Porphyria Educational Services
Vol. 2 No. 15
April 9, 2000
FOCUS: The Heme Pathway
What is the Heme Pathway?
Whenever someone begins the tedious task of learning about
porphyria the first thing that they encounter in
researching is reading about heme.
Heme, which is an iron-containing pigment, is the nonprotein
functional component of hemoproteins. This substance is found
in all tissues.
The heme biosynthetic pathway has eight different anzymes.
The eight different enzymes that
drive the sequential steps in this pathway. The first enzyme and
the last three are found in mitochondria. Many porphyria
patients have found
themselves tested for mitrochrondial while pursuing their
porphyria diagnosis.
The other enzymes in the pathway, the intermediate enzymes occur
in the cytosol.
The eight different enzymes
will be briefly described in order below: 1.ALA
synthase, the first enzyme of the heme biosynthetic pathway,
catalyzes the
condensation of glycine and succinyl coenzyme A to form ALA.
This enzyme is
localized in the inner membrane of mitochondria.
Separate genes encode erythroid and nonerythroid ALA synthases.
2.ALA dehydratase, a cytosolic enzyme, converts two molecules of
ALA into a
monopyrrole, PBG, with the removal
of two molecules of water. 3.PBG deaminase catalyzes the
condensation of four molecules of PBG to yield a linear
tetrapyrrole, hydroxymethylbilane (HMB). 4.Uroporphyrinogen III cosynthase
catalyzes the formation of uroporphyrinogen III from
HMB. 5.Uroporphyrinogen decarboxylase, a
cytosolic enzyme, catalyzes four sequential
decarboxylations of the carboxymethyl side chains in
uroporphyrinogen III (an octacarboxyl
porphyrin) to yield heptacarboxyl porphyrin, hexacarboxyl
porphyrin, pentacarboxyl porphyrin, and, finally,
coproporphyrinogen III (a tetracarboxyl porphyrin).
This enzyme can also metabolize
uroporphyrinogen I to coproporphyrinogen I.
6.Coproporphyrinogen oxidase, a mitochondrial enzyme in mammalian
cells, catalyzes the
removal of the carboxyl group and two hydrogens from the
proprionic groups of pyrrolerings A and B of coproporphyrinogen
III to form vinyl groups at these positions, forming
protoporphyrinogen. This
enzyme is unable to metabolize coproporphyrinogen I.
7.Protoporphyrinogen oxidase
mediates the oxidation of protoporphyrinogen IX to
protoporphyrin IX, catalyzing the removal of six hydrogen atoms
from the porphyrinogen
nucleus. 8.Ferrochelatase
catalyzes the insertion of iron into protoporphyrin, which
represents the final step in the heme biosynthetic pathway.
The intermediates of the pathway are conserved within
cells and therefore are normally excreted only in small amounts.
They differ markedly from each
other in molecular size, solubility, and other
properties. ALA,
PBG, and porphyrinogens (hexahydroporphyrins, ie, porphyrins in
the
chemically reduced state) are colorless and nonfluorescent.
Protoporphyrin, the
final intermediate in the pathway, is the only intermediate
that is an oxidized porphyrin. Porphyrins in the oxidized state are
reddish and fluoresce when exposed to long-wave ultraviolet light.
Porphyrinogens that
leak into extracellular fluid undergo auto-oxidation and are
excreted primarily as porphyrins.
But please note that appreciable amounts of unoxidized
coproporphyrinogen may be excreted in urine.
ALA, PBG, uroporphyrin, hepta-, hexa-, and pentacarboxyl
porphyrins are water-soluble
and are excreted mostly in urine. Coproporphyrin (a tetracarboxyl
porphyrin) is excreted in urine and bile.
Harderoporphyrin (a tricarboxyl porphyrin) and protoporphyrin (a
dicarboxyl porphyrin) are
poorly soluble in water and thus cannot be excreted by the
kidneys. If they accumulate in bone marrow or liver they appear
in plasma, are taken up by the liver, and are excreted in bile
and feces.
Heme is synthesized in
largest amounts by the bone marrow, where it is incorporated into
hemoglobin, which is an oxygen transport protein, and by
the liver, where most is incorporated into cytochromes,
which are electron transport proteins. The most abundant cytochromes in liver
are the cytochrome P-450 enzymes that metabolize drugs and many
other foreign and endogenous chemicals.
Heme biosynthesis is managed
differently in liver than in the bone marrow. Hepatic heme
biosynthesis is rate-limited and primarily regulated by the first
enzyme, ALA synthase.
Certain drugs and
hormones induce hepatocytes to make more ALA synthase, heme, and
cytochrome P-450. In the bone marrow, heme is made
in erythroblasts and reticulocytes that still contain
mitochondria, whereas circulating erythrocytes lack
mitochondria and cannot form heme. Bone marrow cells
express erythroid-specific forms of some pathway enzymes.
For a more in depth
understanding of the heme pathway and the actions of the various enzymes see the basic medical
textbook and "Porphyria Bible", "Metabolic Basis for
Inherited Disease". The authors of much
of the material on
Porphyria in this medical text is by the world reknown porphyria
researchers Kappas and
Sassa.