Editing Polyketide (section)

== 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>