Please note: this site relies heavily on the use of javascript. Without a javascript-enabled browser, this site will not function correctly. Please enable javascript and reload the page, or switch to a different browser.
177  structures 6745  species 3  interactions 13023  sequences 32  architectures

Family: ACP_syn_III (PF08545)

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...

Beta-ketoacyl-%28acyl-carrier-protein%29 synthase III Edit Wikipedia article

β-ketoacyl-(acyl-carrier-protein) synthase III
Identifiers
EC number 2.3.1.180
CAS number 9077-10-5
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO
3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III
PDB 1ebl EBI.jpg
Structure and active-site architecture of beta-ketoacyl-acyl carrier protein synthase III (FabH) from escherichia coli.[1]
Identifiers
Symbol ACP_syn_III
Pfam PF08545
InterPro IPR013751

In enzymology, a β-ketoacyl-[acyl-carrier-protein] synthase III (EC 2.3.1.180) is an enzyme that catalyzes the chemical reaction

acetyl-CoA + malonyl-[acyl carrier protein] acetoacetyl-[acyl carrier protein] + CoA + CO2

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. β-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,[2] Streptococcus pneumoniae,[3] and Streptomyces coelicolor.[4]

Nomenclature

The systematic name of this enzyme class is acetyl-CoA:malonyl-[acyl-carrier-protein] C-acyltransferase. Other names in common use include:

  • 3-Oxoacyl:ACP synthase III
  • 3-Ketoacyl-acyl carrier protein synthase III,
  • KASIII
  • KAS III
  • FabH
  • β-Ketoacyl-acyl carrier protein synthase III
  • β-Ketoacyl-ACP synthase III
  • β-Ketoacyl (acyl carrier protein) synthase III
  • β-Ketoacyl-acyl-carrier-protein synthase III.

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.[5] According to in silico flux balance analyses,[6] mtFabH is essential but not according to transposon site hybridization analysis.[7] 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 structure of mtFabH. The enzyme is a homodimer of mixed α-helices and β-sheets, or a thiolase fold. The catalytic triads of C122, H258, and N289 are shown in colour and are largely buried in hydrophobic pockets.

Crystal structures of FabH have been reported from Mycobacterium tuberculosis,[1]{[8][9] Staphylococcus aureus,[10] Escherichia coli,[11] and Thermus thermophilus.[12]

The catalytic activity and substrate specificity of mtFabH has been measured[13] then further probed using crystallographic and directed mutagenesis methods[14] Structures have been determined of ecFabH bound with substrates, (CoA, malonyl CoA, degraded CoA).[8] Specific inhibitors developed using rational design have recently been reported.[15][16][17] In 2005, the structure of a catalytically disabled mtFabH mutant with lauroyl-CoA was reported.[18]

Native mtFabH is a homodimer with Mr = 77 ± 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.[19]

Substrate specificity of mtFabH in relation to acyl-CoA chain length. The optimum length is lauroyl-CoA, C12.

Inhibitors

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.[20] Derivatives of TLM and related compounds are being screened to improve efficacy.[21][22][23][24]

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.[19]

Following the discovery that phomallenic acids isolated from a leaf litter fungus identified as Phoma sp. are inhibitors of the FabH/FabF.[25][26] 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.[27] 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.[28]

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.[29][30]

Therapeutic potential

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.[31][32] 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$16–35 will buy a full six-month drug course[33] Nevertheless, new drugs are in clinical trials.[34][35]

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.[36][37]

References

  1. ^ a b 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): 185–95. PMID 10673437. doi:10.1016/S0969-2126(00)00094-0. 
  2. ^ Han L, Lobo S, Reynolds KA (1998). "Characterization of β-Ketoacyl-Acyl Carrier Protein Synthase III from Streptomyces glaucescens and Its Role in Initiation of Fatty Acid Biosynthesis". J. Bacteriol. 180 (17): 4481–6. PMC 107458Freely accessible. PMID 9721286. 
  3. ^ 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): 30024–30. PMID 11375394. doi:10.1074/jbc.M101769200. 
  4. ^ 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): 3795–9. PMC 1112031Freely accessible. PMID 15901703. doi:10.1128/JB.187.11.3795-3799.2005. 
  5. ^ 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): 1442–54. PMID 17555433. doi:10.1111/j.1365-2958.2007.05761.x. 
  6. ^ 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. PMC 1246807Freely accessible. PMID 16261191. doi:10.1371/journal.pcbi.0010046. 
  7. ^ Sassetti CM, Boyd DH, Rubin EJ (April 2003). "Genes required for mycobacterial growth defined by high density mutagenesis". Mol. Microbiol. 48 (1): 77–84. PMID 12657046. doi:10.1046/j.1365-2958.2003.03425.x. 
  8. ^ a b PDB: 1HND​, 1HNH​, 1HNJ​; 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): 341–56. PMID 11243824. doi:10.1006/jmbi.2000.4457. 
  9. ^ PDB: 1HZP​; 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): 20516–22. PMID 11278743. doi:10.1074/jbc.M010762200. 
  10. ^ PDB: 1ZOW​; Qiu X, Choudhry AE, Janson CA, Grooms M, Daines RA, Lonsdale JT, Khandekar SS (August 2005). "Crystal structure and substrate specificity of the β-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus". Protein Sci. 14 (8): 2087–94. PMC 2279320Freely accessible. PMID 15987898. doi:10.1110/ps.051501605. 
  11. ^ PDB: 1HN9​; 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): 36465–71. PMID 10593943. doi:10.1074/jbc.274.51.36465. 
  12. ^ PDB: 1UB7​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.
  13. ^ 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): 28201–7. PMID 10840036. doi:10.1074/jbc.M003241200. 
  14. ^ PDB: 1M1M​, 2AJ9​; 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): 32539–47. PMID 16040614. doi:10.1074/jbc.M413216200. 
  15. ^ PDB: 1MZS​; 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): 5–8. PMID 12502353. doi:10.1021/jm025571b. 
  16. ^ 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): 1596–609. PMID 15743201. doi:10.1021/jm049141s. 
  17. ^ 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): 1474–82. PMID 16275103. doi:10.1016/j.bmc.2005.10.001. 
  18. ^ PDB: 1U6S​; 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): 1313–21. PMID 15713483. doi:10.1016/j.jmb.2004.12.044. 
  19. ^ a b Veyron-Churlet R, Molle V, Taylor RC, Brown AK, Besra GS, Zanella-Cléon I, Fütterer K, Kremer L (March 2009). "The Mycobacterium tuberculosis β-Ketoacyl-Acyl Carrier Protein Synthase III Activity Is Inhibited by Phosphorylation on a Single Threonine Residue". J. Biol. Chem. 284 (10): 6414–24. PMC 2649087Freely accessible. PMID 19074144. doi:10.1074/jbc.M806537200. 
  20. ^ 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): 197–225. PMID 12164478. doi:10.2174/1389201023378328. 
  21. ^ 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): 3685–8. PMID 14552758. doi:10.1016/j.bmcl.2003.08.015. 
  22. ^ 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): 373–6. PMID 14698162. doi:10.1016/j.bmcl.2003.10.061. 
  23. ^ 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): 3093–102. PMC 478545Freely accessible. PMID 15273125. doi:10.1128/AAC.48.8.3093-3102.2004. 
  24. ^ 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 β-Ketoacyl-ACP Synthase mtFabH". PLoS ONE. 4 (5): e5617. Bibcode:2009PLoSO...4.5617A. PMC 2680598Freely accessible. PMID 19440303. doi:10.1371/journal.pone.0005617. 
  25. ^ 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): 519–26. PMC 1366929Freely accessible. PMID 16436705. doi:10.1128/AAC.50.2.519-526.2006. 
  26. ^ 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): 377–80. PMID 16562839. doi:10.1021/np050416w. 
  27. ^ 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, González 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): 7612–6. Bibcode:2007PNAS..104.7612W. PMC 1863502Freely accessible. PMID 17456595. doi:10.1073/pnas.0700746104. 
  28. ^ Brown AK, Taylor RC, Bhatt A, Fütterer K, Besra GS (2009). Ahmed N, ed. "Platensimycin Activity against Mycobacterial β-Ketoacyl-ACP Synthases". PLoS ONE. 4 (7): e6306. Bibcode:2009PLoSO...4.6306B. PMC 2707616Freely accessible. PMID 19609444. doi:10.1371/journal.pone.0006306. 
  29. ^ Viader-Salvadó JM, Garza-González E, Valdez-Leal R, del Bosque-Moncayo MA, Tijerina-Menchaca R, Guerrero-Olazarán M (July 2001). "Mycolic Acid Index Susceptibility Method for Mycobacterium tuberculosis". J. Clin. Microbiol. 39 (7): 2642–5. PMC 88200Freely accessible. PMID 11427584. doi:10.1128/JCM.39.7.2642-2645.2001. 
  30. ^ 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): 107–14. PMID 10860506. doi:10.1006/abio.2000.4594. 
  31. ^ 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): 1009–21. PMID 12742798. doi:10.1001/archinte.163.9.1009. 
  32. ^ "Global Tuberculosis Control 2007". World Health Organization. 2007. Archived from the original on 2010-02-02. Retrieved 2010-01-02. 
  33. ^ "TB Alliance — An Outdated Treatment". Global Alliance for TB Drug Development. Archived from the original on 2010-01-13. Retrieved 2010-01-02. 
  34. ^ Casenghi M, Cole ST, Nathan CF (November 2007). "New Approaches to Filling the Gap in Tuberculosis Drug Discovery". PLoS Med. 4 (11): e293. PMC 2062479Freely accessible. PMID 17988169. doi:10.1371/journal.pmed.0040293. 
  35. ^ "TB Alliance — TB Drug Portfolio". Global Alliance for TB Drug Development. Archived from the original on 2010-01-13. Retrieved 2010-01-02. 
  36. ^ "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. 
  37. ^ "The Economics of TB Drug Development" (PDF). Global Alliance for TB Drug Development. 2001. Retrieved 2010-01-02. 

Further reading

  • Tsay JT, Oh W, Larson TJ, Jackowski S, Rock CO (1992). "Isolation and characterization of the beta-ketoacyl-acyl carrier protein synthase III gene (fabH) from Escherichia coli K-12". J. Biol. Chem. 267 (10): 6807–14. PMID 1551888. 

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.

3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III Provide feedback

This domain is found on 3-Oxoacyl-[acyl-carrier-protein (ACP)] synthase III EC:2.3.1.180, the enzyme responsible for initiating the chain of reactions of the fatty acid synthase in plants and bacteria.

Literature references

  1. 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

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. Acyl-[ACP] + malonyl-[ACP] = 3-oxoacyl-[ACP] + CO(2) + [ACP] The oxoacyl-ACP formed by this reaction subsequently enters the elongation cycle, where the acyl chain is progressively lengthened by the combined activities of several enzymes.

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.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

Loading domain graphics...

Pfam Clan

This family is a member of clan Thiolase (CL0046), which has the following description:

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 [1]. 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 16 members:

ACP_syn_III ACP_syn_III_C Chal_sti_synt_C Chal_sti_synt_N Docking FAE1_CUT1_RppA HMG_CoA_synt_C HMG_CoA_synt_N KAsynt_C_assoc ketoacyl-synt Ketoacyl-synt_2 Ketoacyl-synt_C PikAIV_N SpoVAD Thiolase_C Thiolase_N

Alignments

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...

View options

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.

  Seed
(136)
Full
(13023)
Representative proteomes UniProt
(37062)
NCBI
(62779)
Meta
(1879)
RP15
(2636)
RP35
(7470)
RP55
(11776)
RP75
(17071)
Jalview View  View  View  View  View  View  View  View  View 
HTML View                 
PP/heatmap 1                

1Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: ✓ available, x not generated, not available.

Format an alignment

  Seed
(136)
Full
(13023)
Representative proteomes UniProt
(37062)
NCBI
(62779)
Meta
(1879)
RP15
(2636)
RP35
(7470)
RP55
(11776)
RP75
(17071)
Alignment:
Format:
Order:
Sequence:
Gaps:
Download/view:

Download options

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.

  Seed
(136)
Full
(13023)
Representative proteomes UniProt
(37062)
NCBI
(62779)
Meta
(1879)
RP15
(2636)
RP35
(7470)
RP55
(11776)
RP75
(17071)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

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...

Trees

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.

Curation View help on the curation process

Seed source: Pfam-B_135 (release 18.0)
Previous IDs: none
Type: Domain
Sequence Ontology: SO:0000417
Author: Mistry J
Number in seed: 136
Number in full: 13023
Average length of the domain: 80.20 aa
Average identity of full alignment: 34 %
Average coverage of the sequence by the domain: 23.38 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.6 20.6
Trusted cut-off 20.6 20.6
Noise cut-off 20.5 20.5
Model length: 80
Family (HMM) version: 10
Download: download the raw HMM for this family

Species distribution

Sunburst controls

Hide

Weight segments by...


Change the size of the sunburst

Small
Large

Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

Align selected sequences to HMM

Generate a FASTA-format file

Clear selection

This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

Loading sunburst data...

Tree controls

Hide

The tree shows the occurrence of this domain across different species. More...

Loading...

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.

Interactions

There are 3 interactions for this family. More...

ACP_syn_III ACP_syn_III_C ACP_syn_III_C

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 ACP_syn_III domain has been found. There are 177 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...