Coproporphyrinogen oxidase (CPO): Mitochondrial enzyme that cat-
alyzes specifically the conversion of coproporphyrinogen III to proto-
porphyrinogen IX.
Ferrochelatase: Assists in the insertion of the ferrous iron into the proto-
porphyrin IX; the final step in heme synthesis.
Hematin: Compound similar in structure to heme, except that the iron is in
the ferric state (tetracoordinated with the pyrrole nitrogens and a
hydroxyl group); can restore negative regulation of ALAS.
Heme: An essential metalloorganic cofactor, consisting of one ferrous iron
atom coordinated within a tetrapyrrole ring, protoporphyrin IX.
Porphobilinogen deaminase (PBGD): Cytosolic enzyme that processes
six PBG molecules through a hexapyrrole adduct to catalyze the forma-
tion of a free linear tetrapyrrole, hydroxymethylbilane (aka uropor-
phyrinogen I synthase).
Porphyria: Any of a number of diseases characterized by derangement in
porphyrin metabolism; many are caused by genetic defects in the
biosynthetic enzymes.
Protoporphyrinogen oxidase (PPO): Catalyzes the oxidation of protopor-
phyrinogen IX to produce protoporphyrin IX.
Pyridoxal phosphate: Coenzyme active derivative of vitamin B6.
Uroporphyrinogen (URO) III cosynthase: Cytosolic enzyme that cat-
alyzes formation of the URO III isomer from hydroxymethylbilane.
URO decarboxylase (UROD): Cytosolic enzyme that catalyzes the
removal of the carboxyl groups from the side chains of both URO iso-
forms converting them to their respective coproporphyrinogens (i.e.,
The cofactor heme is required for numerous processes throughout the body.
Most importantly, the heme iron facilitates systemic oxygen transfer via hemo-
globin, participates in mitochondrial electron transport, and mediates oxidative
drug metabolism in the liver through various cytochromes P450. All cellular tis-
sues are capable of synthesizing heme, but expression of the pathway enzymes
and levels of intermediates are greatest in erythropoietic and hepatic tissues due
to high demand for heme incorporation into hemoglobin and cytochromes,
respectively. Heme is a metalloorganic compound, consisting of one ferrous
iron atom coordinated within a tetrapyrrole ring, protoporphyrin IX.
Protoporphyrin IX is derived from eight molecules each of succinyl-CoA and
glycine. Heme is a relatively planar molecule and highly stabilized by strong
resonance throughout the tetrapyrrole ring system. The structure of heme is
shown in Figure 44-1.
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