Amino acids as biosynthetic precursors (L718)

Some amino acids, in addition to their function as protein building

blocks, are also essential precursors of a variety of essential and
important biomolecules, including nucleotides and nucleotides
coenzymes, heme, various hormones and neurotransmitters and
glutathione.

The Heme prosthetic group

It is a fact that the capacity of myoglobin or hemoglobin to bind oxygen

depends on the presence of a non-polypeptide unit called the Heme. It is
the heme that give myoglobin and hemoglobin their distinctive color>
Many protein require tightly bound, specific non-polypetide units for
their biological activities, such units are known as the prosthetic group.
(what is a prosthetic group?).A protein without a prosthetic group is
termed apoprotein.

The heme characteristics: It consists of an organic part and an iron

atom. The organic part, protoporphyrin is made up of four pyrrole rings
(A-D) see Fig 1-4. These rings are linked by, methane bridges to form
tetrapyrrole ring with four methyl, two vinyl, and two propionate side
chains attached to the tetrapyrrole ring. These substitution, are known
to have fifteen different possibilities.

The iron atom in heme binds to four nitrogens in the center of the
protoporphyrin (only this present in biological system) ring. The iron
can form two additional bonds one on either side of the heme plane. The
iron atom can be in the ferrous (+2) or the ferric (+3) oxidation state.
Note that it is only the +2 oxidation state also known as
ferrohemoglobin that can bind oxygen.

Heme biosynthesis: The initial reaction (Fig 1-4) leading to the

biosynthesis of heme, are common to the formation of other
tetrapyrroles such as chlorophyll in plant and coenzyme B12 in bacteria.
Fig 1-4: Structure of Heme.

Porphyrin biosynthesis with a net yield of heme

The biosynthesis of products that yield heme take place partly in the
mitochondria and partly in the cytosol
Experiments conducted by Shemin D and Rittenberg D showed that the
first step in the biosynthesis of porpherins in mammals is the
condensation or decarboxylation of glycine and succinyl CoA to form -
aminolevulinic acid (ALA). This reaction is catalyzed by the PLP
(pyridoxal 5-phosphate (vitamin B6)) dependent enzyme -
aminolevulinate synthase, in the mitochondria. This committed step in
porpherins biosynthesis is regulated by two molecules of -
aminolevulinate that are condense to form porphobilinogen (PBG) in
the cytosol, this is a dehydration reaction catalyzed by -
aminolevulinate dehydrase. Four molecules of PBG condense to form
porphyrin ring. Following two-oxidation process of the pyrrole ring
substituents that yield protoporphyrinogen IX, is transported back to
the mitochondria. Whilst in the mitochondrion protoporphyrinogen
oxidase catalyze the oxidation of the methylene groups linking the
pyrroles to yield protoporphrin IX take place, from here, ferrochelatase
catalyzes the insertion of Fe2+, yielding heme.

Regulation of heme biosynthesis

Several factors regulating heme in animals have been elucidated.
Importantly, - aminolevulinate synthase (enzyme that catalyze the
committed step in the biosynthesis of heme), is feed back inhibited by
heme, as is -aminolevulinate dehydrase and ferrochelatase (Define
feedback inhibition). However, its, been found that heme are regulated
differently in erythroid and liver cells being the two major sites of heme
biosynthesis (the two major sites of heme synthesis in eukaryotic cells
are?). Note: an important function of heme in liver is as prosthetic
groups of the cytochrome P450 (a family of oxidative enzymes involved
in detoxification).

In the liver heme biosynthesis is regulated via ALA (- aminolevulinate)

synthase. Heme, or its Fe(III) oxidation product hemin, control enzyme
activity through one of three mechanisms:
 Feedback inhibition
 Inhibition of the transport of ALA synthase (ALAS) from its site of
synthesis in the cytosol to the reaction site in the mitochondria
 Repression of ALAS synthesis.
What are the processes involved in Heme biosynthesis in the liver?
However, in the erythroid cells, heme exerts quite a different effect on its
biosynthesis. Here, heme induces rather than represses, protein
synthesis in the reticulocyte (immature erythrocyte). The antimalaria
drug, chloroquine prevents malaria by the inhibition of the plasmodial
heme sequestration.

Degradation of heme to bile pigments

The normal human erythrocyte has an average life span of 120 days.
Hence, old cells are removed from the circulation and degraded by the
spleen. Thus, the first step in the degradation of heme begin with an
oxidative cleavage by heme oxygenase of the porphyrin between ring A
and B (see fig), to form biliverdin, which is a green linear tetrapyrrole.
Note, in this reaction:
 The heme oxygenase is a mono-oxygenase hence O2 and NADPH
are required for the cleavage reaction.
 A methenyl-bridge carbon is released as carbon monoxide this
endogenous CO posed a problem for the evolution of oxygen
carriers in the body.
Further, this is followed by the reduction (biliverdin reductase) of the
central methenyl-bridge (between ring C and D), of biliverdin,
forming the red-orange bilirubin. Note, the changing color of a healing
wound are a visible manifestation of heme degradation. Bilirubin
form complex with serum albumin and is transported to the liver,
where it is rendered more soluble via attachment of sugar
(glucuronic) residue to its two-propionate side chain, yielding
bilirubin diglucuronide, this is secreted into the bile. Bacterial
enzymes in the large intestine hydrolyze the glucuronic acid groups
and in a multistep process convert bilirubin to several products
including urobilinogen. Some of this is reabsorbed and transported
via blood stream to the kidney where it is converted to the yellow
urobilin and excreted, it is this that give urine its characteristics color.
It is also thought that via yet un-explained microbial convertion most
urobilinogen are converted to the deeply red-brownish stercobilin,
which form the major pigment of feaces.

Note: when blood contains excessive amount of bilirubin, it colors the

skin and the whites of the eyes yellow, leading to a medical condition
termed jaundice. Thus, this condition signals either an abnormally
high rate of red cell destruction, liver dysfunction, or bile duct
obstruction.