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==Biosynthesis==
==Biosynthesis==
⚫
Polyketides are synthesized by multienzyme polypeptides that resemble eukaryotic fatty acid synthase but are often much larger.<ref name=":02" /> 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" />
⚫
The 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 and yields a beta-keto functional group. The first condensation yields an acetoacetyl group, a '''diketide'''. Subsequent condensations yield '''triketides''', '''tetraketide''', etc.<ref name = Voet>{{cite book|title = [[Fundamentals of Biochemistry: Life at the Molecular Level]]|first1 = Donald|last1 = Voet|first2 = Judith G.|last2 = Voet|first3 = Charlotte W.|last3 = Pratt|authorlink1 = Donald Voet|authorlink2 = Judith G. Voet|authorlink3 = Charlotte W. Pratt|edition = 4th|publisher = [[John Wiley & Sons]]|year = 2013|page = 688|isbn = 9780470547847}}</ref><ref>{{cite journal|title = Polyketide Biosynthesis: A Millennium Review|last1 = Staunton|first1 = James|last2 = Weissman|first2 = Kira J.|journal = [[Natural Product Reports]]|year = 2001|volume = 18|issue = 4|pages = 380–416|doi = 10.1039/a909079g|pmid = 11548049}}</ref>


=== Polyketide Synthase (PKS) ===
⚫
The polyketide chains produced by a minimal [[polyketide synthase]] are almost invariably modified. Modifications include reduction of the keto groups to methylene and cyclization. Many of these conversions proceed by the enol tautomers of the polyketide.<ref name="Robinson">{{cite journal|first1 = John A.|last1 = Robinson|first2 = Alan Roy|last2 = Fersht|authorlink2 = Alan Fersht|first3 = D.|last3 = Gani|year= 1991|title=Polyketide synthase complexes: Their structure and function in antibiotic biosynthesis|journal=[[Philos. Trans. R. Soc. Lond. B Biol. Sci.]]|volume=332|pages=107–114|pmid=1678529|doi=10.1098/rstb.1991.0038|issue=1263|bibcode = 1991RSPTB.332..107R}}</ref> Polyketides are structurally diverse family.<ref>{{cite journal | last = Katz | first = Leonard | year = 1997 | title = Manipulation of Modular Polyketide Synthases | journal = [[Chem. Rev.]] | volume = 97 | issue = 7 | pages = 2557–2576 | doi = 10.1021/cr960025+| pmid = 11851471 }}</ref> They are broadly divided into three classes: type I polyketides (often [[macrolides]] produced by [[multimodular megasynthase]]s), type II polyketides (often [[aromatic]] molecules produced by the iterative action of dissociated [[enzymes]]), and type III polyketides (often small aromatic molecules produced by fungal species).
⚫
Polyketides are produced by [[Polyketide synthase|polyketide synthases]]. 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]]|first1 = Donald|last1 = Voet|first2 = Judith G.|last2 = Voet|first3 = Charlotte W.|last3 = Pratt|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|title = Polyketide Biosynthesis: A Millennium Review|last1 = Staunton|first1 = James|last2 = Weissman|first2 = Kira J.|journal = [[Natural Product Reports]]|year = 2001|volume = 18|issue = 4|pages = 380–416|doi = 10.1039/a909079g|pmid = 11548049}}</ref> Other starter units include isobutyrate, cyclohexanecarboxylate, malonate, and benzoate.<ref>{{Cite journal|last=S. Moore|first=Bradley|last2=Hertweck|first2=Christian|date=2002|title=Biosynthesis and attachment of novel bacterial polyketide synthase starter units|url=https://pubs.rsc.org/en/content/articlelanding/2002/np/b003939j|journal=Natural Product Reports|language=en|volume=19|issue=1|pages=70–99|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 od the starter unit and extender units) are almost invariably modified.<ref>{{Cite journal|last=Wang|first=Jia|last2=Zhang|first2=Ruihua|last3=Chen|first3=Xin|last4=Sun|first4=Xinxiao|last5=Yan|first5=Yajun|last6=Shen|first6=Xiaolin|last7=Yuan|first7=Qipeng|date=2020-05-24|title=Biosynthesis of aromatic polyketides in microorganisms using type II polyketide synthases|url=https://doi.org/10.1186/s12934-020-01367-4|journal=Microbial Cell Factories|volume=19|issue=1|pages=110|doi=10.1186/s12934-020-01367-4|issn=1475-2859|pmc=PMC7247197|pmid=32448179}}</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 ketodeductase), an olefin (via a dehydratase), or a methylene (via an enoylreductase).<ref>{{Cite journal|last=Moretto|first=Luisa|last2=Heylen|first2=Rachel|last3=Holroyd|first3=Natalie|last4=Vance|first4=Steven|last5=Broadhurst|first5=R. William|date=2019-02-20|title=Modular type I polyketide synthase acyl carrier protein domains share a common N-terminally extended fold|url=https://www.nature.com/articles/s41598-019-38747-9|journal=Scientific Reports|language=en|volume=9|issue=1|pages=2325|doi=10.1038/s41598-019-38747-9|issn=2045-2322}}</ref>
⚫
Polyketides are synthesized by multienzyme polypeptides that resemble eukaryotic fatty acid synthase but are often much larger. 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 />

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.

⚫
Polyketides are structurally diverse family.<ref>{{cite journal | last = Katz | first = Leonard | year = 1997 | title = Manipulation of Modular Polyketide Synthases | journal = [[Chem. Rev.]] | volume = 97 | issue = 7 | pages = 2557–2576 | doi = 10.1021/cr960025+| pmid = 11851471 }}</ref> They are broadly divided into three classes: type I polyketides (often [[macrolides]] produced by multimodular megasynthases), type II polyketides (often [[aromatic]] molecules produced by the iterative action of dissociated [[enzymes]]), and type III polyketides (often small aromatic molecules produced by fungal species).

=== Post-tailoring enzymes ===
Further possible modifications to the polyketide scaffolds can be made. This can include glycolysation via glucosyltransferase or oxidation via monooxygenase.<ref>{{Cite journal|last=Risdian|first=Chandra|last2=Mozef|first2=Tjandrawati|last3=Wink|first3=Joachim|date=2019-05-06|title=Biosynthesis of Polyketides in Streptomyces|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560455/|journal=Microorganisms|volume=7|issue=5|pages=124|doi=10.3390/microorganisms7050124|issn=2076-2607|pmc=6560455|pmid=31064143}}</ref> Similarly, cyclization and aromaticity can be formed, sometimes proceeded by the enol tautomers of the polyketide.<ref name="Robinson">{{cite journal|last1=Robinson|first1=John A.|last2=Fersht|first2=Alan Roy|last3=Gani|first3=D.|year=1991|title=Polyketide synthase complexes: Their structure and function in antibiotic biosynthesis|journal=[[Philos. Trans. R. Soc. Lond. B Biol. Sci.]]|volume=332|issue=1263|pages=107–114|bibcode=1991RSPTB.332..107R|doi=10.1098/rstb.1991.0038|pmid=1678529|authorlink2=Alan Fersht}}</ref> These enzymes are not part of the domains of the polyketide synthase. Instead, they are found in gene clusters in the genome close to the polyketide syntase genes.<ref>{{Cite journal|last=Noar|first=Roslyn D.|last2=Daub|first2=Margaret E.|date=2016-07-07|title=Bioinformatics Prediction of Polyketide Synthase Gene Clusters from Mycosphaerella fijiensis|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936691/|journal=PLoS ONE|volume=11|issue=7|pages=e0158471|doi=10.1371/journal.pone.0158471|issn=1932-6203|pmc=4936691|pmid=27388157}}</ref>


==Applications==
==Applications==

Revision as of 06:34, 19 November 2021

Polyketides are a large group of secondary metabolites which either contain alternating carbonyl groups and methylene groups (-CO-CH2-), or are derived from precursors which contain such alternating groups.[1] Many polyketides are medicinal or exhibit acute toxicity.

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 detectible amounts of orcinol by heating dehydracetic acid with barium hydroxide causing the pyrone ring to open into a triketide.[2] 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.[3]

Biosynthesis of orsellinic acid from polyketide intermediate.

It wasn't until 1955 that the biosynthesis of polyketides were understood.[4] Arthur Birch used radioisotope labeling of carbon in acetate to trace the biosynthesis of 2-hydroxy-6-methylbenzoic acid in Penicillium patulum and demonstrate the head-to-tail linkage of acetic acids to form the polyketide.[5] In the 1980's and 1990's, advancements in genetics allowed for isolation of the genes associated to polyketides to understand of the biosynthesis.[6]

Discovery

Polyketides can be produced in bacteria, fungi, plants, and certain marine organisms.[7] Earlier discovery of naturally occurring polyketides involved the isolation of the compounds being produced by the specific organism using organic chemistry purification methods. Later technology allowed for the isolation of the genes and heterolygous expression of the genes to understand the biosynthesis.[8] 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.[9]

Biosynthesis

Polyketides are synthesized by multienzyme polypeptides that resemble eukaryotic fatty acid synthase but are often much larger.[4] 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.[10]

Polyketide Synthase (PKS)

Polyketides are produced by polyketide synthases. 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.[10] The first condensation yields an acetoacetyl group, a diketide. Subsequent condensations yield triketides, tetraketide, etc.[11] Other starter units include isobutyrate, cyclohexanecarboxylate, malonate, and benzoate.[12]

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 od the starter unit and extender units) are almost invariably modified.[13] 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 ketodeductase), an olefin (via a dehydratase), or a methylene (via an enoylreductase).[14]

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.

Polyketides are structurally diverse family.[15] They are broadly divided into three classes: type I polyketides (often macrolides produced by multimodular megasynthases), type II polyketides (often aromatic molecules produced by the iterative action of dissociated enzymes), and type III polyketides (often small aromatic molecules produced by fungal species).

Post-tailoring enzymes

Further possible modifications to the polyketide scaffolds can be made. This can include glycolysation via glucosyltransferase or oxidation via monooxygenase.[16] Similarly, cyclization and aromaticity can be formed, sometimes proceeded by the enol tautomers of the polyketide.[17] These enzymes are not part of the domains of the polyketide synthase. Instead, they are found in gene clusters in the genome close to the polyketide syntase genes.[18]

Applications

Polyketide antibiotics,[19] antifungals,[6] cytostatics,[20] anticholesteremic,[21] antiparasitics,[6] coccidiostats, animal growth promoters and natural insecticides[22] are in commercial use.

Examples

See also

Wikimedia Commons has media related to Polyketides.

References

  1. ^ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "Polyketides". doi:10.1351/goldbook.P04734
  2. ^ Collie, N.; Myers, W. S. (1893). "VII.—The formation of orcinol and other condensation products from dehydracetic acid". J. Chem. Soc., Trans. 63 (0): 122–128. doi:10.1039/CT8936300122. ISSN 0368-1645.
  3. ^ Collie, John Norman (1907-01-01). "CLXXI.—Derivatives of the multiple keten group". Journal of the Chemical Society, Transactions. 91 (0): 1806–1813. doi:10.1039/CT9079101806. ISSN 0368-1645.
  4. ^ a b Smith, Stuart; Tsai, Shiou-Chuan (2007-09-26). "The type I fatty acid and polyketide synthases: a tale of two megasynthases". Natural Product Reports. 24 (5): 1041–1072. doi:10.1039/B603600G. ISSN 1460-4752. PMC 2263081. PMID 17898897.{{cite journal}}: CS1 maint: PMC format (link)
  5. ^ Birch, A. J.; Massy-Westropp, R. A.; Moye, C. J. (1955). "Studies in relation to biosynthesis. VII. 2-Hydroxy-6-methylbenzoic acid in Penicillium griseofulvum Dierckx". Australian Journal of Chemistry. 8 (4): 539–544. doi:10.1071/ch9550539. ISSN 1445-0038.
  6. ^ a b c Smith, Stuart; Tsai, Shiou-Chuan (2007-09-26). "The type I fatty acid and polyketide synthases: a tale of two megasynthases". Natural Product Reports. 24 (5): 1041–1072. doi:10.1039/B603600G. ISSN 1460-4752. PMC 2263081. PMID 17898897.{{cite journal}}: CS1 maint: PMC format (link) Cite error: The named reference ":0" was defined multiple times with different content (see the help page).
  7. ^ Lane, Amy L.; Moore, Bradley S. (2011-01-25). "A sea of biosynthesis: marine natural products meet the molecular age". Natural Product Reports. 28 (2): 411–428. doi:10.1039/C0NP90032J. ISSN 1460-4752.
  8. ^ Pfeifer, Blaine A.; Khosla, Chaitan (2001-3). "Biosynthesis of Polyketides in Heterologous Hosts". Microbiology and Molecular Biology Reviews. 65 (1): 106–118. doi:10.1128/MMBR.65.1.106-118.2001. ISSN 1092-2172. PMID 11238987. {{cite journal}}: Check date values in: |date= (help)
  9. ^ Gomes, Elisângela Soares; Schuch, Viviane; de Macedo Lemos, Eliana Gertrudes (2014-03-10). "Biotechnology of polyketides: New breath of life for the novel antibiotic genetic pathways discovery through metagenomics". Brazilian Journal of Microbiology. 44 (4): 1007–1034. ISSN 1517-8382. PMC 3958165. PMID 24688489.
  10. ^ a b Voet, Donald; Voet, Judith G.; Pratt, Charlotte W. (2013). Fundamentals of Biochemistry: Life at the Molecular Level (4th ed.). John Wiley & Sons. p. 688. ISBN 9780470547847.
  11. ^ Staunton, James; Weissman, Kira J. (2001). "Polyketide Biosynthesis: A Millennium Review". Natural Product Reports. 18 (4): 380–416. doi:10.1039/a909079g. PMID 11548049.
  12. ^ S. Moore, Bradley; Hertweck, Christian (2002). "Biosynthesis and attachment of novel bacterial polyketide synthase starter units". Natural Product Reports. 19 (1): 70–99. doi:10.1039/B003939J. {{cite journal}}: no-break space character in |last= at position 3 (help)
  13. ^ Wang, Jia; Zhang, Ruihua; Chen, Xin; Sun, Xinxiao; Yan, Yajun; Shen, Xiaolin; Yuan, Qipeng (2020-05-24). "Biosynthesis of aromatic polyketides in microorganisms using type II polyketide synthases". Microbial Cell Factories. 19 (1): 110. doi:10.1186/s12934-020-01367-4. ISSN 1475-2859. PMC 7247197. PMID 32448179.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  14. ^ Moretto, Luisa; Heylen, Rachel; Holroyd, Natalie; Vance, Steven; Broadhurst, R. William (2019-02-20). "Modular type I polyketide synthase acyl carrier protein domains share a common N-terminally extended fold". Scientific Reports. 9 (1): 2325. doi:10.1038/s41598-019-38747-9. ISSN 2045-2322.
  15. ^ Katz, Leonard (1997). "Manipulation of Modular Polyketide Synthases". Chem. Rev. 97 (7): 2557–2576. doi:10.1021/cr960025+. PMID 11851471.
  16. ^ Risdian, Chandra; Mozef, Tjandrawati; Wink, Joachim (2019-05-06). "Biosynthesis of Polyketides in Streptomyces". Microorganisms. 7 (5): 124. doi:10.3390/microorganisms7050124. ISSN 2076-2607. PMC 6560455. PMID 31064143.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ^ Robinson, John A.; Fersht, Alan Roy; Gani, D. (1991). "Polyketide synthase complexes: Their structure and function in antibiotic biosynthesis". Philos. Trans. R. Soc. Lond. B Biol. Sci. 332 (1263): 107–114. Bibcode:1991RSPTB.332..107R. doi:10.1098/rstb.1991.0038. PMID 1678529.
  18. ^ Noar, Roslyn D.; Daub, Margaret E. (2016-07-07). "Bioinformatics Prediction of Polyketide Synthase Gene Clusters from Mycosphaerella fijiensis". PLoS ONE. 11 (7): e0158471. doi:10.1371/journal.pone.0158471. ISSN 1932-6203. PMC 4936691. PMID 27388157.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  19. ^ "5.13E: Polyketide Antibiotics". Biology LibreTexts. 2017-05-09. Retrieved 2021-07-05.
  20. ^ Jiang, Lin; Pu, Hong; Xiang, Jingxi; Su, Meng; Yan, Xiaohui; Yang, Dong; Zhu, Xiangcheng; Shen, Ben; Duan, Yanwen; Huang, Yong (2018). "Huanglongmycin A-C, Cytotoxic Polyketides Biosynthesized by a Putative Type II Polyketide Synthase From Streptomyces sp. CB09001". Frontiers in Chemistry. 6: 254. Bibcode:2018FrCh....6..254J. doi:10.3389/fchem.2018.00254. ISSN 2296-2646. PMC 6036704. PMID 30013965.
  21. ^ Chan, Yolande A.; Podevels, Angela M.; Kevany, Brian M.; Thomas, Michael G. (2009). "Biosynthesis of polyketide synthase extender units". Natural Product Reports. 26 (1): 90–114. doi:10.1039/b801658p. ISSN 0265-0568. PMC 2766543. PMID 19374124.
  22. ^ Kim, Hak Joong; Choi, Sei-hyun; Jeon, Byung-sun; Kim, Namho; Pongdee, Rongson; Wu, Qingquan; Liu, Hung-wen (2014-12-01). "Chemoenzymatic synthesis of spinosyn A". Angewandte Chemie International Edition in English. 53 (49): 13553–13557. doi:10.1002/anie.201407806. ISSN 1521-3773. PMC 4266379. PMID 25287333.
  23. ^ Brockmann, Hans; Henkel, Willfried (1951). "Pikromycin, ein bitter schmeckendes Antibioticum aus Actinomyceten" [Pikromycin, a bitter tasting antibiotic from an actinomycete]. Chem. Ber. (in German). 84 (3): 284–288. doi:10.1002/cber.19510840306.
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