Summary: Polyketide synthase dehydratase
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Polyketide synthase Edit Wikipedia article
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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.
PKSs can be classified into three groups with the following subdivisions:
- Type I polyketide synthases are large, highly modular proteins.
- Iterative Type I PKSs reuse domains in a cyclic fashion.
- Modular Type I PKSs contain a sequence of separate modules and do not repeat domains (with the exception of trans-AT domains).
- Type II polyketide synthases are aggregates of monofunctional proteins.
- Type III polyketide synthases do not use ACP domains.
Modules and domains
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):
- Starting or loading module: AT-ACP-
- Elongation or extending modules: -KS-AT-[DH-ER-KR]-ACP-
- Termination or releasing domain: -TE
- AT: Acyltransferase
- ACP: Acyl carrier protein with an SH group on the cofactor, a serine-attached 4'-phosphopantetheine
- KS: Keto-synthase with an SH group on a cysteine side-chain
- KR: Ketoreductase
- DH: Dehydratase
- ER: Enoylreductase
- MT: Methyltransferase O- or C- (Î± or Î²)
- SH: PLP-dependent cysteine lyase
- TE: Thioesterase
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)OH + HS-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.
- The starter group, usually acetyl-CoA or its analogues, is loaded onto the ACP domain of the starter module catalyzed by the starter module's AT domain.
- The polyketide chain is handed over from the ACP domain of the previous module to the KS domain of the current module, catalyzed by the KS domain.
- The elongation group, usually malonyl-CoA or methylmalonyl-CoA, is loaded onto the current ACP domain catalyzed by the current AT domain.
- The ACP-bound elongation group reacts in a Claisen condensation with the KS-bound polyketide chain under CO2 evolution, leaving a free KS domain and an ACP-bound elongated polyketide chain. The reaction takes place at the KSn-bound end of the chain, so that the chain moves out one position and the elongation group becomes the new bound group.
- Optionally, the fragment of the polyketide chain can be altered stepwise by additional domains. The KR (keto-reductase) domain reduces the Î²-keto group to a Î²-hydroxy group, the DH (dehydratase) domain splits off H2O, resulting in the Î±-Î²-unsaturated alkene, and the ER (enoyl-reductase) domain reduces the Î±-Î²-double-bond to a single-bond. It is important to note that these modification domains actually affect the previous addition to the chain (i.e. the group added in the previous module), not the component recruited to the ACP domain of the module containing the modification domain.
- This cycle is repeated for each elongation module.
- The TE domain hydrolyzes the completed polyketide chain from the ACP-domain of the previous module.
Polyketide synthases are an important source of naturally occurring small molecules used for chemotherapy. 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).
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. 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. 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.
- Khosla, C.; Gokhale, R. S.; Jacobsen, J. R.; Cane, D. E. (1999). "Tolerance and Specificity of Polyketide Synthases". Annual Review of Biochemistry. 68: 219â€“253. doi:10.1146/annurev.biochem.68.1.219. PMID 10872449.
- Jenke-Kodama, H.; Sandmann, A.; MÃ¼ller, R.; Dittmann, E. (2005). "Evolutionary Implications of Bacterial Polyketide Synthases". Molecular Biology and Evolution. 22 (10): 2027â€“2039. doi:10.1093/molbev/msi193. PMID 15958783.
- Koehn, F. E.; Carter, G. T. (2005). "The evolving role of natural products in drug discovery". Nature Reviews Drug Discovery. 4 (3): 206â€“220. doi:10.1038/nrd1657. PMID 15729362.
- 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): 2232â€“2238. doi:10.1128/AEM.71.5.2232-2238.2005. PMC 1087561. PMID 15870305.
- Von Nussbaum, F.; Brands, M.; Hinzen, B.; Weigand, S.; HÃ¤bich, D. (2006). "Antibacterial Natural Products in Medicinal Chemistryâ€”Exodus or Revival?". Angewandte Chemie International Edition. 45 (31): 5072â€“5129. doi:10.1002/anie.200600350. PMID 16881035.
- 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 (1â€“2): 47â€“58. doi:10.1016/j.gene.2006.11.005. PMID 17207587.
- 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): 4595â€“4600. doi:10.1073/pnas.0710107105. PMC 2290765. PMID 18250311.
- MetsÃ¤-KetelÃ¤, M.; Salo, V.; Halo, L.; Hautala, A.; Hakala, J.; MÃ¤ntsÃ¤lÃ¤, P.; Ylihonko, K. (1999). "An efficient approach for screening minimal PKS genes from Streptomyces". FEMS Microbiology Letters. 180 (1): 1â€“6. doi:10.1016/S0378-1097(99)00453-X. PMID 10547437.
- 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): 2982â€“2989. doi:10.1128/AEM.02611-06. PMC 1892886. PMID 17337547.
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Polyketide synthase dehydratase Provide feedback
This is the dehydratase domain of polyketide synthases . Structural analysis shows these DH domains are double hotdogs in which the active site contains a histidine from the N-terminal hotdog and an aspartate from the C-terminal hotdog. Studies have uncovered that a substrate tunnel formed between the DH domains may be essential for loading substrates and unloading products .
Akey DL, Razelun JR, Tehranisa J, Sherman DH, Gerwick WH, Smith JL;, Structure. 2010;18:94-105.: Crystal structures of dehydratase domains from the curacin polyketide biosynthetic pathway. PUBMED:20152156 EPMC:20152156
Internal database links
|SCOOP:||4HBT DUF4442 FabA|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
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EGFdomains, and finally a single
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The HotDog fold was first observed in the structure of Escherichia coli beta-hydroxydecanoyl thiol ester dehydratase (FabA), where Leesong et al. noticed that each subunit of this dimeric enzyme contained a mixed alpha + beta 'hot dog' fold. They described the seven-stranded antiparallel beta-sheet as the 'bun', which wraps around a five-turn alpha-helical 'sausage', This superfamily contains a diverse range of enzymes. Membership includes numerous prokaryotic, archaeal and eukaryotic proteins involved in several related, but distinct, catalytic activities, from metabolic roles such as thioester hydrolysis in fatty acid metabolism, to degradation of phenylacetic acid and the environmental pollutant 4-chlorobenzoate. The superfamily also includes FapR, a non-catalytic bacterial homologue that is involved in transcriptional regulation of fatty acid biosynthesis .
The clan contains the following 13 members:4HBT 4HBT_2 4HBT_3 Acyl-ACP_TE Acyl_CoA_thio AfsA DUF4442 FabA FcoT MaoC_dehydrat_N MaoC_dehydratas PS-DH YiiD_C
We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...
There are various ways to view or download the sequence alignments that we store. We provide several sequence viewers and a plain-text Stockholm-format file for download.
We make a range of alignments for each Pfam-A family:
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- alignment generated by searching the UniProtKB sequence database using the family HMM
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You can see the alignments as HTML or in three different sequence viewers:
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
Note: You can also download the data file for the tree.
Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_852 (release 26.0)|
|Number in seed:||79|
|Number in full:||15220|
|Average length of the domain:||278.00 aa|
|Average identity of full alignment:||18 %|
|Average coverage of the sequence by the domain:||12.21 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 47079205 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||7|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
There are 6 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the PS-DH domain has been found. There are 98 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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