The globins are broken down to amino acids aa , which are then used for protein synthesis. The porphyrin ring of heme is oxidized by microsomal heme oxygenase, producing biliverdin and releasing the iron. Biliverdin is reduced by biliverdin reductase to unconjugated bilirubin. The unconjugated bilirubin is released into the plasma, where it binds to albumin and is taken up by hepatocytes not shown.
The BLVRA gene is located on chromosome 7p13 and is composed of 11 exons generate two alternatively spliced mRNAs, both of which encode the same amino acid precursor protein.
Bilirubin is significantly less extensively conjugated than biliverdin causing a change in the color of the molecule from blue-green biliverdin to yellow-red bilirubin. The latter catabolic changes in the structure of tetrapyrroles are responsible for the progressive changes in color of a hematoma, or bruise, in which the damaged tissue changes its color from an initial dark blue to a red-yellow and finally to a yellow color before all the pigment is transported out of the affected tissue.
Peripherally arising bilirubin is transported to the liver in association with albumin, where the remaining catabolic reactions take place. Pathway for the degradation of heme to bilirubin. The product of the heme oxygenase reaction is biluverdin. Biliverdin is converted to bilirubin via the action of biliverdin reductase. The various substituents on the pentameric rings of biliverdin and bilirubins are M: methyl, P: propyl, V: vinyl. In hepatocytes, bilirubin-UDP-glucuronosyltransferase bilirubin-UGT: a member of the large UDP glucuronosyltransferase family of enzymes adds two equivalents of glucuronic acid to bilirubin to produce the more water soluble, bilirubin diglucuronide derivative.
The increased water solubility of the tetrapyrrole facilitates its excretion with the remainder of the bile as the bile pigments. The bilirubin UDP-glucuronosyltransferase gene UGT1A which encodes the enzyme that carries out this reaction is located on chromosome 2q The 5' region of the UGT1A complex contains 13 tandemly arrayed first exons, including 4 pseudo exons. These tandemly arrayed exons are identified as 1A1, 1A2, 1A3, etc. Exons 2, 3, 4, and 5 are located in the UGT1A 3' region.
All UGT isoforms contain the same C-terminal domain encoded by exons 2 through 5. Each first exon has its own promoter element. The 9 viable first exons are independently spliced to the common exons 2 through 5 to generate 9 UGT1A transcripts with unique 5' ends and identical 3' ends. The N-terminal region encoded by each unique first exon determines acceptor substrate specificity, while the amino acid C-terminal region encoded by the 4 common exons specifies interactions with the common donor substrate, UDP-glucuronic acid.
Bilirubin diglucuronide In newborn infants, or in individuals with abnormally high red cell lysis, or liver damage with obstruction of the bile duct, the bilirubin and its precursors accumulate in the circulation; the result is hyperbilirubinemia, the cause of the abnormal yellowish pigmentation of the eyes and tissues known as jaundice.
All newborn infants undergo turnover of the red blood cells that contain fetal hemoglobin HbF so that new red blood cells containing adult hemoglobin HbA can be produced. In some cases the activation of the UGT1A gene at birth is insufficient to handle all the red cell turnover resulting in neonatal jaundice, apparent around day 2 or 3.
If the blood levels of bilirubin do not decline in a short period of time these infants will need to be treated by phototherapy. The blue-green wavelength light nm used in biliblankets is sufficient to induce breakdown of bilirubin in the skin so that it can be cleared from the blood.
In rare cases the phototherapy does not work fast enough and in these cases it is appropriate to treat the infants with phenobarbital which enhances the induction of the UGT1A gene. In normal individuals, intestinal bilirubin is acted on by bacteria to produce the final porphyrin products, urobilinogens and stercobilins, that are found in the feces. The stercobilins oxidize to brownish pigments which impart the brown to brown-black color to normal feces. Indeed, the color of the stool can be quite diagnostic since chalky clay colored feces are indicative of a defect in the hepato-biliary circulation, such as in bile obstruction.
Some of the urobilinogen produced by intestinal bacteria is reabsorbed from the gut and enter the circulation. These urobilinogens are converted to the urobilins which are then excreted in the urine. Oxidation of the urobilins imparts the yellowish coloration to urine. Disorders that arise from defects in the enzymes of heme biosynthesis are termed the porphyrias see Table below and the Porphyrias page and cause elevations in the serum and urine content of intermediates in heme synthesis.
Inherited disorders in bilirubin metabolism lead to hyperbilirubinemia see the Bilirubinemias page. Hyperbilirubinemias Bilirubin levels are measured in the serum by an assay utilizing Ehrlich diazo reagent and results in the formation of an azobilirubin product.
Conjugated bilirubin does not require addition of alcohol to promote the azotization reaction and thus, this is referred to as measurement of direct bilirubin. The reaction with unconjugated bilirubin requires the addition of alcohol and thus is referred to as the measurement of indirect bilirubin. Normal bilirubin measurements are 0. Direct type bilirubin does not exist in the plasma, however, a small portion of indirect type bilirubin may present as direct reacting type and thus the serum measurement may show a direct bilirubin but this is never above 0.
Excess circulation and accumulation of bilirubin hyperbilirubinemia results in a yellow-orange discoloration of the tissues and is most easily visible as icteric yellowish discoloration in the sclera of the eyes. Bilirubin toxicity bilirubin encephalopathy can be life threatening in neonates. Bilirubin encephalopathy is characterized by yellow discoloration of the basal ganglia in babies with intense jaundice and was first described over a century ago and the term "kernicterus" was coined to describe these physical changes.
However, individual differences in bilirubin sensitivity can result in kernicterus at lower bilirubin levels. Kernicterus occurs in infants with severe unconjugated hyperbilirubinemia and in young adults with high serum levels of unconjugated bilirubin. The latter is the result of inherited deficiencies in the enzyme responsible for bilirubin conjugation to glucuronic acid, bilirubin UDP glucuronosyltransferase bilirubin-UGT.
Bilirubin has been shown to inhibit DNA synthesis, uncouple oxidative phosphorylation, and inhibit ATPase activity in brain mitochondria. Bilirubin also inhibits a variety of different classes of enzymes including dehydrogenases, electron transport proteins, hydrolyases, and enzymes of RNA synthesis, protein synthesis and carbohydrate metabolism.
All of these toxic effects of bilirubin are reversed by binding to albumin. In fact, albumin plays a vital role in the disposition of bilirubin in the body by keeping the compound in solution and transporting it from its sites of production primarily bone marrow and spleen to its site of excretion which is the liver. Several inherited disorders in bilirubin metabolism have been identified.
Gilbert syndrome and the Crigler-Najjar syndromes result from predominantly unconjugated hyperbilirubinemia. Dubin-Johnson syndrome and Rotor syndrome result from conjugated hyperbilirubinemia. Once conjugated to glucuronate, bilirubin is water soluble, therefore, conjugated hyperbilirubinemias are less severe in their symptomology than are the unconjugated hyperbilirubinemias.
Porphyrias The porphyrias are both inherited and acquired disorders in heme synthesis. These disorders are classified as either erythroid or hepatic, depending upon the principal site of expression of the enzyme defect. Eight different porphyrias have been classified encompassing defects in each of the enzymes of heme synthesis. In the skin, uroporphyrin III can absorb photons and then react with molecular oxygen to produce reactive oxygen species; the latter inflict the skin tissue damage that is illustrated in the slide.
An important aspect of treatment is the protection of skin from direct sunlight. The absorbed wavelength range or absorption spectrum differs between the various porphyrins. Uroporphyrin III has an absorption peak at nm, which is at the blue end of the visible spectrum; this peak is readily detectable in blood serum samples left.
The sun light is more intense in the visible range than in the UV range. Sun screen lotion, which is designed to absorb UV light but not visible light, will not prevent photosensitization by uroporphyrin III.
In homozygous form, this gene defect causes hemochromatosis, a disease that is characterized by severe iron overload. HFE knockout mice show increased intestinal expression and activity of iron uptake transporters.
Excess iron may facilitate the non-enzymatic oxidation of uroporphyrinogen to uroporphyrin. An intermediate of this oxidation, uroporphomethene see slide Iron overload of the liver can also occur in chronic infections and in other chronic inflammatory diseases see section Blood letting—which depletes iron—is reportedly beneficial in PCT, regardless of the cause of the iron overload.
If the enzyme is deficient, protoporphyrin accumulates and causes skin manifestations similar to those observed in porphyria cutanea tarda. Porphobilinogen is excreted with the urine and, through spontaneous oxidation, forms a characteristic red pigment.
The dysregulation mainly affects heme synthesis in the liver. As the name of the disease suggests, it is not always manifest but only intermittently. Heme is the prosthetic group of cytochrome P enzymes, which are important in drug metabolism and are induced in the liver by various drugs see slide It appears that ALA synthase is induced along with the cytochrome P enzymes, and AIP attacks are often triggered or aggravated by the application of such drugs.
Specific drugs that induce cytochrome P and ALA synthase include barbituric acid derivatives and carbamazepine, which were, and occasionally still are, used in the treatment of psychiatric symptoms. Fatal outcomes have occurred when AIP patients were misdiagnosed and treated with barbituric acid derivatives.
At the end of this lifespan, they are captured and ingested by phagocytes in the spleen and the liver. When the globin protein is proteolytically degraded, heme is released. Heme itself undergoes degradation mostly in the liver. Ring cleavage by heme oxygenase produces biliverdin, which is in turn reduced to bilirubin. Some bilirubin is excreted into the bile as such; however, the greater share is first conjugated with glucuronic acid by UDP-glucuronosyltransferase, form 1A1, and excreted thereafter.
The major transport protein responsible for excretion of the diglucuronide is an ABC transporter ABCC2 , the same one that also secretes bile acids see slide In the anaerobic environment that prevails inside the colon, the released bilirubin subsequently undergoes reduction, again by bacterial enzymes, to variously colored pigments that produce the stool color. Another reduction product, urobilinogen, is taken up and excreted with the urine, causing the yellow color of the latter.
Causes: mechanically blocked excretion: bile duct blocked by bile stone or tumor increased production: hemolytic anemia premature decay of red blood cells decreased conjugation: enzyme defect, liver disease decreased excretion of conjugated heme: deficiency of ABCC2 transporter Dubin-Johnson syndrome Some fairly simple clues can narrow down the cause of jaundice in a given patient.
If excretion of bilirubin is blocked, the pigments derived from it will be absent, and the stool will have a grayish color.Each first exon has its own promoter element. Gradual formation of vesicles, bullae, blisters, and sores occurs in sun-exposed areas, especially the hands. On the other hand, when the flow of the bile is backed up, the conjugated bilirubin will spill back into the serum and will be increased.
Genetics[ edit ] Hemoglobin consists of protein subunits the "globin" molecules , and these proteins, in turn, are folded chains of a large number of different amino acids called polypeptides. HbF has a stronger oxygen affinity than HbA, allowing oxygen to flow from maternal to fetal circulation through the placenta. These include the same nutrients that are essential to the production and maintenance of any cell, such as glucose, lipids, and amino acids.
They also lack endoplasmic reticula and do not synthesize proteins.
Of significance to patients harboring a defective heme biosynthetic enzyme is the fact that defects prior to hydroxymethylbilane synthesis ARE NOT associated with photosensitivity, whereas, defects from this point on ARE associated with photosensitivity. Erythrocytes are biconcave discs with very shallow centers.
It does not, however, help to counteract a decrease in blood pH. First, the porphyrin ring is hydrophobic and must be solubilized to be excreted.
This improves oxygen delivery in the periphery and contributes to the control of respiration. Since they lack most organelles, there is more interior space for the presence of the hemoglobin molecules that, as you will see shortly, transport gases. As in neonatal jaundice, phototherapy is also used in Crigler-Najjar syndrome, but its efficiency decreases with time, since the growth of the body reduces its surface to volume ratio, and therefore a diminishing fraction of the bilirubin in the body can be reached by illumination. In the figure, the brown stipples represent the hemosiderin. NO binds reversibly to a specific cysteine residue in globin; the binding depends on the state R or T of the hemoglobin. Some disorders of heme biosynthesis are more insidious such as the various porphyrias, a list of which can be found below and in the Inborn Errors Page.
Beta-globin gene mutations that negatively impact beta-globin subunit synthesis cause both. B vitamins. Figure prepared from original data in [ ].
In erythroid cells all of the heme is synthesized for incorporation into hemoglobin and occurs only upon differentiation when synthesis of hemoglobin proceeds. The globins are broken down to amino acids aa , which are then used for protein synthesis. The alignments were created using Uniprot's alignment tool available online. The Various Heme Molecules In addition to the heme b found in hemoglobin, there are two additional forms of heme found in cytochromes such as those involved in the process of oxidative phosphorylation. In reticulocytes immature erythrocytes heme stimulates protein synthesis. Heme is the prosthetic group of cytochrome P enzymes, which are important in drug metabolism and are induced in the liver by various drugs see slide
The bright red, oxygenated hemoglobin travels to the body tissues, where it releases some of the oxygen molecules, becoming darker red deoxyhemoglobin, sometimes referred to as reduced hemoglobin.
Synthesis[ edit ] Hemoglobin Hb is synthesized in a complex series of steps. The major function of heme in humans is its role in the coordination of O2 molecules in hemoglobin. Figure 4.
This latter symptom lends to the description of "werewolf syndrome" in many porphyria patients. This forced low-spin pairing is indeed thought to happen in iron when oxygen binds, but is not enough to explain iron's change in size. ALAS1 is considered a house-keeping gene and is expressed in all cells.
The bright red, oxygenated hemoglobin travels to the body tissues, where it releases some of the oxygen molecules, becoming darker red deoxyhemoglobin, sometimes referred to as reduced hemoglobin. In the third step, porphobilinogen deaminase takes four molecules of PBG and produces hydroxymethylbilane. Lead intoxication causes inhibition of porphobilinogen synthase see slide Several inherited disorders in bilirubin metabolism have been identified.