Figure 44-1. Structure of heme.
The biosynthetic pathway includes eight steps, shown in Figure 44-2. The
first step is the rate-limiting condensation reaction between succinyl-CoA and
glycine to form 8-aminolevulinic acid (ALA). This reaction is catalyzed by a
mitochondrial matrix enzyme, ALA synthase (ALAS), and requires the cofac-
tor pyridoxal phosphate. The ALAS protein is produced in the cytosol but
remains unfolded or inactive until it is directed to the mitochondrial matrix
where its A-terminal signaling sequence is cleaved. Additionally, this enzyme
catalyzes the primary regulatory step in heme biosynthesis and is negatively
regulated by any accumulation of free heme in the mitochondrial matrix. In the
next step of the pathway, ALA dehydratase catalyzes the asymmetric con-
densation of two molecules of ALA to form porphobilinogen (PBG). Through
the addition of water and the removal of four amino groups, PBG deaminase
produces the linear tetrapyrrole intermediate, hydroxymethylbilane (HMB)
from four molecules of PBG. At this point, HMB can close either in an
enzyme-independent manner to form uroporphyrinogen (URO) I, or in an
enzyme-dependent manner through uroporphyrinogen III cosynthase to
form uroporphyrinogen III, the intermediate that will ultimately lead to heme
formation. URO I and URO III differ in the order of the carboxymethyl and
carboxy ethyl substituents around the tetrapyrrole ring. In the last cytosolic
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