Polyketide synthase

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Polyketide synthases (PKSs) are a family of multi-domain enzymes or enzyme complexes that produce polyketides, a large class of secondary metabolites, in bacteria, fungi, plants, and a few animal lineages. The biosyntheses of polyketides share striking similarities with fatty acid biosynthesis. [1] [2]

Contents

The PKS genes for a certain polyketide are usually organized in one operon or in gene clusters. Type I and type II PKSs form either large modular protein complexes or dissociable molecular assemblies; type III PKSs exist as smaller homodimeric proteins. [3] [4]

Classification

Reaction mechanisms of type I, II and III PKSs. Decarboxylation of malonyl unit followed by thio-Claisen condensation. a) (cis-AT) type I PKS with acyl carrier protein (ACP), keto synthase (KS) and acyl transferase (AT) domains covalently bound to another . b) Type II PKS with KSa-KSb heterodimer and ACP as separate proteins. c) ACP-independent Type III PKS. PKS Overview.jpg
Reaction mechanisms of type I, II and III PKSs. Decarboxylation of malonyl unit followed by thio-Claisen condensation. a) (cis-AT) type I PKS with acyl carrier protein (ACP), keto synthase (KS) and acyl transferase (AT) domains covalently bound to another . b) Type II PKS with KSα-KSβ heterodimer and ACP as separate proteins. c) ACP-independent Type III PKS.

PKSs can be classified into three types:

Modules and domains

Biosynthesis of the doxorubicin precursor, ie-rhodomycinone. The polyketide synthase reactions are shown on top. Anthracycline aglycone biosyn1.png
Biosynthesis of the doxorubicin precursor, є-rhodomycinone. The polyketide synthase reactions are shown on top.

Each type I polyketide-synthase module consists of several domains with defined functions, separated by short spacer regions. The order of modules and domains of a complete polyketide-synthase is as follows (in the order N-terminus to C-terminus):

Domains:

The polyketide chain and the starter groups are bound with their carboxy functional group to the SH groups of the ACP and the KS domain through a thioester linkage: R-C(=O)O H + H S-protein <=> R-C(=O)S-protein + H2O.

The ACP carrier domains are similar to the PCP carrier domains of nonribosomal peptide synthetases, and some proteins combine both types of modules.

Stages

The growing chain is handed over from one thiol group to the next by trans-acylations and is released at the end by hydrolysis or by cyclization (alcoholysis or aminolysis).

Starting stage:

Elongation stages:

Termination stage:

Pharmacological relevance

Polyketide synthases are an important source of naturally occurring small molecules used for chemotherapy. [15] For example, many of the commonly used antibiotics, such as tetracycline and macrolides, are produced by polyketide synthases. Other industrially important polyketides are sirolimus (immunosuppressant), erythromycin (antibiotic), lovastatin (anticholesterol drug), and epothilone B (anticancer drug). [16]

Polyketides are a large family of natural products widely used as drugs, pesticides, herbicides, and biological probes. [17]

There are antifungal and antibacterial polyketide compounds, namely ophiocordin and ophiosetin.[ citation needed ]

And are researched for the synthesis of biofuels and industrial chemicals. [18]

Ecological significance

Only about 1% of all known molecules are natural products, yet it has been recognized that almost two thirds of all drugs currently in use are at least in part derived from a natural source. [19] This bias is commonly explained with the argument that natural products have co-evolved in the environment for long time periods and have therefore been pre-selected for active structures. Polyketide synthase products include lipids with antibiotic, antifungal, antitumor, and predator-defense properties; however, many of the polyketide synthase pathways that bacteria, fungi and plants commonly use have not yet been characterized. [20] [21] Methods for the detection of novel polyketide synthase pathways in the environment have therefore been developed. Molecular evidence supports the notion that many novel polyketides remain to be discovered from bacterial sources. [22] [23]

See also

References

  1. Khosla, C.; Gokhale, R. S.; Jacobsen, J. R.; Cane, D. E. (1999). "Tolerance and Specificity of Polyketide Synthases". Annual Review of Biochemistry. 68: 219–253. doi:10.1146/annurev.biochem.68.1.219. PMID   10872449.
  2. Jenke-Kodama, H.; Sandmann, A.; Müller, R.; Dittmann, E. (2005). "Evolutionary Implications of Bacterial Polyketide Synthases". Molecular Biology and Evolution. 22 (10): 2027–2039. doi: 10.1093/molbev/msi193 . PMID   15958783.
  3. Weng, Jing-Ke; Noel, Joseph P. (2012). "Structure–Function Analyses of Plant Type III Polyketide Synthases". Natural Product Biosynthesis by Microorganisms and Plants, Part A. Methods in Enzymology. Vol. 515. pp. 317–335. doi:10.1016/B978-0-12-394290-6.00014-8. ISBN   978-0-12-394290-6. PMID   22999180.
  4. Pfeifer, Blaine A.; Khosla, Chaitan (March 2001). "Biosynthesis of Polyketides in Heterologous Hosts". Microbiology and Molecular Biology Reviews. 65 (1): 106–118. doi:10.1128/MMBR.65.1.106-118.2001. PMC   99020 . PMID   11238987.
  5. Sattely, Elizabeth S.; Fischbach, Michael A.; Walsh, Christopher T. (2008). "Total biosynthesis: in vitro reconstitution of polyketide and nonribosomal peptide pathways". Natural Product Reports. 25 (4): 757–793. doi:10.1039/b801747f. PMID   18663394.
  6. Weissman, Kira J. (2020). "Bacterial Type I Polyketide Synthases". Comprehensive Natural Products III: 4–46. doi:10.1016/b978-0-12-409547-2.14644-x. ISBN   9780081026915. S2CID   201202295.
  7. Helfrich, Eric J. N.; Piel, Jörn (2016). "Biosynthesis of polyketides by trans-AT polyketide synthases". Natural Product Reports. 33 (2): 231–316. doi:10.1039/c5np00125k. PMID   26689670.
  8. "The polyketide metabolites". General Pharmacology: The Vascular System. 23 (6): 1228. November 1992. doi:10.1016/0306-3623(92)90327-g.
  9. Hertweck, Christian; Luzhetskyy, Andriy; Rebets, Yuri; Bechthold, Andreas (2007). "Type II polyketide synthases: gaining a deeper insight into enzymatic teamwork". Nat. Prod. Rep. 24 (1): 162–190. doi:10.1039/B507395M. PMID   17268612.
  10. Sattely, Elizabeth S.; Fischbach, Michael A.; Walsh, Christopher T. (2008). "Total biosynthesis: in vitro reconstitution of polyketide and nonribosomal peptide pathways". Natural Product Reports. 25 (4): 757–793. doi:10.1039/b801747f. PMID   18663394.
  11. Abe, Ikuro; Morita, Hiroyuki (2010). "Structure and function of the chalcone synthase superfamily of plant type III polyketide synthases". Natural Product Reports. 27 (6): 809–838. doi:10.1039/b909988n. PMID   20358127.
  12. Shen, B (April 2003). "Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms". Current Opinion in Chemical Biology. 7 (2): 285–295. doi:10.1016/S1367-5931(03)00020-6. PMID   12714063.
  13. Wong, Chin Piow; Morita, Hiroyuki (2020). "Bacterial Type III Polyketide Synthases". Comprehensive Natural Products III: 250–265. doi:10.1016/b978-0-12-409547-2.14640-2. ISBN   9780081026915. S2CID   195410516.
  14. Shimizu, Yugo; Ogata, Hiroyuki; Goto, Susumu (3 January 2017). "Type III Polyketide Synthases: Functional Classification and Phylogenomics". ChemBioChem. 18 (1): 50–65. doi: 10.1002/cbic.201600522 . PMID   27862822. S2CID   45980356.
  15. Koehn, F. E.; Carter, G. T. (2005). "The evolving role of natural products in drug discovery". Nature Reviews Drug Discovery. 4 (3): 206–220. doi:10.1038/nrd1657. PMID   15729362. S2CID   32749678.
  16. Wawrik, B.; Kerkhof, L.; Zylstra, G. J.; Kukor, J. J. (2005). "Identification of Unique Type II Polyketide Synthase Genes in Soil". Applied and Environmental Microbiology. 71 (5): 2232–2238. Bibcode:2005ApEnM..71.2232W. doi:10.1128/AEM.71.5.2232-2238.2005. PMC   1087561 . PMID   15870305.
  17. Pankewitz, Florian; Hilker, Monika (May 2008). "Polyketides in insects: ecological role of these widespread chemicals and evolutionary aspects of their biogenesis". Biological Reviews. 83 (2): 209–226. doi:10.1111/j.1469-185X.2008.00040.x. PMID   18410406. S2CID   27702684.
  18. Cai, Wenlong; Zhang, Wenjun (1 April 2018). "Engineering modular polyketide synthases for production of biofuels and industrial chemicals". Current Opinion in Biotechnology. 50: 32–38. doi:10.1016/j.copbio.2017.08.017. PMC   5862724 . PMID   28946011.
  19. Von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.; Häbich, D. (2006). "Antibacterial Natural Products in Medicinal Chemistry—Exodus or Revival?". Angewandte Chemie International Edition. 45 (31): 5072–5129. doi:10.1002/anie.200600350. PMID   16881035.
  20. Castoe, T. A.; Stephens, T.; Noonan, B. P.; Calestani, C. (2007). "A novel group of type I polyketide synthases (PKS) in animals and the complex phylogenomics of PKSs". Gene. 392 (1–2): 47–58. doi:10.1016/j.gene.2006.11.005. PMID   17207587.
  21. Ridley, C. P.; Lee, H. Y.; Khosla, C. (2008). "Chemical Ecology Special Feature: Evolution of polyketide synthases in bacteria". Proceedings of the National Academy of Sciences. 105 (12): 4595–4600. Bibcode:2008PNAS..105.4595R. doi: 10.1073/pnas.0710107105 . PMC   2290765 . PMID   18250311.
  22. Metsä-Ketelä, M.; Salo, V.; Halo, L.; Hautala, A.; Hakala, J.; Mäntsälä, P.; Ylihonko, K. (1999). "An efficient approach for screening minimal PKS genes from Streptomyces". FEMS Microbiology Letters. 180 (1): 1–6. doi:10.1111/j.1574-6968.1999.tb08770.x. PMID   10547437.
  23. Wawrik, B.; Kutliev, D.; Abdivasievna, U. A.; Kukor, J. J.; Zylstra, G. J.; Kerkhof, L. (2007). "Biogeography of Actinomycete Communities and Type II Polyketide Synthase Genes in Soils Collected in New Jersey and Central Asia". Applied and Environmental Microbiology. 73 (9): 2982–2989. Bibcode:2007ApEnM..73.2982W. doi:10.1128/AEM.02611-06. PMC   1892886 . PMID   17337547.