{{Chembox <!-- Images --> | ImageFile = Granadaene.svg | ImageSize = 300px | ImageAlt = <!-- Names --> | IUPACName = (2''S'')-5-Amino-2-<nowiki>[[</nowiki>(2''E'',4''E'',6''E'',8''E'',10''E'',12''E'',14''E'',16''E'',18''E'',20''E'',22''E'',24''E'')-27-[(2''R'',3''R'',4''R'',5''R'',6''S'')-3,4,5-trihydroxy-6-methyloxan-2-yl]oxyoctacosa-2,4,6,8,10,12,14,16,18,20,22,24-dodecaenoyl]amino]pentanoic acid | OtherNames = <!-- Sections --> | Section1 = {{Chembox Identifiers | CASNo = | ChemSpiderID = 78444511 | PubChem = 101411594 | SMILES = C[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](O1)OC(C)C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C=C/C(=O)N[C@@H](CCCN)C(=O)O | InChI=1S/C39H52N2O8/c1-31(48-39-37(45)36(44)35(43)32(2)49-39)27-24-22-20-18-16-14-12-10-8-6-4-3-5-7-9-11-13-15-17-19-21-23-25-29-34(42)41-33(38(46)47)28-26-30-40/h3-25,29,31-33,35-37,39,43-45H,26-28,30,40H2,1-2H3,(H,41,42)(H,46,47)/b4-3+,7-5+,8-6+,11-9+,12-10+,15-13+,16-14+,19-17+,20-18+,23-21+,24-22+,29-25+/t31?,32-,33-,35-,36+,37+,39+/m0/s1 | InChIKey = PPFISAQUKQQDHW-OBEWLBDZSA-N }} | Section2 = {{Chembox Properties | C=39|H=52|N=2|O=8 | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = }} | Section3 = {{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }}
'''Granadaene''' is the trivial name of a polyene of non-isoprenoid biosynthetic origin, that constitutes the red pigment characteristic of ''Streptococcus agalactiae'' (group B streptococcus).
== Characteristics == Granadaene contains a conjugated system made up of a linear chain of 12 conjugated carbon-carbon double bonds which is connected to the amino acid ornithine at one end and the sugar rhamnose at the other.<ref name="Rosa 2006">{{cite journal|vauthors=Rosa-Fraile M, Rodríguez-Granger J, Haidour-Benamin A, Cuerva JM, Sampedro A|title=Granadaene: Proposed Structure of the Group B Streptococcus Polyenic Pigment|journal=Appl Environ Microbiol|date=2006|volume=72|issue=9|pages=6367–6370|doi=10.1128/aem.00756-06|pmid=16957264|pmc=1563658|bibcode=2006ApEnM..72.6367R }}</ref><ref name="Paradas 2012">{{cite journal|vauthors=Paradas M, Jurado R, Haidour A, Rodríguez Granger J, Sampedro Martínez A, de la Rosa Fraile M, Robles R, Justicia J, Cuerva JM|title=Clarifying the structure of granadaene: Total synthesis of related analogue - granadaene and confirmation of its absolute stereochemistry|journal=Bioorg Med Chem |date=2012|volume=20|issue=22|pages=6655–6661|doi=10.1016/j.bmc.2012.09.017|pmid=23043725}}</ref> Granadaene contains 12 conjugated double bonds, a feature which is unprecedented among non-isoprenoid pigments.
Granadaene is dark red, odorless, insoluble in water, methanol, ethanol, diethyl ether, acetone, hexane, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, chloroform, and in most solvents, it is soluble in DMSO–0.1% trifluoroacetic acid (TFA).<ref name="Rosa 2006" /> Granadaene, can be extracted from cultures of ''S.agalactiae'' in granada broth (granada medium without agar) with 0.1 M potassium hydroxide (KOH) and purified by size-exclusion chromatography on Sephadex LH using DMSO–0.1%TFA.<ref name="Rosa 2006" />
thumb|''Streptococcus agalactiae'' in granada broth thumb|''Streptococcus agalactiae'' on granada agar, anaerobic incubation thumb|Ultraviolet/visible spectrum of granadaene, in DMSO+TFA thumb|Proposed metabolic pathway for granadaene biosynthesis The fine-structure of the ultraviolet-visible absorption spectrum of the granadaene (in DMSO/TFA) is almost identical to that of a carotene with a similar conjugated system of 12 double bonds (e.g. alpha-carotene), which is why the GBS pigment was considered to be a carotene for many years.<ref name="Merrit 1978">{{cite journal|vauthors=Merrit K, Jacobs NJ|title=Characterization and Incidence of Pigment Production by Human Clinical Group B Streptococci|journal=J Clin Microbiol|date=1978|volume=8|issue=1|pages=105–107|doi=10.1128/jcm.8.1.105-107.1978 |pmc=275130|pmid=353069}}</ref>
Non-terpenoid polyenes up to 10 conjugated double bonds are also a bizarre class of biologically natural products (laetiporic acids) found in the basidiomycete ''Laetiporus sulphureus''.<ref name="Seibold 2020">{{cite journal |last1=Seibold PS. Lenz C. Gressler M. Hoffmeister D. |title=The Laetiporus polyketide synthase LpaA produces a series of antifungal polyenes |journal=J Antibiot (Tokyo) |date=2020 |volume=73 |issue=10 |pages=711–720 |doi=10.1038/s41429-020-00362-6 |pmid=32820242 |pmc=7473843 }}</ref>
==Granadaene and ''S.agalactiae'' detection and identification == Production of the red pigment granadaene is a phenotypic trait specific to β-hemolytic GBS, and because of that, detection of red colonies from clinical samples, when cultivated on granada medium, allows the straightforward identification of GBS.<ref name="Rosa-Fraile 1999B">{{cite journal |last1=M Rosa-Fraile, J Rodriguez-Granger, M Cueto-Lopez, A Sampedro, E B Gaye, J M Haro, A Andreu |title=Use of Granada medium to detect group B streptococcal colonization in pregnant women |journal=J Clin Microbiol |date=1999 |volume=37 |issue=8 |pages=2674–2677 |doi=10.1128/JCM.37.8.2674-2677.1999 |pmid=10405420 |pmc=85311 }}</ref><ref name=Verani2010>{{cite journal|vauthors=Verani JR, McGee L, Schrag SJ|title=Prevention of perinatal group B streptococcal disease: revised guidelines from CDC, 2010|journal=MMWR Recomm Rep|date=2010|volume=59(RR-10)|pages=1–32|url=https://www.cdc.gov/mmwr/pdf/rr/rr5910.pdf}}</ref><ref name="ASM 2021">{{cite web |last1=Filkins L , Hauser J, Robinson-Dunn B, Tibbetts R, Boyanton B , Revell P |title=Guidelines for the Detection and Identification of Group B Streptococcus. 2021 |url=https://asm.org/Guideline/Guidelines-for-the-Detection-and-Identification-of |publisher=American Society for Microbiology |access-date=23 May 2023}}</ref>
==Biological relevance == Granadaene is an organic compound produced by ''S.agalactiae''. It is the product of a metabolic pathway similar to that of biosynthesis of fatty acids. The enzymes necessary for the biosynthesis of granadaene in GBS are coded by a gene cluster of 12 genes, the ''cyl'' operon, Among the cyl operon, the cylE gene is required for pigment production, and transcription of cyl genes is regulated by the CovR/S two-component system,<ref name=Rosa-Fraile2014>{{cite journal|vauthors=Rosa-Fraile M, Dramsi S, Spellerberg B|title=Group B streptococcal haemolysin and pigment, a tale of twins.|journal=FEMS Microbiol. Rev.|date=2014|volume=38|issue=5|pages=932–946 |doi=10.1111/1574-6976.12071|pmid=24617549|pmc=4315905}}</ref> and a pathway for the pigment biosynthesis requiring all the genes of the ''cyl'' operon has been proposed.
Like the biosynthesis of the pigment, the hemolytic activity also requires in GBS the 12 genes of the ''cyl'' operon.<ref name="Spellerberg 1999">{{cite journal|vauthors=Spellerberg B, Pohl B, Haase G, Martin S, Weber-Heynemann J, Lütticken R|title=Identification of genetic determinants for the hemolytic activity of Streptococcus agalactiae by ISS1 transposition.|journal=J. Bacteriol.|date=1999|volume=181|issue=10|pages=3212–3219| doi=10.1128/JB.181.10.3212-3219.1999|pmc=93778|pmid=10322024}}</ref><ref name="Spellerberg 2000">{{cite journal|vauthors=Spellerberg B, Martin S, Brandt C, Lütticken R|title=The cyl genes of Streptococcus agalactiae are involved in the production of pigment|journal=FEMS Microbiol. Lett.|date=2000|volume=188|issue=2|pages=125–128|doi=10.1111/j.1574-6968.2000.tb09182.x|pmid=10913694|doi-access=free}}</ref> Moreover,it has been proposed that granadaene is indeed the hemolysin of ''S.agalactiae''
The pigment is localized, in GBS, in the cell membrane,<ref name="Merrit 1978" /> where it could play a role in membrane stabilization, similar to the role of carotenes in other bacterial membranes.<ref name="Taylor 1984">{{cite journal|author= Taylor RF |title=Bacterial tryterpenoids|journal=Microbiol. Rev.|date=1984|volume=48|issue=3|pages=181–198|doi=10.1128/MMBR.48.3.181-198.1984|pmc=373008|pmid=6387426}}</ref> In addition to ''S.agalactiae'' the presence of granadaene and the ''cyl'' genes has been reported in pigmented ''Acidipropionibacterium'' spp. (former ''Propionibacterium'') as ''A.jensenii'', ''A.thoenii'', and ''A.virtanenii'',<ref>Deptula P, Loivamaa L , Smolander OP, Laine P , Roberts RJ, Piironen V, Paulin L, Savijoki K, Auvinen P, Varmanen P (2019). "Red-Brown Pigmentation of Acidipropionibacterium jensenii Is Tied to Haemolytic Activity and cyl-Like Gene Cluster". ''Microorganisms'' 7: 512. https://doi.org/10.3390/microorganisms7110512 |https://pmc.ncbi.nlm.nih.gov/articles/PMC6920887/|</ref> where it can cause defects such as red spots in some cheeses.<ref name="Vanberg 2007">{{cite journal|vauthors=Vanberg C, Lutnaes BF, Langsrud T, Nees IF, Holo H|title=Propionibacterium jensenii produces the polyene pigment granadaene and has hemolytic properties similar to those of Streptococcus agalactiae.|journal=Appl Environ Microbiol|date=2007|volume=73|issue=17|pages=5501–5506|pmc=2042088|pmid=17630313| doi=10.1128/AEM.00545-07|bibcode=2007ApEnM..73.5501V}}</ref> Probably granadaene is also present in other related species such as ''Pseudopropionibacterium rubrum''.<ref name=Rosa-Fraile2014 /><ref name="Vanberg 2007" /><ref name="Saito 2018">{{cite journal |last1=Masanori Saito, Noriko Shinozaki-Kuwahara, Osamu Tsudukibashi, Tomomi Hashizume-Takizawa, Ryoki Kobayashi, Tomoko Kurita-Ochiai |title=Pseudopropionibacterium rubrum sp. nov., a novel red-pigmented species isolated from human gingival sulcus |journal=Microbiol Immunol |date=2018 |volume=62 |issue=6 |pages=388–394|doi=10.1111/1348-0421.12592 |pmid=29687917 |s2cid=22322865 |doi-access=free}}</ref> Granadaene is also produced by strains of ''Lactocococcus garvieae/petaury/formosensis'' group where the ''cyl'' cluster is also present.<ref name="Neuzil">{{cite journal |last1=Neuzil-Bunesova V, Ramirez Garcia A, Modrackova N, Makovska M, Sabolova M, Spröer C, Bunk B, Blom J, Schwab C |title=Feed Insects as a Reservoir of Granadaene-Producing Lactococci |journal=Front. Microbiol. |date=2022 |volume=13 |page=Art 848490 |doi=10.3389/fmicb.2022.848490 |pmid=35615513 |pmc=9125021 |doi-access=free }}</ref>
The ''cyl'' genes have been cloned in ''Lactococcus lactis'' (a non-hemolytic non-pigmented Gram-positive bacterium) and the expression of the GBS cyl operon conferred hemolysis, pigmentation, and cytotoxicity to ''Lactococcus lactis''. Proving that the expression of the genes of the ''cyl'' operon is sufficient for Granadaene production in a heterologous host.<ref name="Armistead 2020 Lactococcus">{{cite journal |last1=Armistead B, Whidbey C, Iyer LM, Herrero-Foncubierta P, Quach P, Haidour A, Aravind L, Cuerva JM, Jaspan HB, Rajagopal L. |title=The cyl Genes Reveal the Biosynthetic and Evolutionary Origins of the Group B Streptococcus Hemolytic Lipid, Granadaene |journal=Front. Microbiol. |date=2020 |volume=10 |page=3123|doi=10.3389/fmicb.2019.03123 |pmid=32038561 |pmc=6985545 |doi-access=free }}</ref>
==Granadaene and GBS Virulence== The hemolytic activity of granadaene is strongly linked to the length of its polyene chain.<ref name="Kristanc">{{cite journal |last1=Kristanc L, Božič B, Jokhadar ŠZ, Dolenc MS, Gomišček G. |title=The pore-forming action of polyenes: From model membranes to living organisms |journal=Biochim Biophys Acta Biomembr |date=2019 |volume=186 |issue=2 |pages=418–430 |doi=10.1016/j.bbamem.2018.11.006 |pmid=30458121 |s2cid=53735664 |doi-access=free }}</ref><ref name="Armistead, Herrero">{{cite journal |last1=Armistead B, Herrero-Foncubierta P, Coleman M, Quach P, Whidbey C, Justicia J, Tapia R, Casares R, Millán A, Haidour A, Rodriguez Granger J, Vornhagen J, Santana-Ufret V, Merillat S, Waldorf KA, Cuerva JM, Rajagopal L |title=Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection |journal=Nature Communications |date=2020 |volume=11 |issue=1 |page=1502 |doi=10.1038/s41467-020-15282-0 |pmid=32198389 |pmc=7083881 |bibcode=2020NatCo..11.1502A }}</ref>
It has been proposed that granadaene is indeed the hemolysin of ''S.agalactiae'', the GBS hemolysin is a broad-spectrum cytolysin able to destroy many eukaryotic cells, including platelets. Because of this, granadaene is considered an important virulence factor for GBS.<ref name=Rosa-Fraile2014 /><ref name="Whidbey 2013">{{cite journal|vauthors=Whidbey C, Harrell MI, Burnside K, Ngo L, Becraft AK, Iyer LM, Aravind L, Hitti J, Waldorf KM, Rajagopal L|title=A hemolytic pigment of Group B Streptococcus allows bacterial penetration of human placenta.|journal=J Exp Med |date=2013|volume=210|issue=6|pages=1265–1281|doi=10.1084/jem.20122753|pmid=23712433|pmc=3674703 |url=https://rupress.org/jem/article-pdf/210/6/1265/1211750/jem_20122753.pdf}}</ref><ref name="Liu 2022">{{cite journal |last1=Liu Y, Liu J. |title=Group B Streptococcus: Virulence Factors and Pathogenic Mechanism. |journal=Microorganisms |date=2022 |volume=15 |issue=12 |page=2483 |doi=10.3390/microorganisms10122483 |pmid=36557736 |pmc=9784991 |doi-access=free }}</ref><ref name="Whidbey 2015">{{cite journal|vauthors=Whidbey C, Vornhagen J, Gendrin C, Boldenow E, Samson JM, Doering K, Ngo L, Ezekwe EA Jr, Gundlach JH, Elovitz MA, Liggitt D, Duncan JA, Adams Waldorf KM, Rajagopal L|title=A streptococcal lipid toxin induces membrane permeabilization and pyroptosis leading to fetal injury.|journal=EMBO Mol. Med.|date=2015|volume=7|issue=4|pages=488–505|pmc=4403049|doi=10.15252/emmm.201404883|pmid=25750210}}</ref><ref name="Aemistead 2019">{{cite journal |last1=Armistead B, Oler E, Adams Waldorf K, Rajagopal L. |title=The Double Life of Group B Streptococcus: Asymptomatic Colonizer and Potent Pathogen |journal=J Mol Biol |date=2019 |volume=431 |issue=16 |pages=2914–2931|doi=10.1016/j.jmb.2019.01.035 |pmid=30711542 |pmc=6646060 }}</ref><ref name="Armistead Herrero 2020">{{cite journal |last1=Armistead B, Herrero-Foncubierta P, Coleman M, Quach P, Whidbey C, Justicia J, Tapia R, Casares R, Millán A, Haidour A, Granger JR, Vornhagen J, Santana-Ufret V, Merillat S, Adams Waldorf K, Cuerva JM, Rajagopal L. |title=Lipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection. |journal=Nat. Commun. |date=2020 |volume=11 |issue=1 |page=1502 |doi=10.1038/s41467-020-15282-0 |pmid=32198389 |pmc=7083881 |bibcode=2020NatCo..11.1502A }}</ref><ref name="Huebner">{{cite journal |last1=Huebner EM, Gudjónsdóttir MJ, Dacanay MB, Nguyen S, Brokaw A, Sharma K, Elfvin A, Hentz E, Rivera YR, Burd N, Shivakumar M, Coler B, Li M, Li A, Munson J, Orvis A, Coleman M, Jacobsson B, Rajagopal L, Adams Waldorf KM. |title=Virulence, phenotype and genotype characteristics of invasive group B Streptococcus isolates obtained from Swedish pregnant women and neonates |journal=Ann Clin Microbiol Antimicrob |date=2022 |volume=21 |issue=1 |page=43 |doi=10.1186/s12941-022-00534-2 |pmid=36229877 |pmc=9560721 |doi-access=free }}</ref><ref name="Jahn">{{cite journal |last1=Jahn, K.; Shumba, P.; Quach, P.; Müsken, M.; Wesche, J.; Greinacher, A.; Rajagopal, L.; Hammerschmidt, S.; Siemens, N. |title=Group B Streptococcal Hemolytic Pigment Impairs Platelet Function in a Two-Step Process |journal=Cells |date=2022 |volume=11 |issue=10 |page=1637 |doi=10.3390/cells11101637 |pmid=35626674 |pmc=9139542 |doi-access=free }}</ref>
Nevertheless, 1–5% of GBS strains are non-hemolytic and do not produce pigment.<ref name=Rosa-Fraile2014 /> These non-hemolytic and non-pigmented GBS strains (lacking pigment and hemolysin) are considered less virulent because of that.<ref name="Whidbey 2013" /><ref name="Whidbey 2015" /><ref name="Rodriguez-Granger 2015">{{cite journal|vauthors=Rodriguez-Granger J, Spellerberg B, Asam D, Rosa-Fraile M |title=Non-haemolytic and non-pigmented group b streptococcus, an infrequent cause of early onset neonatal sepsis.|journal = Pathogens and Disease|date=2015|volume=73|issue=9|doi=10.1093/femspd/ftv089|pmid=26449711|article-number=ftv089|pmc=4626576}}</ref><ref name="Armistead Quach 2020">{{cite journal |last1=Armistead B, Quach P, Snyder JM, Santana-Ufret V, Furuta A, Brokaw A, Rajagopal L. |title=Hemolytic membrane vesicles of Group B Streptococcus promote infection. |journal = The Journal of Infectious Diseases|date=2020 |volume=jiaa548 |issue=8 |pages=1488–1496 |doi=10.1093/infdis/jiaa548 |pmid=32861213 |pmc=8064051}}</ref>
== References == {{Reflist}}
Category:Rhamnosides Category:Polyenes Category:Biological pigments