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Urobilin
View on Wikipediafrom Wikipedia
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| Names | |
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| IUPAC name
3,3′-[(4S,16S)-3,18-Diethyl-2,7,13,17-tetramethyl-1,19-dioxo-1,4,5,15,16,19,22,24-octahydro-21H-biline-8,12-diyl]dipropanoic acid
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| Systematic IUPAC name
3,3′-([12S,4(52)Z,72S]-13,74-Diethyl-14,33,54,73-tetramethyl-15,75-dioxo-12,15,72,75-tetrahydro-11H,31H,71H-1,7(2),3,5(2,5)-tetrapyrrolaheptaphan-4(52)-ene-34,53-diyl)dipropanoic acid | |
| Other names
Urochrome
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| Identifiers | |
3D model (JSmol)
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| ChemSpider | |
| ECHA InfoCard | 100.015.870 |
| MeSH | Urobilin |
PubChem CID
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| UNII | |
CompTox Dashboard (EPA)
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| Properties | |
| C33H42N4O6 | |
| Molar mass | 590.721 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Urobilin is the chemical primarily responsible for the yellow color of urine. It is a linear tetrapyrrole compound that, along with the related colorless compound urobilinogen, are degradation products of the cyclic tetrapyrrole heme.
Metabolism
[edit]Urobilin is generated from the degradation of heme, which is first degraded through biliverdin to bilirubin. Bilirubin is then excreted as bile, which is further degraded by microbes present in the large intestine to urobilinogen. The enzyme responsible for the degradation is bilirubin reductase, which was identified in 2024.[1][2] Some of this remains in the large intestine, and its conversion to stercobilin gives feces their brown color. Some is reabsorbed into the bloodstream and then delivered to the kidneys. When urobilinogen is exposed to air, it is oxidized to urobilin, which has a yellow color.[3]
Importance
[edit]Many urine tests (urinalysis) monitor the amount of urobilin in urine, as its levels can give insight on the effectiveness of urinary tract function. Normally, urine would appear as either light yellow or colorless. A lack of water intake, for example following sleep or dehydration, reduces the water content of urine, thereby concentrating urobilin and producing a darker color of urine. Obstructive jaundice reduces biliary bilirubin excretion, which is then excreted directly from the blood stream into the urine, giving a dark-colored urine but with a paradoxically low urobilin concentration, no urobilinogen, and usually with correspondingly pale faeces. Darker urine can also be due to other chemicals, such as various ingested dietary components or drugs, porphyrins in patients with porphyria, and homogentisate in patients with alkaptonuria.
See also
[edit]References
[edit]- ^ Hall, Brantley; Levy, Sophia; Dufault-Thompson, Keith; Arp, Gabriela; Zhong, Aoshu; Ndjite, Glory Minabou; Weiss, Ashley; Braccia, Domenick; Jenkins, Conor; Grant, Maggie R.; Abeysinghe, Stephenie; Yang, Yiyan; Jermain, Madison D.; Wu, Chih Hao; Ma, Bing (January 2024). "BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen". Nature Microbiology. 9 (1): 173–184. doi:10.1038/s41564-023-01549-x. ISSN 2058-5276. PMC 10769871. PMID 38172624.
- ^ Rayne, Elizabeth (2024-01-27). "Gotta go? We've finally found out what makes urine yellow". Ars Technica. Retrieved 2024-01-28.
- ^ John E. Hall (2016). "The liver as an organ". Guyton and Hall Textbook of Medical Physiology, 13th edition. Elsevier. p. 885. ISBN 978-1455770052.
Further reading
[edit]- Bishop, Michael; Duben-Engelkirk, Janet L., and Fody, Edward P. (1992). "Chapter 19, Liver Function, Clinical Chemistry Principles, Procedures, Correlations, 2nd Ed." Philadelphia, J.B. Lippincott Company.
- Miyabara, Yuichi; Tabata, Masako; Suzuki, Junzo; Suzuki, Shizuo (1992). "Separation and sensitive determination of i-urobilin and 1-stercobilin by high-performance liquid chromatography with fluorimetric detection". Journal of Chromatography B: Biomedical Sciences and Applications. 574 (2): 261–265. doi:10.1016/0378-4347(92)80038-R. PMID 1618958.
- Miyabara, Y.; Sakata, Y.; Suzuki, J.; Suzuki, S. (1994). "Estimation of faecal pollution based on the amounts of urobilins in urban rivers". Environmental Pollution. 84 (2): 117–122. doi:10.1016/0269-7491(94)90093-0. PMID 15091706.
- Munson-Ringsrud, Karen and Jorgenson-Linné, Jean (1995). "Urinalysis and Body Fluids, a ColorText and Atlas." St. Louis, Mosby.
- Nelson, L.; David, Cox M.M. (2005). “Chapter 22 – Biosynthesis of Amino Acids, Nucleotides, and Related Molecules”, pp. 856, In Lehninger Principles of Biochemistry. Freeman, New York. pp. 856.
- Voet, Donald; Voet, Judith G.; Pratt, Charlotte W. (2018-01-23). Voet's Principles of Biochemistry, Global Edition, 5th Edition. Wiley. p. 1200. ISBN 978-1-119-45166-2. Retrieved 2024-02-01.
Urobilin
View on Grokipediafrom Grokipedia
Chemical Properties
Molecular Structure
Urobilin is a linear tetrapyrrole pigment derived from heme degradation, characterized by an open-chain structure consisting of four pyrrole rings interconnected by three methylene bridges (-CH₂- groups). This arrangement contrasts with the cyclic tetrapyrrole of heme, resulting in a flexible, acyclic biladiene system responsible for its distinctive chemical behavior.[6][7] The molecular formula of urobilin is , with a molar mass of 590.7 g/mol. Its systematic IUPAC name is 3-[(2E)-2-[[3-(2-carboxyethyl)-5-[(3-ethyl-4-methyl-5-oxo-1,2-dihydropyrrol-2-yl)methyl]-4-methyl-1H-pyrrol-2-yl]methylidene]-5-[(4-ethyl-3-methyl-5-oxo-1,2-dihydropyrrol-2-yl)methyl]-4-methylpyrrol-3-yl]propanoic acid, reflecting the two propanoic acid side chains at positions 8 and 12, methyl substituents at 2, 7, 13, and 17, and ethyl groups at 3 and 18.[6][7] Urobilin exhibits specific stereochemistry, with chiral centers at carbons 4 and 16 in the natural (levorotatory) form adopting the (4S,16S) configuration, which influences its optical activity and helical conformation in solution. The structure includes a defined (E) configuration at the exocyclic double bond between rings B and C, contributing to its conjugated system.[8][6] In comparison to bilirubin, an earlier intermediate in heme catabolism, urobilin features ethyl groups at positions 3 and 18 (reduced from bilirubin's vinyl groups) and partially reduced pyrrole rings, particularly the outer A and D rings existing as 1,2-dihydropyrrole-5-ones rather than the fully conjugated pyrrolenone and pyrrole units in bilirubin. This reduction alters the degree of conjugation and saturation, shifting the chromophore properties.[6][7][9]Physical and Chemical Characteristics
Urobilin is a yellow-orange pigment derived from the tetrapyrrole backbone, primarily responsible for the characteristic coloration of human urine through its selective absorption of visible light in the wavelength range of 450-470 nm. This absorption profile, with maxima around 460-490 nm depending on solvent and aggregation state, contributes to its vivid hue and distinguishes it from related bile pigments.[10][11][12] In terms of solubility, urobilin exhibits moderate solubility in water, approximately 0.048 g/L at neutral pH, rendering it sparingly soluble under physiological conditions where it often binds to proteins like albumin. It shows greater solubility in organic solvents such as ethanol, allowing for preparation of stock solutions up to 1.6 × 10^{-4} M, and can form soluble salts with bases, which facilitates its handling in laboratory settings.[1][12] Urobilin demonstrates reasonable stability as the oxidized product of urobilinogen, with urobilin IXα as the predominant isomer formed during heme degradation; however, it is sensitive to environmental factors, including oxidation in air, exposure to light, and variations in pH, which can induce aggregation and shifts in its absorption spectrum. At acidic pH, it forms stable H-aggregates with blue-shifted absorption around 500 nm, while neutral or basic conditions favor monomeric forms at approximately 540 nm.[13][12] The compound's acid-base properties stem from its two propionic acid side chains, conferring weakly acidic character with a pKa of around 3.9-5.0, akin to free propionic acid (pKa 4.87), which influences its ionization and interactions in aqueous media. For isolation, urobilin is typically extracted from urine or feces through acidification with glacial acetic acid to protonate and precipitate the pigment, followed by solvent extraction (e.g., with petroleum ether or chloroform) and purification via column chromatography on materials like aluminum oxide or sugar columns.[1][14]51699-8/fulltext)Biosynthesis and Metabolism
Heme Degradation Pathway
The degradation of heme, the prosthetic group of hemoglobin and other hemoproteins, initiates the pathway leading to bilirubin formation and ultimately urobilin. This process primarily occurs in the reticuloendothelial system, with the highest activity of the key enzyme heme oxygenase in the spleen, followed by the liver and bone marrow.[15] Heme oxygenase, mainly the inducible isoform HO-1 expressed in macrophages, catalyzes the stereospecific oxidation of heme at the α-meso carbon bridge, incorporating molecular oxygen and electrons from NADPH-cytochrome P450 reductase to produce biliverdin IXα, ferrous iron (Fe²⁺), and carbon monoxide (CO).[16] This reaction represents the rate-limiting step in heme catabolism, with CO serving as an endogenous signaling molecule and the released iron being sequestered by ferritin to prevent oxidative damage.[17] Biliverdin IXα, the initial green pigment product, is rapidly reduced to the yellow unconjugated bilirubin (also known as indirect bilirubin) by the enzyme biliverdin reductase (BVR), utilizing NADPH as a cofactor.[18] This conversion occurs in the same cellular compartments as heme oxidation, primarily within splenic and hepatic macrophages, yielding bilirubin in its IXα isomer form, which is lipophilic and poorly soluble in aqueous environments.[19] Unconjugated bilirubin circulates in the plasma tightly bound to albumin, which prevents its deposition in tissues and facilitates its delivery to the liver; this binding is reversible but high-affinity, with a stoichiometry of approximately one bilirubin molecule per albumin.[16] Upon reaching the liver, unconjugated bilirubin dissociates from albumin and is actively taken up by hepatocytes across the sinusoidal membrane via organic anion-transporting polypeptides (OATPs), such as OATP1B1 and OATP1B3, which mediate sodium-independent transport.[20] Inside the hepatocytes, bilirubin undergoes conjugation in the endoplasmic reticulum, catalyzed by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which transfers glucuronic acid from UDP-glucuronic acid to the propionic acid side chains of bilirubin.[16] This process predominantly forms bilirubin diglucuronide (direct bilirubin), with lesser amounts of monoglucuronide, enhancing water solubility and enabling excretion; the diglucuronide is the major conjugate in human bile, comprising about 80-90% of excreted bilirubin.[21] Conjugated bilirubin is then transported across the canalicular membrane into bile by the ATP-dependent multidrug resistance-associated protein 2 (MRP2), secreted into the biliary canaliculi, and ultimately delivered via the bile duct to the duodenum in the small intestine.[16] This hepatic processing ensures efficient elimination of the lipophilic heme breakdown products, preventing toxicity while setting the stage for further metabolism in the gut.[22]Formation of Urobilinogen and Oxidation
In the intestines, gut microbiota play a crucial role in converting bilirubin, the precursor derived from heme degradation, into urobilinogen through a reduction process. Specifically, bacteria such as those in the classes Clostridia (e.g., Clostridium species) and Bacteroidia (e.g., Bacteroides species), predominantly from the phyla Firmicutes and Bacteroidetes, express the enzyme bilirubin reductase (BilR), encoded by the blrB gene. This enzyme, discovered in 2024, catalyzes the stereospecific reduction of bilirubin to the colorless compound urobilinogen in a two-step process involving hydride transfers, limiting the reabsorption of potentially toxic unconjugated bilirubin.[23][24] Following its formation, a portion of urobilinogen undergoes enterohepatic circulation. Approximately 10-20% of intestinal urobilinogen is reabsorbed from the colon into the portal vein, transported to the liver, where it is partially re-excreted into bile for recycling, while the remainder enters the systemic circulation and is filtered by the kidneys.[25][26] This reabsorption helps maintain bilirubin homeostasis but also contributes to the small amount of urobilinogen that reaches the urinary tract. The conversion of urobilinogen to urobilin occurs primarily through oxidation, transforming the colorless urobilinogen into the yellow pigment responsible for urine coloration. This oxidation can proceed via spontaneous auto-oxidation upon exposure to atmospheric oxygen or enzymatically, such as by flavin-dependent oxidases in biological fluids, yielding urobilin as the stable end product.00309-3/fulltext)80071-X/pdf) The predominant isomer formed is urobilin IXα, reflecting the IXα configuration of natural bilirubin, with minor amounts of stereoisomers urobilin IIIα and XIIIα arising from bacterial reduction rearrangements.[27] Daily, the human body breaks down approximately 200-300 mg of heme, primarily from senescent red blood cells, leading to the production of about 4 mg of urobilin excreted in urine as the oxidized form.[13][28] This urinary output represents a minor fraction of total urobilinogen, with the majority oxidized to stercobilin and eliminated in feces.Physiological Role
Coloration of Urine
Urobilin serves as the principal pigment imparting the characteristic yellow to amber coloration of normal human urine, derived from the oxidation of urobilinogen during its renal excretion. This compound, a linear tetrapyrrole, absorbs light in the visible spectrum, producing the familiar hue that varies in intensity based on physiological factors. In healthy individuals, urobilin arises from the enterohepatic circulation of bilirubin breakdown products, with only a small fraction escaping hepatic reuptake to appear in urine.[29] The typical concentration of urobilin in urine ranges from 0.2 to 1 mg/100 mL, directly influencing the depth of yellow pigmentation; lower levels in well-hydrated states result in pale urine, while dehydration concentrates the pigment, yielding deeper shades. Daily urinary output of urobilin is approximately 1-4 mg, mirroring the baseline rate of heme catabolism from senescent red blood cells. This excretion reflects efficient bilirubin metabolism, with urobilinogen oxidized to urobilin in the kidneys for final elimination.[30][31] Urine pH can influence the intensity of urobilin's visual impact, with acidic conditions often resulting in darker appearances. Urobilin interacts with other urinary pigments in a complementary manner, including urochrome—which is synonymous with urobilin—and minor contributors like uroerythrin, collectively defining the spectrum of normal urine shades without dominating over one another.[32][33]Integration with Bilirubin Cycle
Urobilin forms a critical component of the bilirubin enterohepatic circulation, where it arises from the oxidation of urobilinogen, a key intermediate in heme degradation. In the intestines, gut bacteria reduce conjugated bilirubin to urobilinogen, with approximately 10-20% of this urobilinogen being reabsorbed into the portal bloodstream and returned to the liver via the enterohepatic loop.[25] Of the reabsorbed urobilinogen, about 95% is taken up by hepatocytes and re-excreted into bile, thereby recycling bilirubin and maintaining systemic homeostasis by preventing excessive accumulation of unconjugated bilirubin in plasma.[34][35] This recycling process regulates bilirubin levels, as disruptions in hepatic uptake or re-excretion can alter the balance between production and elimination. Daily bilirubin production in adults averages around 250 mg, primarily from heme breakdown, with the majority processed through the gut: approximately 200 mg is converted to stercobilin and excreted in feces, while only about 4 mg is oxidized to urobilin and eliminated in urine.[16][36] These quantities reflect the efficiency of the enterohepatic loop in conserving bilirubin for reuse while excreting a small fraction to avoid toxicity. Urobilin and stercobilin represent parallel oxidation products of urobilinogen and stercobilinogen, respectively, contributing to the pigmentation of bodily wastes. In the colon, unreabsorbed urobilinogen oxidizes to stercobilin, the brown pigment responsible for fecal coloration, whereas the minor portion reaching systemic circulation oxidizes to urobilin, imparting the yellow hue to urine upon renal excretion.[36][37] Feedback mechanisms within the cycle further integrate urobilin production with physiological needs. Heme oxygenase-1 (HO-1), the inducible isoform, is upregulated by oxidative stress, enhancing heme catabolism to bilirubin and thereby increasing downstream urobilinogen formation as a protective response against cellular damage.[38] Additionally, the efficiency of bilirubin glucuronidation by UDP-glucuronosyltransferase influences urobilin output, as impaired conjugation reduces biliary excretion of bilirubin, limiting its availability for intestinal reduction to urobilinogen and subsequent oxidation to urobilin.[39] Genetic variations, particularly mutations in the UGT1A1 gene encoding the glucuronosyltransferase enzyme, indirectly modulate urobilin levels by disrupting upstream bilirubin processing. Such mutations, as seen in conditions like Gilbert syndrome, decrease glucuronidation capacity, leading to elevated unconjugated bilirubin and reduced delivery to the gut, which in turn lowers urobilinogen and urobilin production and excretion.[40][41]Clinical and Diagnostic Significance
Urinalysis Applications
Urinalysis for urobilin primarily involves detecting and quantifying its precursor, urobilinogen, due to the latter's stability in standard tests, with urobilin inferred through oxidation products or direct spectroscopic measurement. Routine methods rely on chemical reactions that produce color changes proportional to concentration, while advanced techniques provide precise quantification. These applications are essential in clinical laboratories for assessing heme degradation byproducts in urine samples. Dipstick tests represent a common, rapid approach for urobilinogen detection, employing Ehrlich's reagent, which contains p-dimethylaminobenzaldehyde, to react with urobilinogen and form a red-colored compound measurable by color intensity.[42] This semi-quantitative method allows indirect inference of urobilin levels, as oxidation of urobilinogen to urobilin contributes to urine pigmentation observable on the strip.[43] Results are typically read within 60 seconds to minimize interference from air oxidation. For more precise quantification, spectrophotometry measures urobilin's absorbance at approximately 450 nm, enabling direct assessment of the pigment in extracted urine samples after appropriate dilution to avoid matrix effects.[44] This technique is particularly useful in specialized labs for confirming elevated levels, with linearity in the range of 1 to 35 µmol/L.[45] The Watson-Schwartz test serves as a confirmatory qualitative method to distinguish urobilinogen from porphobilinogen in urine, using a modified Ehrlich reaction followed by solvent extraction.[46] Urine is mixed with Ehrlich's reagent and sodium acetate; a cherry-red color extractable into chloroform indicates urobilinogen, while extraction into butanol points to porphobilinogen, preventing misinterpretation in heme-related disorders.[47] Normal urobilinogen ranges in urine are 0.1 to 1.0 Ehrlich units per 2 hours, where one Ehrlich unit approximates 1 mg of urobilinogen; levels above this may signal increased heme breakdown such as hemolysis.[48] Sample preparation emphasizes using fresh urine, ideally collected within 2 hours and stored cool (2-8°C) while protected from light, to prevent oxidation of urobilinogen to urobilin and resultant artifactual decreases in measured values.[49]Indicators of Pathological Conditions
Elevated levels of urobilin in urine, often exceeding 4 mg per day, serve as an indicator of hemolytic anemias, such as sickle cell disease, where excessive red blood cell breakdown increases heme degradation and subsequent bilirubin production, leading to darkened urine coloration.[50][2] Conversely, decreased or absent urobilin levels signal biliary obstruction, as seen in conditions like gallstone impaction, which blocks the flow of bilirubin to the intestines, preventing its conversion to urobilinogen and resulting in pale urine and clay-colored stools due to the lack of stercobilin pigments.[2][52][53] Urobilin levels also differentiate jaundice types: in pre-hepatic jaundice from hemolysis, urobilin excretion is markedly increased due to heightened unconjugated bilirubin production; hepatic jaundice shows variable urobilin depending on liver impairment extent; and post-hepatic jaundice features low urobilin alongside elevated urinary conjugated bilirubin from backup of processed bile.[54][25][55] In genetic disorders affecting bilirubin conjugation, urobilin monitoring reveals disruptions: Gilbert's syndrome typically presents with mild reductions in urobilin due to partial glucuronyltransferase deficiency, limiting bilirubin delivery to the gut; whereas Crigler-Najjar syndrome causes severe upstream defects, often resulting in negligible urobilin excretion from near-complete enzyme absence.[56][57][58] Recent discoveries, including the 2024 identification of the gut microbial enzyme bilirubin reductase (BilR), which converts bilirubin to urobilinogen, have enhanced understanding of how microbial dysbiosis contributes to altered urobilin levels in liver diseases, with disrupted BilR activity linked to elevated serum bilirubin in conditions like inflammatory bowel disease.[4] As of June 2025, circulating urobilinogen has been found to augment inflammation and corticosteroid resistance in acute-on-chronic liver failure.[59] Additionally, as of January 2025, urobilin derived from bilirubin bioconversion binds to albumin and may compete with bilirubin for binding sites.[11]References
- https://www.sciencedirect.com/topics/[neuroscience](/page/Neuroscience)/urobilinogen