Biliverdin

{{Short description|Green bile pigment}} {{chembox | Watchedfields = changed | verifiedrevid = 443422805 | ImageFile1 = Biliverdin3.svg | ImageSize1 = | ImageFile2 = Biliverdin-based-on-xtal-3D-bs-17.png | IUPACName = 3,3′-(2,17-Diethenyl-3,7,13,18-tetramethyl-1,19-dioxo-19,21,22,24-tetrahydro-1''H''-biline-8,12-diyl)dipropanoic acid | SystematicName = 3,3′-([1²(2)''Z'',4(5²)''Z'',6(7²)''Z'']-1³,7⁴-Diethenyl-1⁴,3³,5⁴,7³-tetramethyl-1⁵,7⁵-dioxo-1¹,1⁵,7¹,7⁵-tetrahydro-3¹''H''-1,7(2),3,5(2,5)-tetrapyrrolaheptaphane-1²(2),4(5²),6(7²)-triene-3⁴,5³-diyl)dipropanoic acid | OtherNames = |Section1={{Chembox Identifiers | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 10628548 | InChI = 1/C33H34N4O6/c1-7-20-19(6)32(42)37-27(20)14-25-18(5)23(10-12-31(40)41)29(35-25)15-28-22(9-11-30(38)39)17(4)24(34-28)13-26-16(3)21(8-2)33(43)36-26/h7-8,13-15,35H,1-2,9-12H2,3-6H3,(H,36,43)(H,37,42)(H,38,39)(H,40,41)/b26-13-,27-14-,28-15- | InChIKey = QBUVFDKTZJNUPP-BBROENKCBK | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 455477 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C33H34N4O6/c1-7-20-19(6)32(42)37-27(20)14-25-18(5)23(10-12-31(40)41)29(35-25)15-28-22(9-11-30(38)39)17(4)24(34-28)13-26-16(3)21(8-2)33(43)36-26/h7-8,13-15,35H,1-2,9-12H2,3-6H3,(H,36,43)(H,37,42)(H,38,39)(H,40,41)/b26-13-,27-14-,28-15- | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = QBUVFDKTZJNUPP-BBROENKCSA-N | CASNo_Ref = {{cascite|correct|CAS}} | CASNo = 114-25-0 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = O9MIA842K9 | PubChem = 251 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 17033 | SMILES = CC\1=C(/C(=C/C2=C(C(=C(N2)/C=C\3/C(=C(C(=O)N3)C)C=C)C)CCC(=O)O)/N/C1=C\C4=NC(=O)C(=C4C)C=C)CCC(=O)O | MeSHName = Biliverdin }} |Section2={{Chembox Properties | Formula = C₃₃H₃₄N₄O₆ | MolarMass = 582.646 | Appearance = Dark green plates or prisms with violet surface color | Density = | MeltingPt = > 300 °C | BoilingPt = | Solubility = }} |Section7={{Chembox Hazards | ExternalSDS = [http://www.sigmaaldrich.com/MSDS/MSDS/DisplayMSDSPage.do?country=PL&language=EN-generic&productNumber=30891&brand=SIGMA&PageToGoToURL=http%3A//www.sigmaaldrich.com/catalog/product/sigma/30891%3Flang%3Dpl Sigma-Aldrich] | MainHazards = Irritant | FlashPt = | AutoignitionPt = }} }}

'''Biliverdin''' (from the Latin for green bile) is a green tetrapyrrolic bile pigment, and is a product of heme catabolism.<ref name="boron">Boron W, Boulpaep E. Medical Physiology: a cellular and molecular approach, 2005. 984–986. Elsevier Saunders, United States. {{ISBN|1-4160-2328-3}}</ref><ref name="mos">{{cite journal | last1 = Mosqueda | first1 = L | last2 = Burnight | first2 = K | last3 = Liao | first3 = S | year = 2005 | title = The Life Cycle of Bruises in Older Adults | journal = Journal of the American Geriatrics Society | volume = 53 | issue = 8| pages = 1339–1343 | doi = 10.1111/j.1532-5415.2005.53406.x | pmid = 16078959 | s2cid = 12394659 }}</ref>

{{chemrxn|width=65%| {{chemrxn/sub||class=skin-invert-image|caption=heme B }} {{chemrxn/arw|direction=forward }} {{chemrxn/cpd|biliverdin|upright=4 }} {{chemrxn/arw|direction=forward }} {{chemrxn/cpd|bilirubin|upright=4 }} }}

It is the pigment responsible for a greenish color sometimes seen in bruises.<ref name="mos" />

== Metabolism == {{stack|thumb|250px|left|Heme metabolism}} Biliverdin results from the breakdown of the heme moiety of hemoglobin in erythrocytes. Macrophages break down senescent erythrocytes and break the heme down into biliverdin along with hemosiderin, in which biliverdin normally rapidly reduces to free bilirubin.<ref name="boron" /><ref>{{cite journal | last1 = Seyfried | first1 = H | last2 = Klicpera | first2 = M | last3 = Leithner | first3 = C | last4 = Penner | first4 = E | title = Bilirubin metabolism (author's transl) | journal = Wiener Klinische Wochenschrift | volume = 88 | issue = 15 | pages = 477–82 | year = 1976 | pmid = 793184 }}</ref>

Biliverdin can be observed during the healing process of bruises, being responsible for the green color of a healing bruise. Its further breakdown into bilirubin leads to the bruise changing to a yellowish color.<ref name="mos" />

== Role in disease == Biliverdin has been found in excess in the blood of humans suffering from hepatic diseases. Jaundice is caused by the accumulation of biliverdin or bilirubin (or both) in the circulatory system and tissues.<ref name="boron" /> Jaundiced skin and sclera (whites of the eyes) are characteristic of liver failure.

== Role in treatment of disease == While typically regarded as a mere waste product of heme breakdown, evidence has been mounting that suggests that biliverdin – and other bile pigments – has a physiological role in humans.<ref name="bul"/><ref name="oh">{{cite journal | last1 = Ohrui | first1 = T. | last2 = Yasuda | first2 = H. | last3 = Yamaya | first3 = M. | last4 = Matsui | first4 = T. | last5 = Sasaki | first5 = H. | title = Transient relief of asthma symptoms during jaundice: a possible beneficial role of bilirubin | journal = The Tohoku Journal of Experimental Medicine | volume = 199 | issue = 3 | pages = 193–196 | year = 2003 | pmid = 12703664 | doi = 10.1620/tjem.199.193 | doi-access = free }}</ref>

Bile pigments such as biliverdin possess significant anti-mutagenic and antioxidant properties and therefore, may fulfill a useful physiological function.<ref name="oh"/> Biliverdin and bilirubin have been shown to be potent scavengers of hydroperoxyl radicals.<ref name="bul">{{cite journal | last1 = Bulmer | first1 = A. C. | last2 = Ried | first2 = K. | last3 = Blanchfield | first3 = J. T. | last4 = Wagner | first4 = K. H. | title = The anti-mutagenic properties of bile pigments | journal = Mutation Research | volume = 658 | issue = 1–2 | pages = 28–41 | year = 2008 | pmid = 17602853 | doi = 10.1016/j.mrrev.2007.05.001 }}</ref><ref name="oh"/> They have also been shown to inhibit the effects of polycyclic aromatic hydrocarbons, heterocyclic amines, and oxidants – all of which are mutagens. Some studies have found that people with higher concentration levels of bilirubin and biliverdin in their bodies have a lower frequency of cancer and cardiovascular disease.<ref name="bul" /> It has been suggested that biliverdin – as well as many other tetrapyrrolic pigments – may function as an HIV-1 protease inhibitor<ref>{{cite journal | last1 = McPhee | first1 = F. | last2 = Caldera | first2 = P. S. | last3 = Bemis | first3 = G. W. | last4 = McDonagh | first4 = A. F. | last5 = Kuntz | first5 = I. D. | last6 = Craik | first6 = C. S. | title = Bile pigments as HIV-1 protease inhibitors and their effects on HIV-1 viral maturation and infectivity in vitro | journal = The Biochemical Journal | volume = 320 | pages = 681–686 | year = 1996 | pmid = 8973584 | pmc = 1217983 | issue = Pt 2 | doi=10.1042/bj3200681}}</ref> as well as having beneficial effects in asthma<ref name="oh" /> though further research is needed to confirm these results. There are currently no practical implications for using biliverdin in the treatment of any disease.

== In non-human animals == Biliverdin is an important pigment component in avian egg shells, especially blue and green shells. Blue egg shells have a significantly higher concentration of biliverdin than brown egg shells.<ref>{{cite journal | doi = 10.1021/acs.jchemed.7b00449 | volume=94 | issue=10 | title=Isolation of Biliverdin IXα, as its Dimethyl Ester, from Emu Eggshells | year=2017 | journal=Journal of Chemical Education | pages=1533–1537 | last1 = Halepas | first1 = Steven | last2 = Hamchand | first2 = Randy | last3 = Lindeyer | first3 = Samuel E. D. | last4 = Brückner | first4 = Christian| bibcode=2017JChEd..94.1533H }}</ref>

Research has shown that the biliverdin of egg shells is produced from the shell gland, rather than from the breakdown of erythrocytes in the blood stream,{{Citation needed|date=April 2017}} although there is no evidence that the sources of the material are neither tetrapyrroles nor free heme from the blood plasma.{{clarify|reason=confusing double negative|date=May 2018}}{{citation needed|date=May 2018}}

Along with its presence in avian egg shells, other studies have also shown that biliverdin is present in the blue-green blood of many marine fish, the blood of the tobacco hornworm, the wings of moth and butterfly, the serum and eggs of frogs, and the placenta of dogs.<ref>{{cite journal | last1 = Fang | first1 = LS | last2 = Bada | first2 = JL | title = The blue-green blood plasma of marine fish | journal = Comparative Biochemistry and Physiology B | volume = 97 | issue = 1 | pages = 37–45 | year = 1990 | pmid = 2253479 | doi = 10.1016/0305-0491(90)90174-R }}</ref> With dogs, this can lead, in extremely rare cases, to the birth of puppies with green fur; however, the green color fades out soon after birth.<ref>{{Cite web| url=https://time.com/2871430/these-puppies-were-born-with-green-fur/| title=These Puppies Were Born with Green Fur| date=13 June 2014| access-date=17 November 2024| archive-date=7 October 2024| archive-url=https://web.archive.org/web/20241007061233/https://time.com/2871430/these-puppies-were-born-with-green-fur/| url-status=dead}}</ref> In the garfish (''Belone belone'') and related species, the bones are bright green because of biliverdin.<ref name=Juttner2013>{{cite journal |author1=Jüttner, Frank |author2=Maike Stiesch |author3=Waldemar Ternes |title=Biliverdin: the blue-green pigment in the bones of the garfish (Belone belone) and eelpout (Zoarces viviparus) |journal=European Food Research and Technology |volume=236 |issue=6 |pages=943–953 |year=2013 |doi=10.1007/s00217-013-1932-y|doi-access=free }}</ref> The green coloration of many grasshoppers and lepidopteran larvae is also due to biliverdin.<ref>{{cite journal |last1=Shamim |first1=G | last2=Ranjan | first2=S | last3=Pandey | first3=D | last4=Ramani | first4=R | year=2014 | title=Biochemistry and biosynthesis of insect pigments |journal = European Journal of Entomology | volume = 111 |issue=2 | page=155 | doi = 10.14411/eje.2014.021 | url=https://www.eje.cz/pdfs/eje/2014/02/01.pdf | access-date=25 June 2023}}</ref>

Biliverdin is also present in the green blood, muscles, bones, and mucosal lining of skinks of the genus ''Prasinohaema'', found in New Guinea. It is uncertain whether this presence of biliverdin is an ecological or physiological adaptation of any kind. It has been suggested that accumulation of biliverdin might deter harmful infection by ''Plasmodium'' malaria parasites, although no statistically significant correlation has been established.<ref>{{cite journal | last1 = Austin | first1 = C | last2 = Perkins | first2 = S | year = 2006 | title = Parasites in a biodiversity hotspot: a survey of hematozoa and a molecular phyolgenetic analysis of plasmodium in New Guinea skinks | journal = Journal of Parasitology | volume = 92 | issue = 4| pages = 770–777 | doi = 10.1645/GE-693R.1 | pmid=16995395| s2cid = 1937837 | url = https://digitalcommons.lsu.edu/biosci_pubs/84 | url-access = subscription }}</ref> The Cambodian frog, ''Chiromantis samkosensis'', also exhibits this characteristic along with turquoise bones.<ref name="grismer">{{cite journal|doi=10.1655/0018-0831(2007)63[392:ANSOCP]2.0.CO;2|year=2007|volume=63|pages=392–400|title=A New Species of Chiromantis Peters 1854 (Anura: Rhacophoridae) from Phnom Samkos in the Northwestern Cardamom Mountains, Cambodia|author=Lee Grismer, L.|journal=Herpetologica|last2=Thy|first2=Neang|last3=Chav|first3=Thou|last4=Holden|first4=Jeremy|issue=3|s2cid=84472376 }}</ref>

== In fluorescence imaging == [[File:Far-Red & Near-infrared Fluorescent Ubiquitination-based Cell Cycle Indicator (FUCCI).gif|thumb|320x320px|Fluorescent proteins visualize the cell cycle progression. IFP2.0-hGem(1/110) fluorescence is shown in green and highlights the S/G₂/M phases. smURFP-hCdtI(30/120) fluorescence is shown in red and highlights the G₀/G₁ phases.]] In a complex with reengineered bacterial phytochrome, biliverdin has been employed as an IR-emitting chromophore for in vivo imaging.<ref name="Tsien">{{cite journal|doi=10.1126/science.1168683|year=2009|volume=324|pages=804–807|title=Mammalian expression of infrared fluorescent proteins engineered from a bacterial phytochrome|author=X. Shu|journal=Science|pmid=19423828|issue=5928|pmc=2763207|display-authors=etal|bibcode=2009Sci...324..804S}}</ref><ref name="Verkhusha">{{cite journal|doi=10.1038/nbt.1918|year=2011|volume=29|pages=757–761|title=Bright and stable near infra-red fluorescent protein for in vivo imaging|author=GSFilonov|journal=Nat Biotechnol|pmid=21765402|pmc=3152693|issue=8|last2=Piatkevich|first2=Kiryl D|last3=Ting|first3=Li-Min|last4=Zhang|first4=Jinghang|last5=Kim|first5=Kami|last6=Verkhusha|first6=Vladislav V|display-authors=etal}}</ref> In contrast to fluorescent proteins which form their chromophore through posttranslational modifications of the polypeptide chain, phytochromes bind an external ligand (in this case, biliverdin), and successful imaging of the first bacteriophytochrome-based probe required addition of the exogenous biliverdin.<ref name="Tsien"/> Recent studies demonstrated that bacteriophytochrome-based fluorescent proteins with high affinity to biliverdin can be imaged in vivo utilizing endogenous ligands only and, thus, with the same ease as the conventional fluorescent proteins.<ref name="Verkhusha"/> Advent of the second and further generations of the biliverdin-binding bacteriophytochrome-based probes should broaden the possibilities for non-invasive in vivo imaging.

A new class of fluorescent protein was evolved from a cyanobacterial (''Trichodesmium erythraeum'') phycobiliprotein, α-allophycocyanin, and named small ultra red fluorescent protein (smURFP) in 2016. smURFP autocatalytically self-incorporates the chromophore biliverdin without the need of an external protein, known as a lyase.<ref name=":0">{{Cite journal|last1=Rodriguez|first1=Erik A.|last2=Tran|first2=Geraldine N.|last3=Gross|first3=Larry A.|last4=Crisp|first4=Jessica L.|last5=Shu|first5=Xiaokun|last6=Lin|first6=John Y.|last7=Tsien|first7=Roger Y.|date=2016-08-01|title=A far-red fluorescent protein evolved from a cyanobacterial phycobiliprotein|journal=Nature Methods|doi=10.1038/nmeth.3935|issn=1548-7105|pmid=27479328|volume=13|issue=9|pages=763–9|pmc=5007177}}</ref> Jellyfish- and coral-derived fluorescent proteins require oxygen and produce a stoichiometric amount of hydrogen peroxide upon chromophore formation.<ref>{{Cite journal|last=Tsien|first=Roger Y.|date=1998-01-01|title=The Green Fluorescent Protein|journal=Annual Review of Biochemistry|volume=67|issue=1|pages=509–544|doi=10.1146/annurev.biochem.67.1.509|pmid=9759496}}</ref> smURFP does not require oxygen or produce hydrogen peroxide and uses the chromophore biliverdin. smURFP has a large extinction coefficient (180,000 M⁻¹ cm⁻¹) and has a modest quantum yield (0.20), which makes it comparable biophysical brightness to eGFP and about 2-fold brighter than most red or far-red fluorescent proteins derived from coral. smURFP spectral properties are similar to the organic dye Cy5.<ref name=":0" />

== See also == * Stercobilin * Tetrapyrrole * Urobilin

== References == {{Reflist}}

==External links== * [http://www.nhs.uk/conditions/Jaundice-newborn/Pages/Introduction.aspx?url=Pages/What-is-it.aspx Explaining jaundice in newborn at NHS] {{Webarchive|url=https://web.archive.org/web/20160303175905/http://www.nhs.uk/conditions/Jaundice-newborn/Pages/Introduction.aspx?url=Pages/What-is-it.aspx |date=2016-03-03 }}

{{Heme metabolism intermediates}} {{Tetrapyrroles}}

Category:Biological pigments Category:Tetrapyrroles