precursor is variously referred to as protoporphyrin III
or protoporphyrin IX.
Solubility
Heme Synthesis
Site: partly in the mitochondria and partly in the cytoplasm.
Reactions:
1) Delta-aminolevulinic acid synthase (ALA synthase)
The substrates are succinyl-CoA and glycine
The product is delta-aminolevulinic acid (ALA).
An essential cofactor is pyridoxal phosphate (vit B-6).
This is the rate-limiting reaction of heme synthesis in all
tissues, and it is therefore tightly regulated.
2) ALA dehydratase
The substrates are two molecules of ALA.
The product is porphobilinogen, the first pyrrole.
ALA dehydratase is a -SH containing enzyme.
It is very susceptible to inhibition by lead.
3) Uroporphyrinogen I synthase and uroporphyrinogen III
cosynthase
Production of uroporphyrin III requires two enzymes.The
substrates are four molecules of porphobilinogen.
4) Uroporphyrinogen decarboxylase
Decarboxylates the acetic acid groups, converting them to
methyl groups.
5) Coproporphyrinogen III oxidase
Catalyzes the conversion of two propionic acid groups to vinyl
groups
6) Protoporphyrinogen IX oxidase
Protoporphyrinogen IX oxidase converts the methylene
bridges between the pyrrole rings to methenyl bridges.
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7) Ferrochelatase
Ferrochelatase adds Fe++ to protoporphyrin IX, forming
heme.
The enzyme requires Fe++, ascorbic acid and cysteine
(reducing agents).
Ferrochelatase is inhibited by lead.
Heme
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succinyl CoA + Glycine protoporphyrin IX
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1
protoporphyrinogen IX
delta- aminolevulinic acid 5
coproporphyrinogen III
cytoplasm mitochondria
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4
uroporphyrinogen I coproporphyrinogen I
Porphyrias:
Porphyrias may be divided into two major types.
Examples of porphyria:
Two of the several types of porphyria will serve to illustrate some
of the biochemical issues involved.
Acute intermittent porphyria (defect of hepatic
uroporphyrinogen I synthase activity).
porphobilinogen (the substrate) accumulates, and is excreted
in the urine.
Heme synthesis is reduced. ALA synthase activity therefore
increases.
There are neurological symptoms, which cannot be
explained.
Congenital erythropoietic porphyria ( defect of
uroroporphyrinogen cosynthase).
Large amounts of type I porphyrins
Skin photosensitivity
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Heme Degradation
Most of the heme which is degraded comes from hemoglobin in
red blood cells, which have a life span of about 120 days. There is
thus a turnover of about 6 g/day of hemoglobin. Normally,
senescent red blood cells and heme from other sources are
engulfed by cells of the reticuloendothelial system. The globin is
recycled or converted into amino acids, which in turn are recycled
or catabolized as required. Heme is oxidized.
Hyperbilirubinemia (jaundice)
2. Hepatic:
2.1 Gilbert's disease
may be caused by an inability of the hepatocytes to uptake
bilirubin from the blood
As a result, unconjugated bilirubin accumulates.
2.2 Physiological jaundice and Crigler-Najjar syndrome
Conjugation is impaired.
Unconjugated bilirubin is retained by the body.
2.3 Dubin-Johnson syndrome
Inability of the hepatocytes to secrete conjugated bilirubin
after it has been formed.
Conjugated bilirubin returns to the blood.