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.