astaxanthin

File:Pandborealisind.jpg (Arctic shrimp) are colored red by astaxanthin, and are used and sold as an extractable source of astaxanthin.]]

File:Three-Dimensional-Ultrastructural-Study-of-Oil-and-Astaxanthin-Accumulation-during-Encystment-in-pone.0053618.s002.ogv cyst filled with astaxanthin (red)]]

File:Antarctic krill (Euphausia superba).jpg

Astaxanthin is present in most red-coloured aquatic organisms. The content varies from species to species, but also from individual to individual as it is highly dependent on diet and living conditions.{{Cite journal |last1=Abd El-Ghany |first1=Mohamed N. |last2=Hamdi |first2=Salwa A. |last3=Elbaz |first3=Reham M. |last4=Aloufi |first4=Abeer S. |last5=El Sayed |first5=Rana R. |last6=Ghonaim |first6=Ghadeer M. |last7=Farahat |first7=Mohamed G. |date=May 24, 2023 |title=Development of a Microbial-Assisted Process for Enhanced Astaxanthin Recovery from Crab Exoskeleton Waste |journal=Fermentation |language=en |volume=9 |issue=6 |pages=505 |doi=10.3390/fermentation9060505 |doi-access=free |issn=2311-5637}} Astaxanthin and other chemically related asta-carotenoids have also been found in a number of lichen species of the Arctic zone.{{cn|date=May 2024}}

The primary natural sources for industrial production of astaxanthin comprise the following:

• Euphausia pacifica (Pacific krill)
• Euphausia superba (Antarctic krill)
• Haematococcus pluvialis (algae)
• Pandalus borealis (Arctic shrimp)

Astaxanthin concentrations in nature are approximately:{{citation needed|date=February 2018}}

Algae are the primary natural source of astaxanthin in the aquatic food chain. The microalgae Haematococcus pluvialis contains high levels of astaxanthin (about 3.8% of dry weight), and is the primary industrial source of natural astaxanthin.{{cite journal |vauthors=Ambati RR, Phang SM, Ravi S, Aswathanarayana RG |title=Astaxanthin: sources, extraction, stability, biological activities and its commercial applications--a review |journal=Marine Drugs |volume=12 |issue=1 |pages=128–52 |date=January 2014 |pmid=24402174 |pmc=3917265 |doi=10.3390/md12010128 |doi-access=free }}

In shellfish, astaxanthin is almost exclusively concentrated in the shells, with only low amounts in the flesh itself, and most of it only becomes visible during cooking as the pigment separates from the denatured proteins that otherwise bind it. Astaxanthin is extracted from Euphausia superba (Antarctic krill) and from shrimp processing waste.Katevas, Dimitri Sclabos (October 6, 2003). [https://web.archive.org/web/20030629005846/http://www.aquafeed.com/article.php?id=365 The Krill]. aquafeed.com

File:Astaxanthin Biosynthesis.jpg

Astaxanthin biosynthesis starts with three molecules of isopentenyl pyrophosphate (IPP) and one molecule of dimethylallyl pyrophosphate (DMAPP) that are combined by IPP isomerase and converted to geranylgeranyl pyrophosphate (GGPP) by GGPP synthase. Two molecules of GGPP are then coupled by phytoene synthase to form phytoene. Next, phytoene desaturase creates four double bonds in the phytoene molecule to form lycopene. After desaturation, lycopene cyclase first forms γ-carotene by converting one of the ψ acyclic ends of the lycopene as a β-ring, then subsequently converts the other to form β-carotene. From β-carotene, hydrolases (blue) are responsible for the inclusion of two 3-hydroxy groups, and ketolases (green) for the addition of two 4-keto groups, forming multiple intermediate molecules until the final molecule, astaxanthin, is obtained.{{Cite journal |last1=Barredo |first1=Jose |last2=García-Estrada |first2=Carlos |last3=Kosalkova |first3=Katarina |last4=Barreiro |first4=Carlos |date=July 30, 2017 |title=Biosynthesis of Astaxanthin as a Main Carotenoid in the Heterobasidiomycetous Yeast Xanthophyllomyces dendrorhous |journal=Journal of Fungi |volume=3 |issue=3 |pages=44 |doi=10.3390/jof3030044 |pmid=29371561 |issn=2309-608X |pmc=5715937|doi-access=free }}

The structure of astaxanthin by synthesis was described in 1975.{{cite journal |last1=Cooper |first1=R. D. G. |last2=Davis |first2=J. B. |last3=Leftwick |first3=A. P. |last4=Price |first4=C. |last5=Weedon |first5=B. |year=1975 |title=Carotenoids and related compounds. XXXII. Synthesis of astaxanthin, hoenicoxanthin, hydroxyechinenone, and the corresponding diosphenols |journal=J. Chem. Soc. Perkin Trans. |volume=1 |issue=21 |pages=2195–2204 |doi=10.1039/p19750002195}} Nearly all commercially available astaxanthin for aquaculture is produced synthetically, with an annual market of about $1 billion in 2019.{{cite journal |vauthors=Elbahnaswy S, Elshopakey GE |title=Recent progress in practical applications of a potential carotenoid astaxanthin in aquaculture industry: a review |journal=Fish Physiology and Biochemistry |volume=50 |issue=1 |pages=97–126 |date=February 2024 |pmid=36607534 |pmc=10927823 |doi=10.1007/s10695-022-01167-0}}

An efficient synthesis from isophorone, cis-3-methyl-2-penten-4-yn-1-ol and a symmetrical C₁₀-dialdehyde has been discovered and is used in industrial production. It combines these chemicals together with an ethynylation and then a Wittig reaction.Ashford's Dictionary of Industrial Chemicals, 3rd Edition, 2011, p. 984, {{ISBN|095226742X}}. Two equivalents of the proper ylide combined with the proper dialdehyde in a solvent of methanol, ethanol, or a mixture of the two, yields astaxanthin in up to 88% yields.Krause, Wolfgang; Henrich, Klaus; Paust, Joachim; et al. Preaparation of Astaxanthin. DE 19509955. March 9, 18, 1995

File:Synthesis of astaxanthin by Wittig reaction.png]]

The cost of astaxanthin extraction, high market price, and lack of efficient fermentation production systems, combined with the intricacies of chemical synthesis, discourage its commercial development. The metabolic engineering of bacteria (Escherichia coli) enables efficient astaxanthin production from beta-carotene via either zeaxanthin or canthaxanthin.{{Cite journal |last1=Scaife |first1=M. A. |last2=Burja |first2=A. M. |last3=Wright |first3=P. C. |title=Characterization of cyanobacterial β-carotene ketolase and hydroxylase genes inEscherichia coli, and their application for astaxanthin biosynthesis |journal=Biotechnology and Bioengineering |volume=103 |issue=5 |pages=944–955 |year=2009 |pmid=19365869 |doi=10.1002/bit.22330|s2cid=10425589 }}{{cite journal |last=Scaife |first=MA |author2=Ma, CA |author3=Ninlayarn, T |author4=Wright, PC |author5=Armenta, RE |title=Comparative Analysis of β-Carotene Hydroxylase Genes for Astaxanthin Biosynthesis |journal=Journal of Natural Products |date=May 22, 2012 |pmid=22616944 |doi=10.1021/np300136t |volume=75 |issue=6 |pages=1117–24}}{{cite journal |last=Lemuth |first=K |author2=Steuer, K |author3=Albermann, C |title=Engineering of a plasmid-free Escherichia coli strain for improved in vivo biosynthesis of astaxanthin |journal=Microbial Cell Factories |date=April 26, 2011 |volume=10 |page=29 |pmid=21521516 |doi=10.1186/1475-2859-10-29 |pmc=3111352 |doi-access=free }}

In addition to structural isomeric configurations, astaxanthin also contains two chiral centers at the 3- and 3{{prime}}-positions, resulting in three unique stereoisomers (3R,3{{prime}}R and 3R,3'S meso and 3S,3'S). While all three stereoisomers are present in nature, relative distribution varies considerably from one organism to another.{{cite journal |last=Bjerkeng |first=Bjørn |title=Chromatographic Analysis of Synthesized Astaxanthin—A Handy Tool for the Ecologist and the Forensic Chemist? |journal=The Progressive Fish-Culturist |volume=59 |issue=2 |year=1997 |issn=0033-0779 |doi=10.1577/1548-8640(1997)059<0129:caosaa>2.3.co;2 |pages=129–140}} Synthetic astaxanthin contains a mixture of all three stereoisomers, in approximately 1:2:1 proportions.{{cite journal |last1=Stachowiak |first1=Barbara |last2=Szulc |first2=Piotr |title=Astaxanthin for the Food Industry |journal=Molecules |volume=26 |issue=9 |date=May 2, 2021 |page=2666 |doi=10.3390/molecules26092666 |pmid=34063189 |pmc=8125449 |quote=It is noteworthy that astaxanthin synthesized in nature occurs in the trans form (3S, 3S), whereas synthetic astaxanthin is a mixture of two optical isomers and the meso form at a ratio of 1:2:1 (3R, 30R), (3R, 30S) and (3S, 30S).|doi-access=free }}

Astaxanthin exists in two predominant forms, non-esterified (yeast, synthetic) or esterified (algal) with various length fatty acid moieties whose composition is influenced by the source organism as well as growth conditions. The astaxanthin fed to salmon to enhance flesh coloration is in the non-esterified form

{{cite journal |last1=Rüfer |first1=Corinna E. |last2=Moeseneder |first2=Jutta |last3=Briviba |first3=Karlis |last4=Rechkemmer |first4=Gerhard |last5=Bub |first5=Achim |title=Bioavailability of astaxanthin stereoisomers from wild (Oncorhynchus spp.) and aquacultured (Salmo salar) salmon in healthy men: a randomised, double-blind study |journal=The British Journal of Nutrition |volume=99 |issue=5 |pages=1048–54 |year=2008 |issn=0007-1145 |pmid=17967218 |doi=10.1017/s0007114507845521 |doi-access=free}} The predominance of evidence supports a de-esterification of fatty acids from the astaxanthin molecule in the intestine prior to or concomitant with absorption resulting in the circulation and tissue deposition of non-esterified astaxanthin. European Food Safety Authority (EFSA) published a scientific opinion on a similar xanthophyll carotenoid, lutein, stating that "following passage through the gastrointestinal tract and/or uptake lutein esters are hydrolyzed to form free lutein again".{{cite journal |title=Scientific Opinion on the re-evaluation of lutein preparations other than lutein with high concentrations of total saponified carotenoids at levels of at least 80% |journal=EFSA Journal |volume=9 |issue=5 |year=2011 |pages=2144 |issn=1831-4732 |doi=10.2903/j.efsa.2011.2144 |doi-access=free}} While it can be assumed that non-esterified astaxanthin would be more bioavailable than esterified astaxanthin due to the extra enzymatic steps in the intestine needed to hydrolyse the fatty acid components, several studies suggest that bioavailability is more dependent on formulation than configuration.{{cite journal |last1=Landrum |first1=J |last2=Bone |first2=R |last3=Mendez |first3=V |last4=Valenciaga |first4=A |last5=Babino |first5=D |title=Comparison of dietary supplementation with lutein diacetate and lutein: a pilot study of the effects on serum and macular pigment. |journal=Acta Biochimica Polonica |volume=59 |issue=1 |year=2012 |issn=0001-527X |pmid=22428144 |pages=167–9 |doi=10.18388/abp.2012_2198 |doi-access=free}}{{cite journal |last1=Norkus |first1=EP |last2=Norkus |first2=KL |last3=Dharmarajan |first3=TS |last4=Schierle |first4=J |last5=Schalch |first5=W |title=Serum lutein response is greater from free lutein than from esterified lutein during 4 weeks of supplementation in healthy adults. |journal=Journal of the American College of Nutrition |volume=29 |issue=6 |year=2010 |issn=0731-5724 |pmid=21677121 |pages=575–85 |doi=10.1080/07315724.2010.10719896|s2cid=5787962 }}

Astaxanthin is used as a dietary supplement and feed supplement as food colorant for salmon, crabs, shrimp, chickens and egg production.

The primary use of synthetic astaxanthin today is as an animal feed additive to impart coloration, including farm-raised salmon and chicken egg yolks.{{cite journal |pmc=4848535 |year=2016 |last1=Shah |first1=M. M |title=Astaxanthin-Producing Green Microalga Haematococcus pluvialis: From Single Cell to High Value Commercial Products |journal=Frontiers in Plant Science |volume=7 |pages=531 |last2=Liang |first2=Y |last3=Cheng |first3=J. J |last4=Daroch |first4=M |doi=10.3389/fpls.2016.00531 |pmid=27200009|doi-access=free }} Synthetic carotenoid pigments colored yellow, red or orange represent about 15–25% of the cost of production of commercial salmon feed.[https://web.archive.org/web/20061219011646/http://www.pac.dfo-mpo.gc.ca/aquaculture/topics/colour_e.htm Fisheries and Oceans Canada – Aquaculture Issues]. pac.dfo-mpo.gc.ca. In the 21st century, most commercial astaxanthin for aquaculture is produced synthetically.{{cite journal |title=Conversion of β-carotene into astaxanthin: Two separate enzymes or a bifunctional hydroxylase-ketolase protein? |author=Juan F Martín, Eduardo Gudiña and José L Barredo |date=February 20, 2008 |journal=Microbial Cell Factories |volume=7 |pages=3 |doi=10.1186/1475-2859-7-3 |pmid=18289382 |pmc=2288588 |doi-access=free }}

Class action lawsuits were filed against some major grocery store chains for not clearly labeling the astaxanthin-treated salmon as "color added".{{cite web |title=Farm-Raised Salmon Cases: Private Action for Violation of California State Law is Not Preempted by the FDC Act |year=2008 |access-date=March 3, 2024 |url=https://www.thefdalawblog.com/2008/02/farm-raised-sal/}} The chains followed up quickly by labeling all such salmon as "color added". Litigation persisted with the suit for damages, but a Seattle judge dismissed the case, ruling that enforcement of the applicable food laws was up to government and not individuals.{{cite web |title=Pigments in Salmon Aquaculture: How to Grow a Salmon-colored Salmon |url=http://www.seafoodmonitor.com/sample/salmon.html |archive-url=https://web.archive.org/web/20071013221146/http://seafoodmonitor.com/sample/salmon.html |archive-date=October 13, 2007 |access-date=July 18, 2009}}

The primary human application for astaxanthin is as a dietary supplement, and it remains under preliminary research. In 2020, the European Food Safety Authority reported that an intake of 8 mg astaxanthin per day from food supplements is safe for adults.{{Cite journal |last1=Turck |first1=Dominique |last2=Knutsen |first2=Helle Katrine |last3=Castenmiller |first3=Jacqueline |last4=de Henauw |first4=Stefaan |last5=Hirsch-Ernst |first5=Karen Ildico |last6=Kearney |first6=John |last7=Maciuk |first7=Alexandre |last8=Mangelsdorf |first8=Inge |last9=McArdle |first9=Harry J |last10=Naska |first10=Androniki |last11=Pelaez |first11=Carmen |last12=Pentieva |first12=Kristina |last13=Siani |first13=Alfonso |last14=Thies |first14=Frank |last15=Tsabouri |first15=Sophia|date=2020 |title=Safety of astaxanthin for its use as a novel food in food supplements |journal=EFSA Journal |volume=18 |issue=2 |pages=4 |doi=10.2903/j.efsa.2020.5993 |pmc=7448075 |pmid=32874213}}

{{expand section|date=August 2017}}

Lobsters, shrimp, and some crabs turn red when cooked because the astaxanthin, which was bound to the protein in the shell, becomes free as the protein denatures and unwinds. The freed pigment is thus available to absorb light and produce the red color.{{cite journal

| last1 = Begum

| first1 = Shamima

| display-authors = etal

| date = 2015

| title = On the origin and variation of colors in lobster carapace

| journal = Physical Chemistry Chemical Physics

| volume = 17

| issue = 26

| pages = 16723–16732

| doi = 10.1039/C4CP06124A

| pmid = 25797168

| bibcode = 2015PCCP...1716723B

| doi-access= free

}}

In April 2009, the United States Food and Drug Administration approved astaxanthin as an additive for fish feed only as a component of a stabilized color additive mixture. Color additive mixtures for fish feed made with astaxanthin may contain only those diluents that are suitable. The color additives astaxanthin, ultramarine blue, canthaxanthin, synthetic iron oxide, dried algae meal, Tagetes meal and extract, and corn endosperm oil are approved for specific uses in animal foods.See 21 CFR 73.35,73.50, 73.75, 73.200, 73.275, 73.295, 73.315, respectively. Haematococcus algae meal (21 CFR 73.185) and Phaffia yeast (21 CFR 73.355) for use in fish feed to color salmonoids were added in 2000.[https://web.archive.org/web/20030917011526/http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=73.35 Code of Federal Regulations Title 21 § 73.35 FDA decision on Astaxanthin]. Accessdata.fda.gov. Retrieved on April 25, 2013.[https://web.archive.org/web/20040229034325/http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=73.185 Code of Federal Regulations Title 21 § 73.185 FDA decision on Haematococcus algae meal]. Accessdata.fda.gov. Retrieved on April 25, 2013.[https://web.archive.org/web/20130314104055/https://www.fda.gov/Food/FoodIngredientsPackaging/FoodAdditives/FoodAdditiveListings/ucm091048.htm Food Additive Status List]. fda.gov

In the European Union, astaxanthin-containing food supplements derived from sources that have no history of use as a source of food in Europe, fall under the remit of the Novel Food legislation, EC (No.) 258/97. Since 1997, there have been five novel food applications concerning products that contain astaxanthin extracted from these novel sources. In each case, these applications have been simplified or substantial equivalence applications, because astaxanthin is recognised as a food component in the EU diet.[https://web.archive.org/web/20110810075220/http://acnfp.food.gov.uk/assess/simproc/astaxanthinextract Astaxanthin extract]. acnfp.food.gov.uk[https://web.archive.org/web/20101018184558/http://www.acnfp.gov.uk/assess/simproc/astacyan Astaxanthin extract: Cyanotech Corporation]. acnfp.gov.uk[https://web.archive.org/web/20101018184558/http://www.acnfp.gov.uk/assess/simproc/algaastax Astaxanthin extract: Algatechnologies (1998) Ltd.] acnfp.gov.uk[https://web.archive.org/web/20101018184558/http://www.acnfp.gov.uk/assess/simproc/astaxextractparry/ Astaxanthin extract: Parry Nutraceuticals]. acnfp.gov.uk

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