The liver and bone marrow are the main locations for heme biosynthesis. The liver produces heme proteins, specifically the CYP proteins, and the bone marrow is responsible for the synthesis of hemoglobin (Hb) in erythrocyte-producing cells. Heme synthesis in the liver can vary greatly depending on the demands for hemeproteins, while in erythroid cells, it remains relatively constant and matches the rate of globin synthesis. It is important to note that over 85% of heme synthesis occurs in erythroid tissue. Mature red blood cells (RBC) lack mitochondria and cannot synthesize heme.

The initial reaction and the final three steps of porphyrin formation occur in mitochondria, while the intermediate steps take place in the cytosol. Fig. 21.8 provides a summary of heme synthesis.

The formation of δ-aminolevulinic acid (ALA) is the first step in porphyrin biosynthesis. This reaction is catalyzed by ALA synthase (ALAS) and requires glycine and succinyl coenzyme A. ALA synthase uses pyridoxal phosphate as a coenzyme. This step is crucial and limits the rate of porphyrin biosynthesis. It is worth noting that there are two isoforms of ALAS, produced by different genes and controlled by different mechanisms. ALAS1 is present in all tissues, whereas ALAS2 is specific to erythroid cells. Loss-of-function mutations in ALAS2 lead to X-linked sideroblastic anemia and iron overload.

When the production of porphyrins exceeds the availability of apoproteins, heme accumulates and is converted to hemin through the oxidation of Fe2+ to Fe3+. Hemin negatively affects ALAS1 by repressing gene transcription, increasing mRNA degradation, and reducing enzyme import into mitochondria. In erythroid cells, ALAS2 is regulated by intracellular iron availability.

The administration of various drugs significantly increases hepatic ALAS1 activity. These drugs are metabolized by the microsomal CYP monooxygenase system, a liver hemeprotein oxidase system. The increased synthesis of CYP proteins in response to these drugs leads to higher heme consumption, resulting in a decrease in heme concentration within liver cells. The reduced intracellular heme concentration triggers an upregulation of ALAS1 synthesis and subsequently prompts an increase in ALA synthesis.

Porphobilinogen formation occurs in the cytosol through the condensation of two ALA molecules catalyzed by zinc-containing ALA dehydratase (PBG synthase). This step is highly sensitive to inhibition by heavy metal ions such as lead, which can replace the zinc in the enzyme. Lead poisoning can result in elevated levels of ALA and anemia.
The major sites of heme biosynthesis are the liver, which synthesizes a number of heme proteins (particularly the CYP proteins), and the erythrocyte-producing cells of the bone marrow, which are active in Hb synthesis. In the liver, the rate of heme synthesis is highly variable, responding to alterations in the cellular heme pool caused by fluctuating demands for hemeproteins. In contrast, heme synthesis in erythroid cells is relatively constant and is matched to the rate of globin synthesis. [Note: Over 85% of all heme synthesis occurs in erythroid tissue. Mature red blood cells (RBC) lack mitochondria and are unable to synthesize heme.] The initial reaction and the last three steps in the formation of porphyrins occur in mitochondria, whereas the intermediate steps of the biosynthetic pathway occur in the cytosol. [Note: Fig. 21.8 summarizes heme synthesis.] 1. δ-Aminolevulinic acid formation: All the carbon and nitrogen atoms of the porphyrin molecule are provided by glycine (a nonessential amino acid) and succinyl coenzyme A (a tricarboxylic acid cycle intermediate) that condense to form δ-aminolevulinic acid (ALA) in a reaction catalyzed by ALA synthase ([ALAS], Fig. 21.3). This reaction requires pyridoxal phosphate ([PLP] see p. 382) as a coenzyme and is the committed and rate-limiting step in porphyrin biosynthesis. [Note: There are two ALAS isoforms, each produced by different genes and controlled by different mechanisms. ALAS1 is found in all tissues, whereas ALAS2 is erythroid specific. Loss-of-function mutations in ALAS2 result in X-linked sideroblastic anemia and iron overload.] (Continued in Figs. 21.4 and 21.5.) a.
Heme (hemin) effects: When porphyrin production exceeds the availability of the apoproteins that require it, heme accumulates and is converted to hemin by the oxidation of Fe2+ to Fe3+ . Hemin decreases the amount (and, thus, the activity) of ALAS1 by repressing transcription of its gene, increasing degradation of its messenger RNA, and decreasing import of the enzyme into mitochondria. [Note: In erythroid cells, ALAS2 is controlled by the availability of intracellular iron (see p. 475).] b.
Drug effects: Administration of any of a large number of drugs results in a significant increase in hepatic ALAS1 activity. These drugs are metabolized by the microsomal CYP monooxygenase system, a hemeprotein oxidase system found in the liver (see p. 149). In response to these drugs, the synthesis of CYP proteins increases, leading to an enhanced consumption of heme, a component of these proteins. This, in turn, causes a decrease in the concentration of heme in liver cells. The lower intracellular heme concentration leads to an increase in the synthesis of ALAS1 and prompts a corresponding increase in the synthesis of ALA.
2.
Porphobilinogen formation: The cytosolic condensation of two ALA to form PBG by zinc-containing ALA dehydratase (PBG synthase) is extremely sensitive to inhibition by heavy metal ions (for example, lead) that replace the zinc (see Fig. 21.3). This inhibition is, in part, responsible for the elevation in ALA and the anemia seen in lead poisoning.
3.