Molecules derived from Amino Acids:
In addition to serving as building blocks for proteins, amino acids are precursors of many nitrogen
containing compounds that have important physiologic functions (Figure 21.1). These molecules
include porphyrins, neurotransmitters, hormones, purines, and pyrimidines.
1. Porphyrins
Glycine (non-essential AA) is the precursor. It condenses with succinyl CoA (intermediate of the
CAC) to form δ-aminolevulinate.
Structure of porphyrins
Porphyrins are cyclic molecules formed by the linkage of four pyrrole rings through methenyl bridges
(Figure 21.2). Three structural features of these molecules are relevant to understanding their medical
significance.
1. Side chains: Different porphyrins vary in the nature of the side chains that are attached to each
of the four pyrrole rings. Uroporphyrin contains acetate (–CH 2–COO–) and prop ionate (–CH2–CH2–
COO–) side chains, coproporphyrin contains methyl (–CH 3) and propionate groups, and
protoporphyrin IX (and heme) contains vinyl (–CH=CH2), methyl, and propionate groups. [Note:
The methyl and vinyl groups are produced by decarboxylation of acetate and propionate side chains,
respectively.]
2. Distribution of side chains: The side chains of porphyrins can be ordered around the
tetrapyrrole nucleus in four different ways, designated by Roman numerals I to IV. Only Type III
porphyrins, which contain an asymmetric substitution on ring D are physiologically important in
humans. [Note: Protoporphyrin IX is a member of the Type III series.]
3. Porphyrinogens: These porphyrin precursors (for example, uroporphyrinogen) exist in a
chemically reduced, colorless form, and serve as intermediates between porphobilinogen and the
oxidized, colored protoporphyrins in heme biosynthesis.
Synthesis:
The porphyrins are constructed from four molecules of the monopyrrole derivative
porphobilinogen, which itself is derived from two molecules of δ-aminolevulinate.
There are two major pathways to δ-aminolevulinate. In higher eukaryotes (Fig. 22–23a),
glycine reacts with succinyl-CoA in the first step to yield α-amino-β-ketoadipate, which is
then decarboxylated to δ-aminolevulinate. (see lecture notes).
This reaction requires pyridoxal phosphate (PLP) as a coenzyme, and is the committed and rate
limiting step in porphyrin biosynthesis.
Note: There are two isoforms of ALAS (δaminolevulinate synthase), 1 and 2, each controlled by
different mechanisms. Erythroid tissue produces only ALAS2, the gene for which is located on the X
chromosome. Loss of function mutations in ALAS2 result in Xlinked sideroblastic anemia.]
In all organisms, two molecules of δ-aminolevulinate condense to form porphobilinogen
and, through a series of complex enzymatic reactions, four molecules of porphobilinogen
come together to form protoporphyrin
(Fig. 22–24). The iron atom is incorporated after the protoporphyrin has been assembled,
in a step catalysed by ferrochelatase.
Regulation: End-product inhibition of ALAS1 by hemin:
Porphyrin biosynthesis is regulated in higher eukaryotes by the concentration of the
heme product, which serves as a feedback inhibitor of early steps in the synthetic
pathway.
, When porphyrin production exceeds the availability of the apoproteins that require it, heme
accumulates and is converted to hemin by the oxidation of Fe 2+ to Fe3+. Hemin decreases the activity
of hepatic ALAS1 by causing decreased synthesis of the enzyme, through inhibition of mRNA
synthesis and use (heme decreases stability of the mRNA), and by inhibiting mitochondrial
import of the enzyme. [Note: In erythroid cells, ALAS2 is controlled by the availability of intracellular
iron.]
Associated Diseases:
Genetic defects in the biosynthesis of porphyrins can lead to the accumulation of
pathway intermediates, causing a variety of human diseases known collectively as
porphyrias.
Porphyrias are rare, inherited (or occasionally acquired) defects in heme synthesis, resulting in the
accumulation and increased excretion of porphyrins or porphyrin precursors. With few exceptions,
porphyrias are inherited as autosomal dominant disorders.
The mutations that cause the porphyrias are heterogenous (not all are at the same DNA locus), and
nearly every affected family has its own mutation. Each porphyria results in the accumulation of a
unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic
pathway. [Note:“Porphyria” refers to the purple color caused by pigmentlike porphyrins in the urine of
some patients with defects in heme synthesis.]
1. Clinical manifestations:
The porphyrias are classified as erythropoietic or hepatic, depending on whether the enzyme
deficiency occurs in the erythropoietic cells of the bone marrow or in the liver. Hepatic porphyrias can
be further classified as chronic or acute. In general, individuals with an enzyme defect prior to the
synthesis of the tetrapyrroles manifest abdominal and neuropsychiatric signs, whereas those with
enzyme defects leading to the accumulation of tetrapyrrole intermediates show photosensitivity—
that is, their skin itches and burns (pruritus) when exposed to visible light. [Note: Photosenstivity is a
result of the oxidation of colorless porphyrinogens to colored porphyrins, which are photosensitizing
molecules that are thought to participate in the formation of superoxide radicals from oxygen. These
reactive oxygen species can oxidatively damage membranes, and cause the release of destructive
enzymes from lysosomes.]
a. Chronic hepatic porphyria:
Porphyria cutanea tarda, the most common porphyria, is a chronic disease of the liver (Debatable). The
disease is associated with a deficiency in uroporphyrinogen decarboxylase, but clinical expression of
the enzyme deficiency is influenced by various factors, such as hepatic iron overload, exposure to
sunlight, alcohol ingestion, and the presence of hepatitis B or C, or HIV infections. Clinical onset is
typically during the fourth or fifth decade of life. Porphyrin accumulation leads to cutaneous symptoms
(Figure 21.6), and urine that is red to brown in natural light (Figure 21.7), and pink to red in
fluorescent light.
b. Acute hepatic porphyrias:
Acute hepatic porphyrias (ALA dehydratase deficiency, acute intermittent porphyria, hereditary
coproporphyria, and variegate porphyria) are characterized by acute attacks of gastro intestinal, neuro
psychiatric, and motor symptoms that may be accompanied by photosensitivity. Porphyrias leading to
accumulation of ALA and porphobilinogen, such as acute intermittent por phyria, cause abdominal
pain and neuro psychiatric disturbances, ranging from anxiety to delirium. Symptoms of the acute
hepatic porphyrias are often precipitated by administration of drugs such as barbiturates and ethanol,
which induce the synthesis of the hemecontaining cytochrome P450 microsomal drug oxidation
system. This further decreases the amount of available heme, which, in turn, promotes the increased
synthesis of ALAS1.
c. Erythropoietic porphyrias:
In addition to serving as building blocks for proteins, amino acids are precursors of many nitrogen
containing compounds that have important physiologic functions (Figure 21.1). These molecules
include porphyrins, neurotransmitters, hormones, purines, and pyrimidines.
1. Porphyrins
Glycine (non-essential AA) is the precursor. It condenses with succinyl CoA (intermediate of the
CAC) to form δ-aminolevulinate.
Structure of porphyrins
Porphyrins are cyclic molecules formed by the linkage of four pyrrole rings through methenyl bridges
(Figure 21.2). Three structural features of these molecules are relevant to understanding their medical
significance.
1. Side chains: Different porphyrins vary in the nature of the side chains that are attached to each
of the four pyrrole rings. Uroporphyrin contains acetate (–CH 2–COO–) and prop ionate (–CH2–CH2–
COO–) side chains, coproporphyrin contains methyl (–CH 3) and propionate groups, and
protoporphyrin IX (and heme) contains vinyl (–CH=CH2), methyl, and propionate groups. [Note:
The methyl and vinyl groups are produced by decarboxylation of acetate and propionate side chains,
respectively.]
2. Distribution of side chains: The side chains of porphyrins can be ordered around the
tetrapyrrole nucleus in four different ways, designated by Roman numerals I to IV. Only Type III
porphyrins, which contain an asymmetric substitution on ring D are physiologically important in
humans. [Note: Protoporphyrin IX is a member of the Type III series.]
3. Porphyrinogens: These porphyrin precursors (for example, uroporphyrinogen) exist in a
chemically reduced, colorless form, and serve as intermediates between porphobilinogen and the
oxidized, colored protoporphyrins in heme biosynthesis.
Synthesis:
The porphyrins are constructed from four molecules of the monopyrrole derivative
porphobilinogen, which itself is derived from two molecules of δ-aminolevulinate.
There are two major pathways to δ-aminolevulinate. In higher eukaryotes (Fig. 22–23a),
glycine reacts with succinyl-CoA in the first step to yield α-amino-β-ketoadipate, which is
then decarboxylated to δ-aminolevulinate. (see lecture notes).
This reaction requires pyridoxal phosphate (PLP) as a coenzyme, and is the committed and rate
limiting step in porphyrin biosynthesis.
Note: There are two isoforms of ALAS (δaminolevulinate synthase), 1 and 2, each controlled by
different mechanisms. Erythroid tissue produces only ALAS2, the gene for which is located on the X
chromosome. Loss of function mutations in ALAS2 result in Xlinked sideroblastic anemia.]
In all organisms, two molecules of δ-aminolevulinate condense to form porphobilinogen
and, through a series of complex enzymatic reactions, four molecules of porphobilinogen
come together to form protoporphyrin
(Fig. 22–24). The iron atom is incorporated after the protoporphyrin has been assembled,
in a step catalysed by ferrochelatase.
Regulation: End-product inhibition of ALAS1 by hemin:
Porphyrin biosynthesis is regulated in higher eukaryotes by the concentration of the
heme product, which serves as a feedback inhibitor of early steps in the synthetic
pathway.
, When porphyrin production exceeds the availability of the apoproteins that require it, heme
accumulates and is converted to hemin by the oxidation of Fe 2+ to Fe3+. Hemin decreases the activity
of hepatic ALAS1 by causing decreased synthesis of the enzyme, through inhibition of mRNA
synthesis and use (heme decreases stability of the mRNA), and by inhibiting mitochondrial
import of the enzyme. [Note: In erythroid cells, ALAS2 is controlled by the availability of intracellular
iron.]
Associated Diseases:
Genetic defects in the biosynthesis of porphyrins can lead to the accumulation of
pathway intermediates, causing a variety of human diseases known collectively as
porphyrias.
Porphyrias are rare, inherited (or occasionally acquired) defects in heme synthesis, resulting in the
accumulation and increased excretion of porphyrins or porphyrin precursors. With few exceptions,
porphyrias are inherited as autosomal dominant disorders.
The mutations that cause the porphyrias are heterogenous (not all are at the same DNA locus), and
nearly every affected family has its own mutation. Each porphyria results in the accumulation of a
unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic
pathway. [Note:“Porphyria” refers to the purple color caused by pigmentlike porphyrins in the urine of
some patients with defects in heme synthesis.]
1. Clinical manifestations:
The porphyrias are classified as erythropoietic or hepatic, depending on whether the enzyme
deficiency occurs in the erythropoietic cells of the bone marrow or in the liver. Hepatic porphyrias can
be further classified as chronic or acute. In general, individuals with an enzyme defect prior to the
synthesis of the tetrapyrroles manifest abdominal and neuropsychiatric signs, whereas those with
enzyme defects leading to the accumulation of tetrapyrrole intermediates show photosensitivity—
that is, their skin itches and burns (pruritus) when exposed to visible light. [Note: Photosenstivity is a
result of the oxidation of colorless porphyrinogens to colored porphyrins, which are photosensitizing
molecules that are thought to participate in the formation of superoxide radicals from oxygen. These
reactive oxygen species can oxidatively damage membranes, and cause the release of destructive
enzymes from lysosomes.]
a. Chronic hepatic porphyria:
Porphyria cutanea tarda, the most common porphyria, is a chronic disease of the liver (Debatable). The
disease is associated with a deficiency in uroporphyrinogen decarboxylase, but clinical expression of
the enzyme deficiency is influenced by various factors, such as hepatic iron overload, exposure to
sunlight, alcohol ingestion, and the presence of hepatitis B or C, or HIV infections. Clinical onset is
typically during the fourth or fifth decade of life. Porphyrin accumulation leads to cutaneous symptoms
(Figure 21.6), and urine that is red to brown in natural light (Figure 21.7), and pink to red in
fluorescent light.
b. Acute hepatic porphyrias:
Acute hepatic porphyrias (ALA dehydratase deficiency, acute intermittent porphyria, hereditary
coproporphyria, and variegate porphyria) are characterized by acute attacks of gastro intestinal, neuro
psychiatric, and motor symptoms that may be accompanied by photosensitivity. Porphyrias leading to
accumulation of ALA and porphobilinogen, such as acute intermittent por phyria, cause abdominal
pain and neuro psychiatric disturbances, ranging from anxiety to delirium. Symptoms of the acute
hepatic porphyrias are often precipitated by administration of drugs such as barbiturates and ethanol,
which induce the synthesis of the hemecontaining cytochrome P450 microsomal drug oxidation
system. This further decreases the amount of available heme, which, in turn, promotes the increased
synthesis of ALAS1.
c. Erythropoietic porphyrias:
