Amino acids serve as precursors for various nitrogen-containing compounds, including porphyrins. When combined with ferrous iron, porphyrins form heme. Heme synthesis primarily takes place in the liver, where hemeproteins, particularly cytochrome P450 enzymes, are synthesized. Erythrocyte-producing cells in the bone marrow are also involved in heme synthesis, specifically in the production of hemoglobin. The rate of heme synthesis in the liver is variable and responds to changes in the cellular heme pool due to fluctuating demands for hemeproteins. On the other hand, heme synthesis in erythroid cells remains relatively constant and matches the rate of globin synthesis.

The process of heme synthesis begins with glycine and succinyl coenzyme A, with the formation of δ-aminolevulinic acid (ALA) being the crucial step. ALA synthase-1 (ALAS1) catalyzes this mitochondrial reaction in the liver, while ALAS2 carries out this process in erythroid tissues. The activity of ALAS1 is inhibited by hemin, the oxidized form of heme that accumulates when heme is underutilized. In contrast, the regulation of ALAS2 in erythroid tissues is dependent on iron levels.

Defects in heme synthesis, whether inherited or acquired (such as lead poisoning), can result in porphyrias. These conditions lead to the accumulation and increased excretion of porphyrins or porphyrin precursors. Enzymic defects occurring early in the pathway cause symptoms such as abdominal pain and neuropsychiatric symptoms, while defects occurring later in the pathway result in photosensitivity.

Heme degradation occurs primarily in the mononuclear phagocyte system, particularly in the liver and spleen. The first step in this process involves heme oxygenase producing biliverdin, which is then reduced to bilirubin. Bilirubin is transported to the liver by albumin, where it is made more soluble by the addition of two molecules of glucuronic acid through the action of bilirubin uridine diphosphate-glucuronosyltransferase (bilirubin UGT). Conjugated bilirubin (bilirubin diglucuronide) is transported into the bile canaliculi and is initially hydrolyzed and reduced by gut bacteria, resulting in the formation of urobilinogen. Further oxidation by bacteria leads to the production of stercobilin.

Jaundice, characterized by the yellowing of the skin and sclerae, occurs when bilirubin is deposited due to increased levels of bilirubin in the blood. There are three common types of jaundice: hemolytic (prehepatic), obstructive (posthepatic), and hepatocellular (hepatic).

In addition to porphyrins, amino acids give rise to other important nitrogen-containing compounds, including catecholamines (dopamine, norepinephrine, and epinephrine), creatine, histamine, serotonin, melanin, and nitric oxide.
Amino acids are precursors of many nitrogen (N)-containing compounds including porphyrins, which, in combination with ferrous (Fe2+) iron, form heme (Fig. 21.20). The major sites of heme biosynthesis are the liver, which synthesizes a number of hemeproteins (particularly cytochrome P450 enzymes), and the erythrocyte-producing cells of the bone marrow, which are active in hemoglobin 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. Heme synthesis starts with glycine and succinyl coenzyme A. The committed step is the formation of δ-aminolevulinic acid (ALA). This mitochondrial reaction is catalyzed by ALA synthase-1 (ALAS1) in the liver (inhibited by hemin, the oxidized form of heme that accumulates when heme is being underutilized) and ALAS2 in erythroid tissues (regulated by iron). Porphyrias are caused by inherited or acquired (lead poisoning) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. Enzymic defects early in the pathway cause abdominal pain and neuropsychiatric symptoms, whereas later defects cause photosensitivity. Degradation of heme occurs in the mononuclear phagocyte system, particularly in the liver and spleen. The first step is the production by heme oxygenase of biliverdin, which is subsequently reduced to bilirubin. Bilirubin is transported by albumin to the liver, where its solubility is increased by the addition of two molecules of glucuronic acid by bilirubin uridine diphosphate-glucuronosyltransferase (bilirubin UGT). Bilirubin diglucuronide (conjugated bilirubin) is transported into the bile canaliculi, where it is first hydrolyzed and reduced by gut bacteria to yield urobilinogen, which is further oxidized by bacteria to stercobilin. Jaundice (icterus) refers to the yellow color of the skin and sclerae that is caused by deposition of bilirubin, secondary to increased bilirubin levels in the blood. Three commonly encountered types of jaundice are hemolytic (prehepatic), obstructive (posthepatic), and hepatocellular (hepatic) (see Fig. 21.20). Other important N-containing compounds derived from amino acids include the catecholamines (dopamine, norepinephrine, and epinephrine), creatine, histamine, serotonin, melanin, and nitric oxide.
bilirubin or decreased secretion of conjugated bilirubin from the liver into bile.] CoA = coenzyme A; CO = carbon monoxide; Fe = iron.
Choose the ONE best answer.
1.1. δ-Aminolevulinic acid synthase activity:
A. catalyzes the committed step in porphyrin biosynthesis.
B. is decreased by iron in erythrocytes.
C. is decreased in the liver in individuals treated with certain drugs such as the barbiturate phenobarbital.
D. occurs in the cytosol.
E. requires tetrahydrobiopterin as a coenzyme.
Correct answer = A. δ-Aminolevulinic acid synthase is mitochondrial and catalyzes the rate-limiting and regulated step of porphyrin synthesis. It requires pyridoxal phosphate as a coenzyme. Iron increases production of the erythroid isozyme. The hepatic isozyme is increased in patients treated with certain drugs.