Editing Polyketide

{{Short description|Natural organic compounds derived from a [C(O)–CH2] chain}}

In [[organic chemistry]], '''polyketides''' are a class of [[natural product]]s derived from a [[Precursor (chemistry)|precursor molecule]] consisting of a [[Polymer backbone|chain]] of alternating [[ketone]] ({{chem2|>C\dO}}, or [[Carbonyl reduction|its reduced forms]]) and [[Methylene group|methylene]] ({{chem2|>CH2}}) groups: {{chem2|[\sC(\dO)\sCH2\s]_{''n''}|}}.<ref>{{GoldBookRef|title = Polyketides|file = P04734}}</ref> First studied in the early 20th century, discovery, biosynthesis, and application of polyketides has evolved. It is a large and diverse group of [[secondary metabolites]] caused by its complex biosynthesis which resembles that of [[fatty acid synthesis]]. Because of this diversity, polyketides can have various medicinal, agricultural, and industrial applications. Many polyketides are medicinal or exhibit acute toxicity. Biotechnology has enabled discovery of more naturally-occurring polyketides and evolution of new polyketides with novel or improved bioactivity.

== History ==
Naturally produced polyketides by various plants and organisms have been used by humans since before studies on them began in the 19th and 20th century. In 1893, [[J. Norman Collie]] synthesized detectable amounts of [[orcinol]] by heating [[Dehydroacetic acid|dehydracetic acid]] with barium hydroxide causing the pyrone ring to open into a triketide.<ref>{{Cite journal| vauthors=Collie N, Myers WS |date=1893 |title=VII.—The formation of orcinol and other condensation products from dehydracetic acid |journal=Journal of the Chemical Society, Transactions |language=en |volume=63 |pages=122–128 |doi=10.1039/CT8936300122|issn=0368-1645|url=https://zenodo.org/record/2088145 }}</ref> Further studies in 1903 by Collie on the triketone polyketide intermediate noted the condensation occurring amongst compounds with multiple keten groups coining the term polyketides.<ref>{{Cite journal| vauthors=Collie JN |date=1907 |title=CLXXI.—Derivatives of the multiple keten group|journal=Journal of the Chemical Society, Transactions |language=en |volume=91 |pages=1806–1813 |doi=10.1039/CT9079101806 |issn=0368-1645|url=https://zenodo.org/record/2168003 }}</ref>
[[File:Orsellinsäure_is.svg|thumb|400px|Biosynthesis of [[orsellinic acid]] from polyketide intermediate.]]
It wasn't until 1955 that the biosynthesis of polyketides were understood.<ref name="Smith_2007" /> Arthur Birch used radioisotope labeling of carbon in acetate to trace the biosynthesis of [[6-Methylsalicylic acid|2-hydroxy-6-methylbenzoic acid]] in ''[[Penicillium patulum]]'' and demonstrate the head-to-tail linkage of acetic acids to form the polyketide.<ref>{{Cite journal| vauthors=Birch AJ, Massy-Westropp RA, Moye CJ |date=1955 |title=Studies in relation to biosynthesis. VII. 2-Hydroxy-6-methylbenzoic acid in Penicillium griseofulvum Dierckx|url=https://www.publish.csiro.au/ch/ch9550539 |journal=Australian Journal of Chemistry|language=en|volume=8 |issue=4|pages=539–544 |doi=10.1071/ch9550539|issn=1445-0038|url-access=subscription}}</ref> In the 1980s and 1990s, advancements in genetics allowed for isolation of the genes associated to polyketides to understand the biosynthesis.<ref name="Smith_2007">{{cite journal |vauthors=Smith S, Tsai SC |title=The type I fatty acid and polyketide synthases: a tale of two megasynthases |journal=Natural Product Reports |volume=24 |issue=5 |pages=1041–1072 |date=October 2007 |pmid=17898897 |pmc=2263081 |doi=10.1039/B603600G}}</ref>

== Discovery ==
Polyketides can be produced in bacteria, fungi, plants, and certain marine organisms.<ref>{{cite journal |vauthors=Lane AL, Moore BS |title=A sea of biosynthesis: marine natural products meet the molecular age |journal=Natural Product Reports |volume=28 |issue=2 |pages=411–428 |date=February 2011 |pmid=21170424 |doi=10.1039/C0NP90032J |pmc=3101795}}</ref> Earlier discovery of naturally occurring polyketides involved the isolation of the compounds being produced by the specific organism using organic chemistry purification methods based on [[Biological activity|bioactivity screens]].<ref>{{Cite journal| vauthors=Johnston C, Ibrahim A, Magarvey N |date=2012-08-01|title=Informatic strategies for the discovery of polyketides and nonribosomal peptides|journal=MedChemComm|language=en|volume=3|issue=8 |pages=932–937|doi=10.1039/C2MD20120H|issn=2040-2511}}</ref> Later technology allowed for the isolation of the genes and [[heterologous expression]] of the genes to understand the biosynthesis.<ref>{{cite journal |vauthors=Pfeifer BA, Khosla C |title=Biosynthesis of polyketides in heterologous hosts |journal=Microbiology and Molecular Biology Reviews |volume=65 |issue=1 |pages=106–118 |date=March 2001 |pmid=11238987 |pmc=99020 |doi=10.1128/MMBR.65.1.106-118.2001}}</ref> In addition, further advancements in biotechnology have allowed for the use of [[metagenomics]] and [[genome mining]] to find new polyketides using similar enzymes to known polyketides.<ref name=":2">{{cite journal |vauthors=Gomes ES, Schuch V, de Macedo Lemos EG |title=Biotechnology of polyketides: new breath of life for the novel antibiotic genetic pathways discovery through metagenomics |journal=Brazilian Journal of Microbiology |volume=44 |issue=4 |pages=1007–1034 |date=December 2013 |pmid=24688489 |pmc=3958165 |doi=10.1590/s1517-83822013000400002}}</ref>

== Biosynthesis ==
Polyketides are synthesized by multienzyme polypeptides that resemble eukaryotic fatty acid synthase but are often much larger.<ref name="Smith_2007"/> They include acyl-carrier domains plus an assortment of enzymatic units that can function in an iterative fashion, repeating the same elongation/modification steps (as in fatty acid synthesis), or in a sequential fashion so as to generate more heterogeneous types of polyketides.<ref name="Voet" />
[[File:Biosynthesis of carminic acid.jpg|thumb|400px|Biosynthesis of carminic acid]]

=== Polyketide synthase ===
Polyketides are produced by [[polyketide synthase]]s (PKSs). The core biosynthesis involves stepwise condensation of a starter unit (typically [[acetyl-CoA]] or [[propionyl-CoA]]) with an extender unit (either [[malonyl-CoA]] or methylmalonyl-CoA). The condensation reaction is accompanied by the decarboxylation of the extender unit, yielding a beta-keto functional group and releasing a carbon dioxide.<ref name="Voet">{{cite book|title = [[Fundamentals of Biochemistry: Life at the Molecular Level]]| vauthors=Voet D, Voet JG, Pratt CW |authorlink1= Donald Voet|authorlink2= Judith G. Voet|authorlink3= Charlotte W. Pratt|edition= 4th|publisher= [[John Wiley & Sons]]|year= 2013|page= 688|isbn= 9780470547847}}</ref> The first condensation yields an acetoacetyl group, a diketide. Subsequent condensations yield triketides, tetraketide, etc.<ref>{{cite journal | vauthors = Staunton J, Weissman KJ |title=Polyketide biosynthesis: a millennium review |journal=Natural Product Reports |volume=18 |issue=4 |pages=380–416 |date=August 2001 |pmid=11548049 |doi=10.1039/a909079g}}</ref> Other starter units attached to a [[Coenzyme A|coezyme A]] include [[isobutyrate]], [[cyclohexanecarboxylate]], [[malonate]], and [[benzoate]].<ref>{{cite journal |vauthors=Moore BS, Hertweck C |title=Biosynthesis and attachment of novel bacterial polyketide synthase starter units |journal=Natural Product Reports |volume=19 |issue=1 |pages=70–99 |date=February 2002 |pmid=11902441 |doi=10.1039/B003939J}}</ref>

PKSs are multi-domain enzymes or enzyme complex consisting of various domains. The polyketide chains produced by a minimal [[polyketide synthase]] (consisting of a [[acyltransferase]] and [[ketosynthase]] for the stepwise condensation of the starter unit and extender units) are almost invariably modified.<ref>{{cite journal |vauthors=Wang J, Zhang R, Chen X, Sun X, Yan Y, Shen X, Yuan Q |display-authors=3|title=Biosynthesis of aromatic polyketides in microorganisms using type II polyketide synthases |journal=Microbial Cell Factories |volume=19 |issue=1 |pages=110 |date=May 2020 |pmid=32448179 |pmc=7247197 |doi=10.1186/s12934-020-01367-4 |doi-access=free }}</ref> Each polyketide synthases is unique to each polyketide chain because they contain different combinations of domains that reduce the carbonyl group to a hydroxyl (via a [[ketoreductase]]), an olefin (via a [[dehydratase]]), or a methylene (via an [[enoylreductase]]).<ref>{{cite journal |vauthors=Moretto L, Heylen R, Holroyd N, Vance S, Broadhurst RW |display-authors=3|title=Modular type I polyketide synthase acyl carrier protein domains share a common N-terminally extended fold |journal=Scientific Reports |volume=9 |issue=1 |pages=2325 |date=February 2019 |pmid=30787330 |doi=10.1038/s41598-019-38747-9 |pmc=6382882 |bibcode=2019NatSR...9.2325M}}</ref>

Termination of the polyketide scaffold biosynthesis can also vary. It is sometimes accompanied by a [[thioesterase]] that releases the polyketide via hydrating the thioester linkage (as in fatty acid synthesis) creating a linear polyketide scaffold. However, if water is not able to reach the active site, the hydrating reaction will not occur and an intramolecular reaction is more probable creating a macrocyclic polyketide. Another possibility is spontaneous hydrolysis without the aid of a thioesterase.<ref name=":1">{{Cite book| vauthors = Walsh C, Tang Y |url=https://www.worldcat.org/oclc/985609285|title=Natural product biosynthesis |date=2017|publisher=Royal Society of Chemistry |isbn=978-1-78801-131-0|language=English|oclc=985609285}}</ref>

=== Post-tailoring enzymes ===
Further possible modifications to the polyketide scaffolds can be made. This can include glycosylation via a [[glucosyltransferase]] or oxidation via a [[monooxygenase]].<ref>{{cite journal | vauthors = Risdian C, Mozef T, Wink J | title = Biosynthesis of Polyketides in ''Streptomyces'' | journal = Microorganisms | volume = 7 | issue = 5 | pages = 124 | date = May 2019 | pmid = 31064143 | pmc = 6560455 | doi = 10.3390/microorganisms7050124 | doi-access = free}}</ref> Similarly, cyclization and aromatization can be introduced via a [[cyclase]], sometimes proceeded by the enol tautomers of the polyketide.<ref name="Robinson">{{cite journal | vauthors = Robinson JA | title = Polyketide synthase complexes: their structure and function in antibiotic biosynthesis | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 332 | issue = 1263 | pages = 107–114 | date = May 1991 | pmid = 1678529 | doi = 10.1098/rstb.1991.0038 | bibcode = 1991RSPTB.332..107R | authorlink2 = Alan Fersht}}</ref> These enzymes are not part of the domains of the polyketide synthase. Instead, they are found in [[gene cluster]]s in the genome close to the polyketide synthase genes.<ref>{{cite journal | vauthors = Noar RD, Daub ME | title = Bioinformatics Prediction of Polyketide Synthase Gene Clusters from Mycosphaerella fijiensis | journal = PLOS ONE | volume = 11 | issue = 7 | pages = e0158471 | date = 2016-07-07 | pmid = 27388157 | pmc = 4936691 | doi = 10.1371/journal.pone.0158471 | bibcode = 2016PLoSO..1158471N | doi-access = free}}</ref>

== Classification ==
Polyketides are a structurally diverse family.<ref>{{cite journal | vauthors = Katz L | title = Manipulation of Modular Polyketide Synthases | journal = Chemical Reviews | volume = 97 | issue = 7 | pages = 2557–2576 | date = November 1997 | pmid = 11851471 | doi = 10.1021/cr960025+}}</ref> There are various subclasses of polyketides including: [[Aromatic compound|aromatics]], macrolactones/[[macrolide]]s, [[decalin]] ring containing, [[polyether]], and [[polyene]]s.<ref name=":1" />

Polyketide synthases are also broadly divided into three classes: Type I PKSs (multimodular megasynthases that are non-iterative, often producing macrolides, polyethers, and polyenes), Type II PKSs (dissociated [[enzymes]] with iterative action, often producing aromatics), and Type III PKSs ([[Chalcone synthase|chalcone synthase-like]], producing small aromatic molecules).<ref>{{Cite journal| vauthors = Shen B |date= April 2003 |title=Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms |journal=Current Opinion in Chemical Biology|language=en|volume=7|issue=2 |pages=285–295|doi=10.1016/S1367-5931(03)00020-6|pmid=12714063}}</ref>

In addition to these subclasses, there also exist polyketides that are hybridized with [[nonribosomal peptide]]s (Hybrid NRP-PK and PK-NRP). Since nonribosomal peptide assembly lines use carrier proteins similar to those use in polyketide synthases, convergence of the two systems evolved to form hybrids, resulting in polypeptides with nitrogen in the skeletal structure and complex function groups similar to those found in amino acids.<ref name="Evolution and Diversity of Assembly">{{cite journal | vauthors = Nivina A, Yuet KP, Hsu J, Khosla C | title = Evolution and Diversity of Assembly-Line Polyketide Synthases | journal = Chemical Reviews | volume = 119 | issue = 24 | pages = 12524–12547 | date = December 2019 | pmid = 31838842 | pmc = 6935866 | doi = 10.1021/acs.chemrev.9b00525}}</ref>

== Applications ==
Polyketide [[antibiotic]]s,<ref>{{Cite web|date=2017-05-09|title=5.13E: Polyketide Antibiotics |url=https://bio.libretexts.org/Bookshelves/Microbiology/Book%3A_Microbiology_(Boundless)/5%3A_Microbial_Metabolism/5.13%3A_Anabolism/5.13E%3A_Polyketide_Antibiotics |access-date=2021-07-05 |website=Biology LibreTexts |language=en}}</ref> [[Antifungal medication|antifungals]],<ref name="Ross_2014">{{cite journal |vauthors=Ross C, Opel V, Scherlach K, Hertweck C |title=Biosynthesis of antifungal and antibacterial polyketides by Burkholderia gladioli in coculture with Rhizopus microsporus |journal=Mycoses |volume=57 |issue=Suppl 3 |pages=48–55 |date=December 2014 |pmid=25250879 |doi=10.1111/myc.12246 |doi-access=free}}</ref> [[cytostatic]]s,<ref>{{cite journal |vauthors=Jiang L, Pu H, Xiang J, Su M, Yan X, Yang D, Zhu X, Shen B, Duan Y, Huang Y |display-authors=3 |title=Huanglongmycin A-C, Cytotoxic Polyketides Biosynthesized by a Putative Type II Polyketide Synthase From ''Streptomyces'' sp. CB09001 | language=en |journal=Frontiers in Chemistry |volume=6 |pages=254 |date=2018 |pmid=30013965 |pmc=6036704 |doi=10.3389/fchem.2018.00254 |doi-access=free |bibcode=2018FrCh....6..254J}}</ref> [[anticholesteremic]],<ref>{{cite journal |vauthors=Chan YA, Podevels AM, Kevany BM, Thomas MG |title=Biosynthesis of polyketide synthase extender units |journal=Natural Product Reports |volume=26 |issue=1 |pages=90–114 |date=January 2009 |pmid=19374124 |pmc=2766543 |doi=10.1039/b801658p}}</ref> [[antiparasitics]],<ref name="Ross_2014"/> [[coccidiostat]]s, [[Growth factor|animal growth promoters]] and natural [[insecticide]]s<ref>{{cite journal |vauthors=Kim HJ, Choi SH, Jeon BS, Kim N, Pongdee R, Wu Q, Liu HW |display-authors=3|title=Chemoenzymatic synthesis of spinosyn A |journal=Angewandte Chemie |volume=53 |issue=49 |pages=13553–13557 |date=December 2014 |pmid=25287333 |pmc=4266379 |doi=10.1002/anie.201407806}}</ref> are in commercial use.

=== Medicinal ===
There are more than 10,000 known polyketides, 1% of which are known to have potential for drug activity.<ref>{{Cite book |url= https://pubs.acs.org/doi/book/10.1021/bk-2007-0955 |title=Polyketides: Biosynthesis, Biological Activity, and Genetic Engineering|chapter=A Plethora of Polyketides: Structures, Biological Activities, and Enzymes |date=2007-01-11 |publisher=American Chemical Society |isbn=978-0-8412-3978-4| veditors=Rimando AM, Baerson SR |series=ACS Symposium Series|volume=955 |location=Washington, DC |language=en |doi=10.1021/bk-2007-0955.ch001 |last1=Baerson |first1=Scott R. |last2=Rimando |first2=Agnes M. |pages=2–14 }}</ref> Polyketides comprise 20% of the top-selling pharmaceuticals with combined worldwide revenues of over USD 18 billion per year.<ref>{{cite journal |vauthors=Weissman K, Leadlay B |year=2005 |pages=925–936 |volume=3 |title=Combinatorial biosynthesis of reduced polyketides |language=en |journal=[[Nature Reviews Microbiology]] |issue=12 |doi=10.1038/nrmicro1287|pmid=16322741 |s2cid=205496204 }}</ref>
{|
|+ '''Polyketides'''
|-
|[[File:Geldanamycin.svg|180px]]
|[[File:Doxycycline.svg|180px]]
|[[File:Erythromycin A.svg|250px]]
|[[File:(–)-Aflatoxin B1 Structural Formulae V.1.svg|150px]]
|-
|style="text-align: center; font-size: 90%;" width=180px |[[Geldanamycin]], an antibiotic.
|style="text-align: center; font-size: 90%;" width=180px |[[Doxycycline]], an antibiotic.
|style="text-align: center; font-size: 90%;" width=250px |[[Erythromycin]], an antibiotic.
|style="text-align: center; font-size: 90%;" width=150px |[[Aflatoxin B1]] known [[carcinogen]]ic compound.
|}

==== Examples ====
* [[Macrolide]]s
** [[Pikromycin]], the first isolated macrolide (1950<ref>{{Cite journal |last=Brockmann |first=Hans |last2=Henkel |first2=Willfried |date=1950-01-01 |title=Pikromycin, ein neues Antibiotikum aus Actinomyceten |url=https://link.springer.com/article/10.1007/BF00638597 |journal=Naturwissenschaften |language=de |volume=37 |issue=6 |pages=138–139 |doi=10.1007/BF00638597 |issn=1432-1904|url-access=subscription }}</ref><ref>{{cite journal | vauthors = Brockmann H, Henkel W | year = 1951 | pages = 284–288 | volume = 84 | issue = 3 | title = Pikromycin, ein bitter schmeckendes Antibioticum aus Actinomyceten | language = German | trans-title = Pikromycin, a bitter tasting antibiotic from an actinomycete | journal = [[Chem. Ber.]] | doi = 10.1002/cber.19510840306}}</ref>)
** The [[antibiotic]]s [[erythromycin|erythromycin A]], [[clarithromycin]], and [[azithromycin]]
** The [[antihelminthic]]s [[ivermectin]]
* [[Ansamycin]]s
** The [[antitumor]] agents [[geldanamycin]] and [[macbecin]],
** The [[antibiotic]] [[rifamycin]]
* [[Polyene]]s
** The [[antifungal medication|antifungals]] [[amphotericin]], [[nystatin]] and [[pimaricin]]
* [[Polyether]]s
** The [[antibiotic]] [[monensin]]
* [[Tetracycline]]s 
** The antibiotic agent [[doxycycline]]
* [[Acetogenin]]s
** [[bullatacin]]
** [[squamocin]]
** [[molvizarin]]
** [[uvaricin]]
** [[annonacin]]
* Others
** The [[immunosuppressant]]s [[tacrolimus|tacrolimus (FK506)]] (a [[calcineurin]] inhibitor) and [[sirolimus]] (rapamycin) (a [[mTOR]] inhibitor)
** [[Radicicol]] and the pochonin family ([[HSP90]] inhibitors)
** The [[cholesterol]] lowering agent [[lovastatin]]
** [[Discodermolide]]
** [[Aflatoxin]]
** [[Usnic acid]]
** [[Anthracimycin]]
** [[Anthramycin]]
** [[Olivetolic acid]] (intermediate in [[cannabinoid]] pathways)<ref>{{cite journal | vauthors = Gagne SJ, Stout JM, Liu E, Boubakir Z, Clark SM, Page JE |display-authors=3| title = Identification of olivetolic acid cyclase from Cannabis sativa reveals a unique catalytic route to plant polyketides | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 31 | pages = 12811–12816 | date = July 2012 | pmid = 22802619 | pmc = 3411943 | doi = 10.1073/pnas.1200330109 | bibcode = 2012PNAS..10912811G | doi-access = free}}</ref>

=== Agricultural ===
Polyketides can be used for crop protection as [[pesticide]]s.<ref>{{cite journal | vauthors = Li S, Yang B, Tan GY, Ouyang LM, Qiu S, Wang W, Xiang W, Zhang L | display-authors = 3 | title = Polyketide pesticides from actinomycetes | journal = Current Opinion in Biotechnology | volume = 69 | pages = 299–307 | date = June 2021 | pmid = 34102376 | doi = 10.1016/j.copbio.2021.05.006 | series = Chemical Biotechnology ● Pharmaceutical Biotechnology | s2cid = 235378697}}</ref>

==== Examples ====
* Pesticides
** [[spinosad]] or spinosyn (an [[insecticide]])
** [[avermectin]]
** polynactins
** tetramycin

=== Industrial ===
Polyketides can be used for industrial purposes, such as pigmentation<ref>{{cite book |vauthors=Caro Y, Venkatachalam M, Lebeau J, Fouillaud M, Dufossé L |veditors=Merillon JM, Ramawat KG |display-authors=3|chapter=Pigments and Colorants from Filamentous Fungi|date=2016|title=Fungal Metabolites|pages=1–70|series=Reference Series in Phytochemistry|place=Cham|publisher=Springer International Publishing|language=en|isbn=978-3-319-19456-1|doi=10.1007/978-3-319-19456-1_26-1}}</ref> and dietary flavonoids.<ref>{{cite journal |vauthors=Tauchen J, Huml L, Rimpelova S, Jurášek M |title=Flavonoids and Related Members of the Aromatic Polyketide Group in Human Health and Disease: Do They Really Work? |journal=Molecules |volume=25 |issue=17 |pages=3846 |date=August 2020 |pmid=32847100 |pmc=7504053 |doi=10.3390/molecules25173846 |doi-access=free}}</ref>

==== Examples ====
* Pigments
** azaphilones
** [[hydroxyanthraquinone]]s
** [[naphthoquinone]]s
* Flavonoids
** [[curcumin]]
** [[silymarin]]
** [[daidzein]]

== Biotechnology ==
[[Protein engineering]] has opened avenues for creating polyketides not found in nature. For example, the modular nature of PKSs allows for domains to be replaced, added or deleted. Introducing diversity in assembly lines enables the discovery of new polyketides with increased bioactivity or new bioactivity.<ref name="Evolution and Diversity of Assembly"/>

Furthermore, the use of [[genome mining]] allows for discovery of new natural polyketides and their assembly lines.<ref name=":2" />

== See also ==
{{Commons category|Polyketides}}
* [[Esterase]]
* [[Nonribosomal peptide]]
* [[ThYme (database)]] (2010)

== References ==
{{reflist}}

[[Category:Polyketides| ]]
[[Category:NADH dehydrogenase inhibitors]]
[[Category:Plant toxin insecticides]]