The development of this condition impairs brain function by mechanisms that are not well-understood, but it can be fatal if left untreated. Bilirubin is also notable for its yellow coloration. Accumulation of this substance in the blood is the basis for jaundice , or a yellow discoloration of the skin and eyes which is a common symptom of liver diseases.
Thus, measurement of bilirubin in the plasma can be a useful marker of such conditions. Bilirubin derives from two main sources. The remainder originates from various heme-containing proteins found in other tissues, notably the liver and muscles.
Bilirubin is produced by a two-stage reaction that occurs in cells of the reticuloendothelial system, including phagocytes, the Kupffer cells of the liver, and cells in the spleen and bone marrow. Heme is taken up into these cells and acted on by the enzyme heme oxygenase, liberating the chelated iron from the heme structure and releasing an equimolar amount of carbon monoxide, which is excreted via the lungs.
The reaction yields a green pigment known as biliverdin Figure 13—1. Biliverdin is then acted on by the enzyme biliverdin reductase, again releasing a molecule of carbon monoxide and producing the yellow bilirubin.
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Learn More. Sign in via OpenAthens. Sign in via Shibboleth. AccessBiomedical Science. AccessEmergency Medicine. The heme portion, on the other hand, undergoes degradation starting with a mixed-function oxidase reaction that causes an opening of the ring and the conversion of one of the methane bridge carbons to carbon monoxide. The next step in the process is the release of the iron from the resulting linear tetrapyrrole. The iron is then transported to storage pools in the bone marrow to be reused in erythrocyte production.
This iron atom that reaches the heme oxygenase is usually oxidized to its hemin or ferric form. After the release of the iron atom and the ring-opening of the heme group, Biliverdin is produced. Biliverdin is a green tetrapyrrolic bile pigment that is responsible for a greenish color during bruises.
The biliverdin is reduced by biliverdin reductase. Biliverdin reductase is an enzyme found in all tissues, especially in reticulo-macrophages of the liver and spleen. This enzyme is responsible for converting the biliverdin to bilirubin by reducing the double bond between the second and third pyrrole ring to form a single bond. The biliverdin reductase catalyzes the reaction through an overlap in the binding sites of the Lys 18 , Lys 22 , Lys , Arg , and Arg as key residues.
These binding sites attach to the biliverdin molecule causing the dissociation of the biliverdin from the heme oxygenase, eventually leading to a reduction of the green biliverdin to the yellow bilirubin.
In the uptake to the liver, bilirubin is taken up at the sinusoidal surface of liver cells by a facilitated transport system. Once the bilirubin molecule enters the cell, it is bound to the cytosolic proteins like glutathione S-transferase , also called ligandin, to prevent its re-entry to the bloodstream.
In the liver, reacting it with two glucuronic acid molecules solubilizes bilirubin. This is then as for bilirubin not to persist in cells because of its highly non-polar nature. The conjugation with glucuronic acids converts bilirubin into a more polar molecule. The enzyme UDP-glucosyltransferase , a bilirubin-specific enzyme in the endoplasmic reticulum, catalyzes the step-wise transfer of two glucosyl moieties from a UDP-glucuronate to the bilirubin molecule.
The solubilized bilirubin, bilirubin diglucuronide is then secreted to the bile and finally excreted via the intestine. Most of the soluble bilirubin conjugated is excreted via the bile into the intestines. Most of the bile acids are reabsorbed into circulation at the terminal ileum, whereas the conjugated bilirubin passes into the large intestines where colonic bacteria deconjugates it into urobilinogen.
The product is later oxidized into stercobilin that gives feces its characteristic color and urobilinogen in urine. A trace of urobilinogen is reabsorbed to enter the hepatic circulation into the liver where it is excreted again via the intestines forming the enterohepatic circulation. Billing BH, Black M. Bilirubin metabolism. Reece, J. Campbell biology. Biliverdin is formed when the heme group in hemoglobin is cleaved at its alpha-methene bridge.
The resulting biliverdin is then reduced to bilirubin, a yellow pigment, by the enzyme biliverdin reductase. The changing color of a bruise from deep purple to yellow over time is a graphical indicator of this reaction.
Biosynthesized from hemoglobin is a precursor of bilirubin. This occurs in the bile of amphibia and of birds, but not in normal human bile or serum. Heme is best known as a constituent of hemoglobin, which is released in association with the breakdown of aging red blood cells. Heme also is contained in a wide range of enzymes whose turnover also leads to free heme release. Free heme can be toxic, so nature evolved a family of heme oxygenase enzymes to degrade heme, and their blockade leads to greatly increased excretion of unmetabolized heme in the bile.
These enzymes cleave the heme ring to form biliverdin, iron, and a 1-carbon fragment as carbon monoxide. CO is increasingly appreciated as a neurotransmitter, and iron, itself toxic, is excreted from cells by a recently characterized pump.
Biliverdin would seem to be an appropriate end product of the pathway, being readily excreted in the bile to enter the intestine and leave the body in the feces.
Indeed, in birds, reptiles, and amphibians, biliverdin is the predominant end product of heme degradation. For reasons that until now have seemed obscure, in mammals, biliverdin undergoes additional metabolism, being reduced by biliverdin reductase BVR to bilirubin, a step that consumes the energy resource nicotinamide adenine dinucleotide phosphate NADPH.
Figure 1. Heme oxygenase and biliverdin reductase enzymatic reactions. Biliverdins are derived formally from hemes by oxidative removal of a methine bridge and loss of the iron atom.
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