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21  structures 1046  species 0  interactions 5569  sequences 1171  architectures

Family: PS-DH (PF14765)

Summary: Polyketide synthase dehydratase

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This is the Wikipedia entry entitled "Polyketide synthase". More...

Polyketide synthase Edit Wikipedia article

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]

The PKS genes for a certain polyketide are usually organized in one operon in bacteria and in gene clusters in eukaryotes.

Classification[edit]

PKSs can be classified into three groups:

  • Type I polyketide synthases are large, highly modular proteins.
  • Type II polyketide synthases are aggregates of monofunctional proteins.
  • Type III polyketide synthases do not use ACP domains.

Type I PKSs are further subdivided:

  • Iterative PKSs reuse domains in a cyclic fashion.
  • Modular PKSs contain a sequence of separate modules and do not repeat domains (with the exception of trans-AT domains).

Iterative PKSs (IPKSs) can be still further subdivided:

  • NR-PKSs — non-reducing PKSs, the products of which are true polyketides
  • PR-PKSs — partially reducing PKSs
  • FR-PKSs — fully reducing PKSs, the products of which are fatty acid derivatives

Modules and domains[edit]

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):

  • Starting or loading module: AT-ACP-
  • Elongation or extending modules: -KS-AT-[DH-ER-KR]-ACP-
  • Termination or releasing module: -TE

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)OH + HS-protein <=> R-C(=O)S-protein + H2O.

Stages[edit]

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:

  • The starter group, usually acetyl-CoA or malonyl-CoA, is loaded onto the ACP domain of the starter module catalyzed by the starter module's AT domain.

Elongation stages:

  • 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 β-keto group to a β-hydroxy group, the DH (dehydratase) domain splits off H2O, resulting in the α-β-unsaturated alkene, and the ER (enoyl-reductase) domain reduces the α-β-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.

Termination stage:

  • The TE (thio-esterase) domain hydrolyzes the completed polyketide chain from the ACP-domain of the previous module.

Pharmacological relevance[edit]

Polyketide synthases are an important source of naturally occurring small molecules used for chemotherapy.[3] For example, many of the commonly used antibiotics, such as tetracyclin and macrolides, are produced by polyketide synthases. Other industrially important polyketides are sirolimus (immunosuppressant), erythromycin (antibiotic), lovastatin (anticholesterol drug), and epothilone B (anticancer drug).[4]

Ecological significance[edit]

Only about 1% of all known molecules are natural products, yet it has been recognized that that almost two thirds of all drugs currently in use are at least in part derived from a natural source.[5] 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.[6][7] 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.[8][9]

See also[edit]

References[edit]

  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.  edit
  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.  edit
  3. ^ 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.  edit
  4. ^ 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. doi:10.1128/AEM.71.5.2232-2238.2005. PMC 1087561. PMID 15870305.  edit
  5. ^ 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.  edit
  6. ^ 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.  edit
  7. ^ 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. doi:10.1073/pnas.0710107105. PMC 2290765. PMID 18250311.  edit
  8. ^ 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:10.1016/S0378-1097(99)00453-X. PMID 10547437.  edit
  9. ^ 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. doi:10.1128/AEM.02611-06. PMC 1892886. PMID 17337547.  edit

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Polyketide synthase dehydratase Provide feedback

This is the dehydratase domain of polyketide synthases [1]. 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 [2].

Literature references

  1. Keatinge-Clay A;, J Mol Biol. 2008;384:941-953.: Crystal structure of the erythromycin polyketide synthase dehydratase. PUBMED:18952099 EPMC:18952099

  2. 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


External database links

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Domain organisation

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Pfam Clan

This family is a member of clan HotDog (CL0050), which has the following description:

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 [1].

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_Cterm

Alignments

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  Seed
(177)
Full
(5569)
Representative proteomes NCBI
(5792)
Meta
(232)
RP15
(518)
RP35
(1299)
RP55
(1894)
RP75
(2255)
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  Seed
(177)
Full
(5569)
Representative proteomes NCBI
(5792)
Meta
(232)
RP15
(518)
RP35
(1299)
RP55
(1894)
RP75
(2255)
Alignment:
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Sequence:
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  Seed
(177)
Full
(5569)
Representative proteomes NCBI
(5792)
Meta
(232)
RP15
(518)
RP35
(1299)
RP55
(1894)
RP75
(2255)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

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Curation and family details

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Curation View help on the curation process

This family is new in this Pfam release.

Seed source: Pfam-B_852 (release 26.0)
Previous IDs: none
Type: Domain
Author: Coggill P
Number in seed: 177
Number in full: 5569
Average length of the domain: 275.10 aa
Average identity of full alignment: 19 %
Average coverage of the sequence by the domain: 12.09 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 27.0 27.0
Trusted cut-off 27.1 27.0
Noise cut-off 26.9 26.7
Model length: 296
Family (HMM) version: 1
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Species distribution

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Structures

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 21 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 seqence.

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