Summary: 3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III
Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.
This is the Wikipedia entry entitled "Beta-ketoacyl-%28acyl-carrier-protein%29 synthase III". More...
The Wikipedia text that you see displayed here is a download from Wikipedia. This means that the information we display is a copy of the information from the Wikipedia database. The button next to the article title ("Edit Wikipedia article") takes you to the edit page for the article directly within Wikipedia. You should be aware you are not editing our local copy of this information. Any changes that you make to the Wikipedia article will not be displayed here until we next download the article from Wikipedia. We currently download new content on a nightly basis.
Does Pfam agree with the content of the Wikipedia entry ?
Pfam has chosen to link families to Wikipedia articles. In some case we have created or edited these articles but in many other cases we have not made any direct contribution to the content of the article. The Wikipedia community does monitor edits to try to ensure that (a) the quality of article annotation increases, and (b) vandalism is very quickly dealt with. However, we would like to emphasise that Pfam does not curate the Wikipedia entries and we cannot guarantee the accuracy of the information on the Wikipedia page.
Editing Wikipedia articles
Before you edit for the first time
Wikipedia is a free, online encyclopedia. Although anyone can edit or contribute to an article, Wikipedia has some strong editing guidelines and policies, which promote the Wikipedia standard of style and etiquette. Your edits and contributions are more likely to be accepted (and remain) if they are in accordance with this policy.
You should take a few minutes to view the following pages:
How your contribution will be recorded
Anyone can edit a Wikipedia entry. You can do this either as a new user or you can register with Wikipedia and log on. When you click on the "Edit Wikipedia article" button, your browser will direct you to the edit page for this entry in Wikipedia. If you are a registered user and currently logged in, your changes will be recorded under your Wikipedia user name. However, if you are not a registered user or are not logged on, your changes will be logged under your computer's IP address. This has two main implications. Firstly, as a registered Wikipedia user your edits are more likely seen as valuable contribution (although all edits are open to community scrutiny regardless). Secondly, if you edit under an IP address you may be sharing this IP address with other users. If your IP address has previously been blocked (due to being flagged as a source of 'vandalism') your edits will also be blocked. You can find more information on this and creating a user account at Wikipedia.
If you have problems editing a particular page, contact us at email@example.com and we will try to help.
The community annotation is a new facility of the Pfam web site. If you have problems editing or experience problems with these pages please contact us.
Beta-ketoacyl-%28acyl-carrier-protein%29 synthase III Edit Wikipedia article
|Î²-ketoacyl-(acyl-carrier-protein) synthase III|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / QuickGO|
|3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III|
Structure and active-site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from escherichia coli.
Thus, the two substrates of this enzyme are acetyl-CoA and malonyl-[acyl-carrier-protein], whereas its 3 products are acetoacetyl-[acyl-carrier-protein], CoA, and CO2. This enzyme belongs to the family of transferases, to be specific those acyltransferases transferring groups other than aminoacyl groups.
This enzyme participates in fatty acid biosynthesis. Î²-Ketoacyl-acyl-carrier-protein synthase III is involved in the dissociated (or type II) fatty-acid biosynthesis system that occurs in plants and bacteria. The role of FabH in fatty acid synthesis has been described in Streptomyces glaucescens, Streptococcus pneumoniae, and Streptomyces coelicolor.
The systematic name of this enzyme class is acetyl-CoA:malonyl-[acyl-carrier-protein] C-acyltransferase. Other names in common use include:
Role in tuberculosis
Mycobacterium tuberculosis, the cause of tuberculosis, evades effective immune clearance through encapsulation, especially with mycolic acids that are particularly resistant to the normal degradative processes of macrophages. Furthermore, this capsule inhibits entry of antibiotics. The enzymes involved in mycolate biosynthesis are essential for survival and pathogenesis, and thus represent excellent drug targets.
In M. tuberculosis, the beta-ketoacyl-[acyl-carrier-protein] synthase III enzyme is designated mtFabH and is a crucial link between the fatty acid synthase-I and fatty acid synthase-II pathways producing mycolic acids. FAS-I is involved in the synthesis of C16 and C26 fatty acids. The C16 acyl-CoA product acts as a substrate for the synthesis of meromycolic acid by FAS-II, whereas the C26 fatty acid constitutes the alpha branch of the final mycolic acid. MtFabH has been proposed to be the link between FAS-I and FAS-II by converting C14-CoA generated by FAS-I to C16-AcpM, which is channelled into the FAS-II cycle. According to in silico flux balance analyses, mtFabH is essential but not according to transposon site hybridization analysis. Unlike the enzymes in FAS-I, the enzymes of FAS-II, including mtFabH, and are not found in mammals, suggesting inhibitors of these enzymes are suitable choices for drug development.
Structure and substrates
The catalytic activity and substrate specificity of mtFabH has been measured then further probed using crystallographic and directed mutagenesis methods Structures have been determined of ecFabH bound with substrates, (CoA, malonyl CoA, degraded CoA). Specific inhibitors developed using rational design have recently been reported. In 2005, the structure of a catalytically disabled mtFabH mutant with lauroyl-CoA was reported.
Native mtFabH is a homodimer with Mr = 77 Â± 25 kDa. Although there is substantial structural homology among all bacterial FabH enzymes determined thus far, with two channels for binding of acyl-CoA and malonyl-ACP substrates and a conserved catalytic triad (C122, H258, N289 in mtFabH), mtFabH contains residues along the acyl-CoA binding channel that preferentially select for longer-chain substrates peaking with lauroyl-CoA (C12). Inhibition strategies based on rational design could include competitive displacement of the substrates or disruption of the catalytic site. Phosphorylation of Thr45, which is located at the entrance of the substrate channel, inhibits activity, perhaps by altering accessibility of substrates.
At least two of the existing drugs for tuberculosis were originally derived from microbes; cerulenin from the fungus Cephalosporium caerulens and thiolactomycin (TLM) from the actinomycete Nocardia spp. Isoniazid (isonicotinic acid hydrazide), ethionamide, triclosan [5-chloro-2-(2,4-dichlorophenoxy)-phenol] and TLM are known to specifically inhibit mycolic acid biosynthesis. Derivatives of TLM and related compounds are being screened to improve efficacy.
While much has been learned from these structural studies and rational design is an excellent approach to develop novel inhibitors, alternative approaches such as bio-prospecting may reveal unexpected compounds such as an allosteric inhibitor discovered by Daines et al. This could be especially important given that phosphorylation of mycolate synthesis enzymes is suggested to be critical to regulation and kinase domains are known to have multiple control mechanisms remote from ligand binding and active sites.
Following the discovery that phomallenic acids isolated from a leaf litter fungus identified as Phoma sp. are inhibitors of the FabH/FabF. Wang et al. recently reported their discovery from the soil bacterium Streptomyces platensis of a novel natural inhibitor of FabH with in vivo activity called platencin. These were found by screening 250,000 extracts of soil bacteria and fungi, demonstrating the viability of bio-prospecting. While a potentially useful antibiotic in its own right, it has now been shown that platensimycin is not specifically active on mtFabH.
It is speculated that novel inhibitors will most likely be small molecules of relatively low polarity, considering that the catalytic sites of the mtFabH homodimer are hidden in relatively hydrophobic pockets and the need to traverse capsules of established bacilli. This is supported by the poor water solubility of an inhibitor to ecFabH. It is also hoped that, by being small molecules, their synthesis or biosynthesis will be simple and cheap, thereby enhancing affordability of subsequent drugs to developing countries. Techniques for screening efficacy of inhibitors are available.
In 2005, tuberculosis caused approximately 1.6 million deaths worldwide, 8.8 million people became sick, with 90% of these cases in developing countries, and an estimated one-third of the world's population has latent TB. Despite the availability of the BCG vaccine and multiple antibiotics, until 2005 TB resurged due to multidrug resistance, exacerbated by incubation in immune-compromised AIDS victims, drug treatment non-compliance, and ongoing systemic deficiencies of healthcare in developing countries. Mortality and infection rates appear to have peaked, but TB remains a serious global problem. New effective drugs are needed to combat this disease. Inhibitors against mtFabH, or against other enzymes of the FAS-II pathway, may have broader utility, such as the treatment of multidrug-resistant Staphylococcus aureus, and Plasmodium falciparum, the causative agent of another serious refractory problem, malaria.
Given the predominance of TB in poor countries, the commercial incentive to develop new drugs has been hampered, along with complacency and reliance on old, well-established, "first-line" drugs such as Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol. The price point is already very low: US$16â€“35 will buy a full six-month drug course Nevertheless, new drugs are in clinical trials.
According to the Global Alliance for TB Drug Development, sales of first-line TB drugs are projected to be approximately US$315 million per year, and US$54 million for second-line treatments, yet the global economic toll of TB is at least $12 billion each year.
- Davies C, Heath RJ, White SW, Rock CO (2000). "The 1.8 A crystal structure and active-site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from escherichia coli". Structure. 8 (2): 185â€“95. doi:10.1016/S0969-2126(00)00094-0. PMID 10673437.
- Han L, Lobo S, Reynolds KA (1998). "Characterization of Î²-Ketoacyl-Acyl Carrier Protein Synthase III from Streptomyces glaucescens and Its Role in Initiation of Fatty Acid Biosynthesis". J. Bacteriol. 180 (17): 4481â€“6. PMC 107458. PMID 9721286.
- Khandekar SS, Gentry DR, Van Aller GS, Warren P, Xiang H, Silverman C, Doyle ML, Chambers PA, Konstantinidis AK, Brandt M, Daines RA, Lonsdale JT (2001). "Identification, substrate specificity, and inhibition of the Streptococcus pneumoniae beta-ketoacyl-acyl carrier protein synthase III (FabH)". J. Biol. Chem. 276 (32): 30024â€“30. doi:10.1074/jbc.M101769200. PMID 11375394.
- Li Y, Florova G, Reynolds KA (2005). "Alteration of the Fatty Acid Profile of Streptomyces coelicolor by Replacement of the Initiation Enzyme 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH)". J. Bacteriol. 187 (11): 3795â€“9. doi:10.1128/JB.187.11.3795-3799.2005. PMC 1112031. PMID 15901703.
- Bhatt A, Molle V, Besra GS, Jacobs WR, Kremer L (June 2007). "The Mycobacterium tuberculosis FAS-II condensing enzymes: their role in mycolic acid biosynthesis, acid-fastness, pathogenesis and in future drug development". Mol. Microbiol. 64 (6): 1442â€“54. doi:10.1111/j.1365-2958.2007.05761.x. PMID 17555433.
- Raman K, Rajagopalan P, Chandra N (October 2005). "Flux Balance Analysis of Mycolic Acid Pathway: Targets for Anti-Tubercular Drugs". PLoS Comput. Biol. 1 (5): e46. Bibcode:2005PLSCB...1...46R. doi:10.1371/journal.pcbi.0010046. PMC 1246807. PMID 16261191.
- Sassetti CM, Boyd DH, Rubin EJ (April 2003). "Genes required for mycobacterial growth defined by high density mutagenesis". Mol. Microbiol. 48 (1): 77â€“84. doi:10.1046/j.1365-2958.2003.03425.x. PMID 12657046.
- doi:10.1006/jmbi.2000.4457. PMID 11243824. , , ; Qiu X, Janson CA, Smith WW, Head M, Lonsdale J, Konstantinidis AK (March 2001). "Refined structures of beta-ketoacyl-acyl carrier protein synthase III". J. Mol. Biol. 307 (1): 341â€“56.
- doi:10.1074/jbc.M010762200. PMID 11278743. ; Scarsdale JN, Kazanina G, He X, Reynolds KA, Wright HT (June 2001). "Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III". J. Biol. Chem. 276 (23): 20516â€“22.
- "Crystal structure and substrate specificity of the Î²-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus". Protein Sci. 14 (8): 2087â€“94. doi:10.1110/ps.051501605. PMC 2279320. PMID 15987898. ; Qiu X, Choudhry AE, Janson CA, Grooms M, Daines RA, Lonsdale JT, Khandekar SS (August 2005).
- doi:10.1074/jbc.274.51.36465. PMID 10593943. ; Qiu X, Janson CA, Konstantinidis AK, Nwagwu S, Silverman C, Smith WW, Khandekar S, Lonsdale J, Abdel-Meguid SS (December 1999). "Crystal structure of beta-ketoacyl-acyl carrier protein synthase III. A key condensing enzyme in bacterial fatty acid biosynthesis". J. Biol. Chem. 274 (51): 36465â€“71.
- Inagaki E, Kuramitsu S, Yokoyama S, Miyano M, Tahirov TH (2007) The Crystal Structure of Beta-Ketoacyl-[Acyl Carrier Protein] Synthase III (Fabh) from Thermus thermophilus.
- Choi KH, Kremer L, Besra GS, Rock CO (September 2000). "Identification and substrate specificity of beta -ketoacyl (acyl carrier protein) synthase III (mtFabH) from Mycobacterium tuberculosis". J. Biol. Chem. 275 (36): 28201â€“7. doi:10.1074/jbc.M003241200. PMID 10840036.
- doi:10.1074/jbc.M413216200. PMID 16040614. , ; Brown AK, Sridharan S, Kremer L, Lindenberg S, Dover LG, Sacchettini JC, Besra GS (September 2005). "Probing the mechanism of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III mtFabH: factors influencing catalysis and substrate specificity". J. Biol. Chem. 280 (37): 32539â€“47.
- doi:10.1021/jm025571b. PMID 12502353. ; Daines RA, Pendrak I, Sham K, Van Aller GS, Konstantinidis AK, Lonsdale JT, Janson CA, Qiu X, Brandt M, Khandekar SS, Silverman C, Head MS (January 2003). "First X-ray cocrystal structure of a bacterial FabH condensing enzyme and a small molecule inhibitor achieved using rational design and homology modeling". J. Med. Chem. 46 (1): 5â€“8.
- Nie Z, Perretta C, Lu J, Su Y, Margosiak S, Gajiwala KS, Cortez J, Nikulin V, Yager KM, Appelt K, Chu S (March 2005). "Structure-based design, synthesis, and study of potent inhibitors of beta-ketoacyl-acyl carrier protein synthase III as potential antimicrobial agents". J. Med. Chem. 48 (5): 1596â€“609. doi:10.1021/jm049141s. PMID 15743201.
- Ashek A, Cho SJ (March 2006). "A combined approach of docking and 3D QSAR study of beta-ketoacyl-acyl carrier protein synthase III (FabH) inhibitors". Bioorg. Med. Chem. 14 (5): 1474â€“82. doi:10.1016/j.bmc.2005.10.001. PMID 16275103.
- doi:10.1016/j.jmb.2004.12.044. PMID 15713483. ; Musayev F, Sachdeva S, Scarsdale JN, Reynolds KA, Wright HT (March 2005). "Crystal structure of a substrate complex of Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III (FabH) with lauroyl-coenzyme A". J. Mol. Biol. 346 (5): 1313â€“21.
- Veyron-Churlet R, Molle V, Taylor RC, Brown AK, Besra GS, Zanella-ClÃ©on I, FÃ¼tterer K, Kremer L (March 2009). "The Mycobacterium tuberculosis Î²-Ketoacyl-Acyl Carrier Protein Synthase III Activity Is Inhibited by Phosphorylation on a Single Threonine Residue". J. Biol. Chem. 284 (10): 6414â€“24. doi:10.1074/jbc.M806537200. PMC 2649087. PMID 19074144.
- Schroeder EK, de Souza N, Santos DS, Blanchard JS, Basso LA (September 2002). "Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis". Curr Pharm Biotechnol. 3 (3): 197â€“225. doi:10.2174/1389201023378328. PMID 12164478.
- Senior SJ, Illarionov PA, Gurcha SS, Campbell IB, Schaeffer ML, Minnikin DE, Besra GS (November 2003). "Biphenyl-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme". Bioorg. Med. Chem. Lett. 13 (21): 3685â€“8. doi:10.1016/j.bmcl.2003.08.015. PMID 14552758.
- Senior SJ, Illarionov PA, Gurcha SS, Campbell IB, Schaeffer ML, Minnikin DE, Besra GS (January 2004). "Acetylene-based analogues of thiolactomycin, active against Mycobacterium tuberculosis mtFabH fatty acid condensing enzyme". Bioorg. Med. Chem. Lett. 14 (2): 373â€“6. doi:10.1016/j.bmcl.2003.10.061. PMID 14698162.
- He X, Reeve AM, Desai UR, Kellogg GE, Reynolds KA (August 2004). "1,2-Dithiole-3-Ones as Potent Inhibitors of the Bacterial 3-Ketoacyl Acyl Carrier Protein Synthase III (FabH)". Antimicrob. Agents Chemother. 48 (8): 3093â€“102. doi:10.1128/AAC.48.8.3093-3102.2004. PMC 478545. PMID 15273125.
- Al-Balas Q, Anthony NG, Al-Jaidi B, Alnimr A, Abbott G, Brown AK, Taylor RC, Besra GS, McHugh TD, Gillespie SH, Johnston BF, Mackay SP, Coxon GD (2009). Todd MH (ed.). "Identification of 2-Aminothiazole-4-Carboxylate Derivatives Active against Mycobacterium tuberculosis H37Rv and the Î²-Ketoacyl-ACP Synthase mtFabH". PLoS ONE. 4 (5): e5617. Bibcode:2009PLoSO...4.5617A. doi:10.1371/journal.pone.0005617. PMC 2680598. PMID 19440303.
- Young K, Jayasuriya H, Ondeyka JG, Herath K, Zhang C, Kodali S, Galgoci A, Painter R, Brown-Driver V, Yamamoto R, Silver LL, Zheng Y, Ventura JI, Sigmund J, Ha S, Basilio A, Vicente F, Tormo JR, Pelaez F, Youngman P, Cully D, Barrett JF, Schmatz D, Singh SB, Wang J (February 2006). "Discovery of FabH/FabF Inhibitors from Natural Products". Antimicrob. Agents Chemother. 50 (2): 519â€“26. doi:10.1128/AAC.50.2.519-526.2006. PMC 1366929. PMID 16436705.
- Ondeyka JG, Zink DL, Young K, Painter R, Kodali S, Galgoci A, Collado J, Tormo JR, Basilio A, Vicente F, Wang J, Singh SB (March 2006). "Discovery of bacterial fatty acid synthase inhibitors from a Phoma species as antimicrobial agents using a new antisense-based strategy". J. Nat. Prod. 69 (3): 377â€“80. doi:10.1021/np050416w. PMID 16562839.
- Wang J, Kodali S, Lee SH, Galgoci A, Painter R, Dorso K, Racine F, Motyl M, Hernandez L, Tinney E, Colletti SL, Herath K, Cummings R, Salazar O, GonzÃ¡lez I, Basilio A, Vicente F, Genilloud O, Pelaez F, Jayasuriya H, Young K, Cully DF, Singh SB (May 2007). "Discovery of platencin, a dual FabF and FabH inhibitor with in vivo antibiotic properties". Proceedings of the National Academy of Sciences of the United States of America. 104 (18): 7612â€“6. Bibcode:2007PNAS..104.7612W. doi:10.1073/pnas.0700746104. PMC 1863502. PMID 17456595.
- Brown AK, Taylor RC, Bhatt A, FÃ¼tterer K, Besra GS (2009). Ahmed N (ed.). "Platensimycin Activity against Mycobacterial Î²-Ketoacyl-ACP Synthases". PLoS ONE. 4 (7): e6306. Bibcode:2009PLoSO...4.6306B. doi:10.1371/journal.pone.0006306. PMC 2707616. PMID 19609444.
- Viader-SalvadÃ³ JM, Garza-GonzÃ¡lez E, Valdez-Leal R, del Bosque-Moncayo MA, Tijerina-Menchaca R, Guerrero-OlazarÃ¡n M (July 2001). "Mycolic Acid Index Susceptibility Method for Mycobacterium tuberculosis". J. Clin. Microbiol. 39 (7): 2642â€“5. doi:10.1128/JCM.39.7.2642-2645.2001. PMC 88200. PMID 11427584.
- He X, Mueller JP, Reynolds KA (June 2000). "Development of a scintillation proximity assay for beta-ketoacyl-acyl carrier protein synthase III". Anal. Biochem. 282 (1): 107â€“14. doi:10.1006/abio.2000.4594. PMID 10860506.
- Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C (May 2003). "The growing burden of tuberculosis: global trends and interactions with the HIV epidemic". Arch. Intern. Med. 163 (9): 1009â€“21. doi:10.1001/archinte.163.9.1009. PMID 12742798.
- "Global Tuberculosis Control 2007". World Health Organization. 2007. Archived from the original on 2010-02-02. Retrieved 2010-01-02.
- "TB Alliance â€” An Outdated Treatment". Global Alliance for TB Drug Development. Archived from the original on 2010-01-13. Retrieved 2010-01-02.
- Casenghi M, Cole ST, Nathan CF (November 2007). "New Approaches to Filling the Gap in Tuberculosis Drug Discovery". PLoS Med. 4 (11): e293. doi:10.1371/journal.pmed.0040293. PMC 2062479. PMID 17988169.
- "TB Alliance â€” TB Drug Portfolio". Global Alliance for TB Drug Development. Archived from the original on 2010-01-13. Retrieved 2010-01-02.
- "New Study Reveals Limitations of a Complex and Challenging Global Tuberculosis Drug Marketplace". TB Alliance Newscenter: News Release. Global Alliance for TB Drug Development. 2007-05-14. Retrieved 2010-01-02.
- "The Economics of TB Drug Development" (PDF). Global Alliance for TB Drug Development. 2001. Retrieved 2010-01-02.
- Overview of all the structural information available in the PDB for UniProt: P9WNG3 (Mycobacterium tuberculosis 3-oxoacyl-[acyl-carrier-protein] synthase 3) at the PDBe-KB.
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.
3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III Provide feedback
This domain is found on 3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III EC:220.127.116.11, the enzyme responsible for initiating the chain of reactions of the fatty acid synthase in plants and bacteria.
Abbadi A, Brummel M, Schutt BS, Slabaugh MB, Schuch R, Spener F; , Biochem J 2000;345:153-160.: Reaction mechanism of recombinant 3-oxoacyl-(acyl-carrier-protein) synthase III from Cuphea wrightii embryo, a fatty acid synthase type II condensing enzyme. PUBMED:10600651 EPMC:10600651
Internal database links
|SCOOP:||Chal_sti_synt_N FAE1_CUT1_RppA HMG_CoA_synt_N ketoacyl-synt SpoVAD Thiolase_N|
|Similarity to PfamA using HHSearch:||ketoacyl-synt Chal_sti_synt_N FAE1_CUT1_RppA|
This tab holds annotation information from the InterPro database.
InterPro entry IPR013751
Fatty acid synthesis (FAS) is a vital aspect of cellular physiology which can occur by two distinct pathways. The FAS I pathway, which generally only produces palmitate, is found in eukaryotes and is performed either by a single polypeptide which contains all the reaction centres needed to form a fatty acid, or by two polypeptides which interact to form a multifunctional complex. The FAS II pathway, which is capable of producing many different fatty acids, is found in mitochondria, bacteria, plants and parasites, and is performed by many distinct proteins, each of which catalyses a single step within the pathway. The large diversity of products generated by this pathway is possible because the acyl carrier protein (ACP) intermediates are diffusible entities that can be diverted into other biosynthetic pathways [ PUBMED:15952903 ].
3-Oxoacyl-[acyl carrier protein (ACP)] synthase III catalyses the first condensation step within the FAS II pathway, using acetyl-CoA as the primer and malonyl-ACP as the acceptor, as shown below.
The enzymes studied so far are homodimers, where each monomer consists of two domains (N-terminal and C-terminal) which are similar in structure, but not in sequence [ PUBMED:11243824 , PUBMED:12429097 ].
This entry represents a conserved region within the N-terminal domain.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||3-oxoacyl-[acyl-carrier-protein] synthase activity (GO:0004315)|
|Biological process||fatty acid biosynthetic process (GO:0006633)|
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:
- the number of sequences which exhibit this architecture
a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
Gladomain, followed by two consecutive
EGFdomains, and finally a single
- a link to the page in the Pfam site showing information about the sequence that the graphic describes
- the UniProt description of the protein sequence
- the number of residues in the sequence
- the Pfam graphic itself.
Note that you can see the family page for a particular domain by clicking on the graphic. You can also choose to see all sequences which have a given architecture by clicking on the Show link in each row.
Finally, because some families can be found in a very large number of architectures, we load only the first fifty architectures by default. If you want to see more architectures, click the button at the bottom of the page to load the next set.
Loading domain graphics...
Thiolases are ubiquitous and form a large superfamily. Thiolases can function either degradatively, in the beta-oxidation pathway of fatty acids, or biosynthetically. Biosynthetic thiolases catalyse the formation of acetoacetyl-CoA from two molecules of acetyl-CoA . This is one of the fundamental categories of carbon skeletal assembly patterns in biological systems and is the first step in a wide range of biosynthetic pathways . Thiolase are usually dimeric or tetrameric enzymes. Within each monomer there are two similar domains related by pseudo dyad. The N-terminal of these two domains contains a large insertion of about 100 amino acids.
The clan contains the following 14 members:ACP_syn_III ACP_syn_III_C Chal_sti_synt_C Chal_sti_synt_N FAE1_CUT1_RppA HMG_CoA_synt_C HMG_CoA_synt_N KAsynt_C_assoc ketoacyl-synt Ketoacyl-synt_2 Ketoacyl-synt_C SpoVAD Thiolase_C Thiolase_N
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 and the UniProtKB 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:
- the curated alignment from which the HMM for the family is built
- the alignment generated by searching the sequence database using the HMM
- Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
- alignment generated by searching the UniProtKB sequence database using the family HMM
You can see the alignments as HTML or in three different sequence viewers:
- a Java applet developed at the University of Dundee. You will need Java installed before running jalview
- an HTML page showing the whole alignment.Please note: full Pfam alignments can be very large. These HTML views are extremely large and often cause problems for browsers. Please use either jalview or the Pfam viewer if you have trouble viewing the HTML version
- an HTML-based representation of the alignment, coloured according to the posterior-probability (PP) values from the HMM. As for the standard HTML view, heatmap alignments can also be very large and slow to render.
You can download (or view in your browser) a text representation of a Pfam alignment in various formats:
You can also change the order in which sequences are listed in the alignment, change how insertions are represented, alter the characters that are used to represent gaps in sequences and, finally, choose whether to download the alignment or to view it in your browser directly.
You may find that large alignments cause problems for the viewers and the reformatting tool, so we also provide all alignments in Stockholm format. You can download either the plain text alignment, or a gzipped version of it.
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.
You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.
HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...
If you find these logos useful in your own work, please consider citing the following article:
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_135 (release 18.0)|
|Number in seed:||129|
|Number in full:||14400|
|Average length of the domain:||80.30 aa|
|Average identity of full alignment:||34 %|
|Average coverage of the sequence by the domain:||23.36 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 57096847 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||12|
|Download:||download the raw HMM for this family|
Weight segments by...
Change the size of the sunburst
selected sequences to HMM
a FASTA-format file
- 0 sequences
- 0 species
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:
- show/hide the summary boxes
- highlight species that are represented in the seed alignment
- expand/collapse the tree or expand it to a given depth
- select a sub-tree or a set of species within the tree and view them graphically or as an alignment
- save a plain text representation of the tree
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.
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 ACP_syn_III domain has been found. There are 209 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.
Loading structure mapping...
AlphaFold Structure Predictions
The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.