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{{Short description|Gene cluster}}
{{More citations needed|date=September 2021}}
'''CRT''' is the [[gene cluster]] responsible for the [[biosynthesis]] of [[carotenoid]]s. Those genes are found in eubacteria,<ref name=":0">Carotenoid biosynthetic pathway: molecular phylogenies and evolutionary behavior of crt genes in eubacteria. Phadwal K, Gene, 17 January 2005, volume 345, issue 1, pages 35-43, {{PMID|15716108}}</ref> in algae<ref name=":1">Molecular phylogenies and evolution of crt genes in algae. Chen Q, Jiang JG and Wang F, Crit Rev Biotechnol., Apr-Jun 2007;, volume 27, issue 2, pages 77-91, {{PMID|17578704}}</ref> and are [[Evolutionary capacitance|cryptic]] in ''[[Streptomyces griseus]]''.<ref>Activation and analysis of cryptic crt genes for carotenoid biosynthesis from Streptomyces griseus. Schumann G1, Nürnberger H, Sandmann G and Krügel H, Mol Gen Genet., 28 October 1996, volume 252, issue 6, pages 658-666, {{PMID|8917308}}</ref>

Carotenoid synthesis is probably present in the common ancestor of [[Bacteria]] and [[Archaea]]; the phytoene synthase gene ''crtB'' is universal among carotenoid synthesizers. Among eukaryotes, plants and algae inherited the cyanobacterial pathway via biosynthesis of their [[plastid]]s, while fungi retain a archaeal-like pathway.<ref name=Sandmann>{{cite book |last1=Sandmann |first1=G |chapter=Diversity and Evolution of Carotenoid Biosynthesis from Prokaryotes to Plants. |date=2021 |volume=1261 |pages=79-94 |title=Carotenoids: Biosynthetic and Biofunctional Approaches|series=Advances in experimental medicine and biology |doi=10.1007/978-981-15-7360-6_7 |pmid=33783732}}</ref> Among all these synthesizers, several possible selection and arrangements of biosynthetic genes exist, consisting of one gene cluster cluster, several clusters, or no clustering at all.<ref name=Sandmann21>{{cite journal |last1=Sandmann |first1=Gerhard |title=Diversity and origin of carotenoid biosynthesis: its history of coevolution towards plant photosynthesis |journal=New Phytologist |date=October 2021 |volume=232 |issue=2 |pages=479–493 |doi=10.1111/nph.17655 |doi-access=free}}</ref>{{efn|1=For concrete examples of the diversity of gene organization, compare the clusters presented in <ref name=pmid16085816/> figure 1 (6 genomes), {{PMID|37887056}} figure 1 (4 genomes), {{PMID|22963379}} figure 1 (10 genomes), and {{PMID|32155882}} figure 3 (11 genomes).}}

== Role of ''CRT'' genes in carotenoid biosynthesis ==
The ''CRT'' gene cluster consists of twenty-five genes such as ''crtA, crtB, crtC, crtD, crtE, crtF, crtG, crtH, crtI, crtO, crtP, crtR, crtT, crtU, crtV, and crtY, crtZ''. These genes play a role in varying stages of the [[Astaxanthin]] biosynthesis and [[Carotenoid]] biosynthesis (Table 1).<ref name=pmid16085816>{{Cite journal|last1=Nishida|first1=Yasuhiro|last2=Adachi|first2=Kyoko|last3=Kasai|first3=Hiroaki|last4=Shizuri|first4=Yoshikazu|last5=Shindo|first5=Kazutoshi|last6=Sawabe|first6=Akiyoshi|last7=Komemushi|first7=Sadao|last8=Miki|first8=Wataru|last9=Misawa|first9=Norihiko|date=August 2005|title=Elucidation of a Carotenoid Biosynthesis Gene Cluster Encoding a Novel Enzyme, 2,2′-β-Hydroxylase, from Brevundimonas sp. Strain SD212 and Combinatorial Biosynthesis of New or Rare Xanthophylls|journal=Applied and Environmental Microbiology|volume=71|issue=8|pages=4286–4296|doi=10.1128/AEM.71.8.4286-4296.2005|issn=0099-2240|pmc=1183362|pmid=16085816|bibcode=2005ApEnM..71.4286N}}</ref>

''crtE'' encodes for an enzyme known as geranylgeranyl diphosphate synthase known to catalyze the condensation reaction of [[isopentenyl pyrophosphate]] (IPP) and [[dimethylallyl pyrophosphate]] (DMAPP) into [[geranylgeranyl diphosphate]] (GGDP).<ref name=":2">{{Cite journal|last1=Sandmann|first1=Gerhard|last2=Misawa|first2=Norihiko|date=January 1992|title=New functional assignment of the carotenogenic genescrtBandcrtEwith constructs of these genes fromErwiniaspecies|journal=FEMS Microbiology Letters|volume=90|issue=3|pages=253–258|doi=10.1111/j.1574-6968.1992.tb05162.x|issn=0378-1097|doi-access=free}}</ref><ref name=":3">{{Cite journal|last1=Giraud|first1=Eric|last2=Hannibal|first2=Laure|last3=Fardoux|first3=Joël|last4=Jaubert|first4=Marianne|last5=Jourand|first5=Philippe|last6=Dreyfus|first6=Bernard|last7=Sturgis|first7=James N.|last8=Verméglio|first8=Andre|date=April 2004|title=Two Distinct crt Gene Clusters for Two Different Functional Classes of Carotenoid in Bradyrhizobium|journal=Journal of Biological Chemistry|volume=279|issue=15|pages=15076–15083|doi=10.1074/jbc.m312113200|pmid=14734565|issn=0021-9258|doi-access=free}}</ref> Two GGDP molecules are subsequently converted into a single [[phytoene]] molecule by [[phytoene synthase]], an enzyme encoded by ''crtB'', known as ''PSY'' in Chlorophyta.<ref name=":1" /><ref name=":2" /><ref name=":3" /> The following desaturation of phytoene into ζ-carotene is catalyzed by the phytoene desaturase encoded by ''crtI, crtP,'' and/or ''PDS.''<ref name=":1" /><ref name=":2" /><ref name=":3" /> ζ -carotene can also be obtained through phytoene using the carotene 2,4-desaturase enzyme (''crtD'').<ref name=":1" /><ref>{{Cite journal|last1=Yang|first1=Ying|last2=Yatsunami|first2=Rie|last3=Ando|first3=Ai|last4=Miyoko|first4=Nobuhiro|last5=Fukui|first5=Toshiaki|last6=Takaichi|first6=Shinichi|last7=Nakamura|first7=Satoshi|date=2015-02-23|title=Complete Biosynthetic Pathway of the C50Carotenoid Bacterioruberin from Lycopene in the Extremely Halophilic Archaeon Haloarcula japonica|url=http://dx.doi.org/10.1128/jb.02523-14|journal=Journal of Bacteriology|volume=197|issue=9|pages=1614–1623|doi=10.1128/jb.02523-14|pmid=25712483|issn=0021-9193|pmc=4403650}}</ref> Depending on the species, varying carotenoids are accumulated following these steps.<ref name=":0" /><ref>{{Cite journal|last=Maoka|first=Takashi|date=2019-10-01|title=Carotenoids as natural functional pigments|url=http://dx.doi.org/10.1007/s11418-019-01364-x|journal=Journal of Natural Medicines|volume=74|issue=1|pages=1–16|doi=10.1007/s11418-019-01364-x|pmid=31588965|issn=1340-3443|pmc=6949322}}</ref>

=== Spirilloxanthin ===
Spirilloxanthin is obtained from lycopene following a hydration, desaturation, and methylation reaction. These reactions are catalyzed by carotene hydratase (''crtC''), carotene 3,4- desaturase (''crtD''), and carotene methyltransferase (''crtF''), respectively.<ref name=":3" /><ref name=":0" />

=== Canthaxanthin ===
Lycopene is cyclized through two enzymes lycopene cyclase and β-C-4-oxygenase/β-carotene ketolase encoded on the ''crtY'' (in Chlorophyta) /''crtL'' (in cyanobacteria), and ''crtW'', respectively. ''crtY'' cyclizes lycopene into β-carotene, which is subsequently oxygenated by ''crtW'' to form canthaxanthin.<ref name=":3" />

=== Zeaxanthin and lutein ===
Zeaxanthin and lutein are obtained through hydroxylation of α- and β-carotene.<ref name=":0" /> Hydroxylation of Zeaxanthin occurs by β-carotene hydroxylase an enzyme encoded on the ''crtR'' (in cyanobacteria) and ''crtZ'' gene (in Chlorophyta).<ref name=":3" />

=== Other ===
Zeaxanthin can be further processed to obtain zeaxanthin-diglucoside by Zeaxanthin glucosyl transferase (''crtX'').

[[Echinenone]] is obtained from β -carotene through the catalyzing enzyme β-C-4-oxygenase/β-carotene ketolase (''crtO'').<ref name=":5">{{Cite journal|last1=Harker|first1=Mark|last2=Hirschberg|first2=Joseph|date=1997-03-10|title=Biosynthesis of ketocarotenoids in transgenic cyanobacteria expressing the algal gene for β-C-4-oxygenase, crtO|url=http://dx.doi.org/10.1016/s0014-5793(97)00110-5|journal=FEBS Letters|volume=404|issue=2–3|pages=129–134|doi=10.1016/s0014-5793(97)00110-5|pmid=9119049|s2cid=9125542|issn=0014-5793|doi-access=free}}</ref> ''CrtO'', also known as ''bkt2'' in Chlorophyta, is also involved in the conversion of other carotenoids into Canthaxanthin, 3-Hydroxyechinenone, 3'-Hydroxyechinenone, Adonixanthin, and Astaxanthin.<ref name=":5" /><ref>{{Cite journal|last1=Fernández-González|first1=Blanca|last2=Sandmann|first2=Gerhard|last3=Vioque|first3=Agustín|date=April 1997|title=A New Type of Asymmetrically Acting β-Carotene Ketolase Is Required for the Synthesis of Echinenone in the Cyanobacterium Synechocystis sp. PCC 6803|journal=Journal of Biological Chemistry|volume=272|issue=15|pages=9728–9733|doi=10.1074/jbc.272.15.9728|pmid=9092504|issn=0021-9258|doi-access=free}}</ref>''CrtZ'', similarly to ''crtO'', is also capable of converting carotenoids into β-cryptoxanthin, Zeaxanthin, 3-Hydroxyechinenone, 3'-Hydroxyechinenone, Astaxanthin, Adonixanthin, and  Adonirubin.<ref name=":5" />

''crtH'' catalyzes the isomerization of cis-carotenes into trans-carotenes through carotenoid isomerase.<ref name=":1" />

''crtG'' encodes for carotenoid 2,2'- β-hydroxylase, this enzyme leads to the formation of 2-hydroxylated and 2,2′-dihydroxylated products in ''[[Escherichia coli|E coli]]''.<ref>{{Cite journal|last1=Nishida|first1=Yasuhiro|last2=Adachi|first2=Kyoko|last3=Kasai|first3=Hiroaki|last4=Shizuri|first4=Yoshikazu|last5=Shindo|first5=Kazutoshi|last6=Sawabe|first6=Akiyoshi|last7=Komemushi|first7=Sadao|last8=Miki|first8=Wataru|last9=Misawa|first9=Norihiko|date=August 2005|title=Elucidation of a Carotenoid Biosynthesis Gene Cluster Encoding a Novel Enzyme, 2,2′-β-Hydroxylase, from Brevundimonas sp. Strain SD212 and Combinatorial Biosynthesis of New or Rare Xanthophylls|url=http://dx.doi.org/10.1128/aem.71.8.4286-4296.2005|journal=Applied and Environmental Microbiology|volume=71|issue=8|pages=4286–4296|doi=10.1128/aem.71.8.4286-4296.2005|pmid=16085816|issn=0099-2240|pmc=1183362|bibcode=2005ApEnM..71.4286N}}</ref> 
{| class="wikitable mw-collapsible"
|+Table 1: role of CRT genes in carotenoid biosynthesis <ref name=":1" />
!Gene
!Enzyme
!Catalyzed reaction
|-
|''crtE''
|GGDP synthase

|IPP and DMAPP conversion to GGDP
|-
|''crtB (PSY*)''
|Phytoene Synthase (universal)
|GGDP conversion to phytoene 
|-
|''crtP (PDS*)''
|Phytoene desaturase (Chlorobi, Cyanobacteria, plant, algae)<ref name=Sandmann21/>
|Conversion of phytoene into ζ- carotene
|-
|''crtI''
|Phytoeine desaturase (Archaea, fungi, most Bacteria)
|Conversion of phytoene into ζ- carotene
|-
|''crtQ''
|ζ- carotene desaturase (Qa: 'evolved from ''CrtI''; Qb: evolved from ''CrtP'')<ref name=Sandmann21/>
|Desaturation of ζ- carotene to lycopene
|-
|''crtH''
|Carotenoid isomerase
|Isomeration of cis to trans  carotones
|-
|''crtY''
|Lycopene cyclase (Bacteria except Firmicutes, Chlorobi, Cyanobacteria, Actinobacteria)<ref name=Sandmann/>
|Cyclization of lycopene
|-
|''crtL''
|Lycopene cyclase (two in Cyanobacteria: ''crtL-b'' became plant ''lcy-B'', ''crtL-e'' became plant ''lcy-E'')<ref name=Sandmann21/>
|Cyclization of lycopene
|-
|''crtD''
|Carotene  3,4-desaturase
|Conversion  of phytoene to ζ-carotene
|-
|''crtA''
|Spheroidene monooxygenase
|Conversion  of spheroidene to spheroidenone
|-
|''crtR<sup>+</sup>''
|β-carotene hydroxylase (various Cyanobacteria)
|Hydroxylation  of β-carotene to  zeaxanthin
|-
|''crtZ*''
|β-carotene  hydroxylase (various Chlorophyta)
|Hydroxylation  of β-carotene to  zeaxanthin
|-
|''crtX''
|Zeaxanthin glucosyl transferase
|Conversion  of zeaxanthin to zeaxanthin-diglucoside
|-
|''crtW (bkt2*)''
|β-C-4-oxygenase/β-carotene ketolase
|Conversion  of β-carotene to canthaxanthin
|-
|''crtO''
|β-C-4-oxygenase/β-carotene ketolase
|Conversion  of β-carotene to  echinenone
|-
|''crtC''
|Carotene hydratase
|Conversion  of neurosporene to demethylspheroidene and lycopene to hydroxy derivatives
|-
|''crtG''
|Carotenoid 2,2′-β-hydroxylase
|Conversion of  myxol to 2-hydroxymyxol and zeaxanthin to nostoxanthin
|-
|''crtK''
|Carotenoid regulation 
| -
|-
| colspan="3" |* In Chlorophyta, <sup>+</sup> In cyanobacteria
|}

== Phylogeny ==
Previous studies have indicated through phylogenetic analysis that evolutionary patterns of ''crt'' genes are characterized by [[horizontal gene transfer]] and [[gene duplication]] events.<ref name=":4">{{Cite journal|last=Phadwal|first=Kanchan|date=January 2005|title=Carotenoid biosynthetic pathway: molecular phylogenies and evolutionary behavior of crt genes in eubacteria|url=http://dx.doi.org/10.1016/j.gene.2004.11.038|journal=Gene|volume=345|issue=1|pages=35–43|doi=10.1016/j.gene.2004.11.038|pmid=15716108|issn=0378-1119|url-access=subscription}}</ref>

Horizontal gene transfer has been hypothesized to have occurred between [[cyanobacteria]] and [[Chlorophyta]], as similarities in these genes have been found across taxa.<ref name=":4" /> Note, however, that some cyanobacteria retained their nature. Horizontal gene transfer among species occurred with a high probability in genes involved in the initial steps of the carotenoid biosynthesis pathway such as ''crtE, crtB, crtY, crtL, PSY'', and ''crtQ''. These genes are often well conserved while others involved in the later stages of Carotenoid biosynthesis such as ''crtW'' and ''crtO'' are less conserved.<ref name=":0" /> The less conserved nature of these genes allowed for the expansion of the carotenoid biosynthesis pathway and its end products. Amino acid variations within ''crt'' genes have evolved due to purifying and adaptive selection.<ref name=":1" />

Gene duplications are suspected to have occurred due to the presence of multiple copies of ctr clusters or genes within a single species.<ref name=":1" /> An example of this can be seen in the ''[[Bradyrhizobium]] ORS278'' strain, where initial ''crt'' genes can be found (excluding ''crtC, crtD,'' and ''crtF'' genes) as well as a second ''crt'' gene cluster. This second gene cluster has been shown to also be involved in carotenoid biosynthesis using its ''crt'' [[paralogs]].<ref name=":3" /><ref>{{Cite journal|last1=Tran|first1=Duc|last2=Haven|first2=James|last3=Qiu|first3=Wei-Gang|last4=Polle|first4=Juergen E. W.|date=2008-12-09|title=An update on carotenoid biosynthesis in algae: phylogenetic evidence for the existence of two classes of phytoene synthase|url=http://dx.doi.org/10.1007/s00425-008-0866-2|journal=Planta|volume=229|issue=3|pages=723–729|doi=10.1007/s00425-008-0866-2|pmid=19066941|issn=0032-0935|pmc=6008256}}</ref>

== References ==
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[[Category:Carotenoids]]
[[Category:Genetics]]