Molecules Derived from Amino Acids:- Heme Is the Source of Bile Pigments
The iron-porphyrin (heme) group of hemoglobin, released from dying erythrocytes in the spleen, is degraded to yield free Fe3+ and, ultimately, bilirubin. This pathway is arresting for its capacity to inject color into human biochemistry. The first step in the two-step pathway, catalyzed by heme oxygenase (HO), converts heme to biliverdin, a linear (open) tetrapyrrole derivative (Fig. 3). The other products of the reaction are free Fe2+ and CO. The Fe2+ is quickly bound by ferritin. Carbon monox ide is a poison that binds to hemoglobin , and the production of CO by heme oxygenase ensures that, even in the absence of environmental exposure, about 1% of an individual’s heme is complexed with CO. Biliverdin is converted to bilirubin in the second step, catalyzed by biliverdin reductase. You can monitor this reaction colorimetrically in a familiar in situ experiment. When you are bruised, the black and/or purple color results from hemoglobin released from damaged erythrocytes. Over time, the color changes to the green of biliverdin, and then to the yellow of bilirubin. Bilirubin is largely insoluble, and it travels in the bloodstream as a complex with serum albumin. In the liver, bilirubin is transformed to the bile pigment bilirubin diglucuronide. This product is sufficiently water-soluble to be secreted with other components of bile into the small intestine, where microbial enzymes convert it to several products, predominantly urobilinogen. Some urobilinogen is reabsorbed into the blood and transported to the kidney, where it is converted to urobilin, the compound that gives urine its yellow color (Fig. 3, left branch). Urobilinogen remaining in the intestine is converted (in another microbe-dependent reaction) to stercobilin (Fig. 3, right branch), which imparts the red-brown color to feces. Impaired liver function or blocked bile secretion causes bilirubin to leak from the liver into the blood, resulting in a yellowing of the skin and eyeballs, a condition called jaundice. In cases of jaundice, determination of the concentration of bilirubin in the blood may be useful in the diagnosis of underlying liver disease. Newborn infants sometimes develop jaundice because they have not yet produced enough glucuronyl bilirubin transferase to process their bilirubin. A traditional treatment to reduce excess bilirubin, exposure to a fluorescent lamp, causes a photochemical conversion of bilirubin to compounds that are more soluble and easily excreted. These pathways of heme breakdown play significant roles in protecting cells from oxidative damage and in regulating certain cellular functions. The CO produced by heme oxygenase is toxic at high concentrations, but at the very low concentrations generated during heme degradation it appears to have some regulatory and/or signaling functions. It acts as a vasodilator, much the same as (but less potent than) nitric oxide (discussed below). Low levels of CO also have some regulatory effects on neurotransmission. Bilirubin is the most abundant antioxidant in mammalian tissues and is responsible for most of the antioxidant activity in serum. Its protective effects appear to be especially important in the developing brain of newborn infants. The cell toxicity associated with jaundice may be due to bilirubin levels in excess of the serum albumin needed to solubilize it. Given these varied roles of heme degradation products, the degradative pathway is subject to regulation, mainly at the first step. Humans have at least three isozymes of heme oxygenase. HO-1 is highly regulated; the expression of its gene is induced by a wide range of stress conditions (shear stress, angiogenesis (uncontrolled development of blood vessels), hypoxia, hyperoxia, heat shock, exposure to ultraviolet light, hydrogen peroxide, and many other metabolic insults). HO-2 is found mainly in brain and testes, where it is continuously expressed. The third isozyme, HO-3, is not yet well characterized.
FIGURE 1 Biosynthesis of -aminolevulinate. (a) In mammals and other higher eukaryotes, δ-aminolevulinate is synthesized from glycine and succinyl-CoA. The atoms furnished by glycine are shown in red. (b) In bacteria and plants, the precursor of -aminolevulinate is glutamate.
FIGURE 2 Biosynthesis of heme from -aminolevulinate. Ac rep resents acetyl (-CH2COO-); Pr, propionyl (-CH2CH2COO-).
FIGURE 3 Bilirubin and its breakdown products. M represents methyl; V, vinyl; Pr, propionyl; E, ethyl. For ease of comparison, these structures are shown in linear form, rather than in their correct stereochemical conformations.
