Summary: Beta-ketoacyl synthase, C-terminal domain
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Beta-ketoacyl-ACP synthase Edit Wikipedia article
|3-oxoacyl-ACP synthase, mitochondrial|
|Locus||Chr. 3 p24.2|
|Beta-ketoacyl synthase, N-terminal domain|
the crystal structure of beta-ketoacyl-[acyl carrier protein] synthase ii from streptococcus pneumoniae, triclinic form
|SCOPe||1kas / SUPFAM|
|Beta-ketoacyl synthase, C-terminal domain|
arabidopsis thaliana mitochondrial beta-ketoacyl acp synthase hexanoic acid complex
|SCOPe||1kas / SUPFAM|
In molecular biology, Beta-ketoacyl-ACP synthase EC 188.8.131.52, is an enzyme involved in fatty acid synthesis. It typically uses malonyl-CoA as a carbon source to elongate ACP-bound acyl species, resulting in the formation of ACP-bound Î²-ketoacyl species such as acetoacetyl-ACP.
Beta-ketoacyl-ACP synthase is a highly conserved enzyme that is found in almost all life on earth as a domain in fatty acid synthase (FAS). FAS exists in two types, aptly named type I and II. In animals, fungi, and lower eukaryotes, Beta-ketoacyl-ACP synthases make up one of the catalytic domains of larger multifunctional proteins (Type I), whereas in most prokaryotes as well as in plastids and mitochondria, Beta-ketoacyl-ACP synthases are separate protein chains that usually form dimers (Type II). Beta-ketoacyl-ACP synthase III, perhaps the most well known of this family of enzymes, catalyzes a Claisen condensation between acetyl CoA and malonyl ACP. The image below reveals how CoA fits in the active site as a substrate of synthase III.
Beta-ketoacyl-ACP synthases I and II only catalyze acyl-ACP reactions with malonyl ACP. Synthases I and II are capable of producing long-chain acyl-ACPs. Both are efficient up to acyl-ACPs with a 14 carbon chain, at which point synthase II is the more efficient choice for further carbon additions. Type I FAS catalyzes all the reactions necessary to create palmitic acid, which is a necessary function in animals for metabolic processes, one of which includes the formation of sphingosines.
Beta-ketoacyl-ACP synthase is found as a component of a number of enzymatic systems, including fatty acid synthetase (FAS); the multi-functional 6-methysalicylic acid synthase (MSAS) from Penicillium patulum, which is involved in the biosynthesis of a polyketide antibiotic; polyketide antibiotic synthase enzyme systems; Emericella nidulans multifunctional protein Wa, which is involved in the biosynthesis of conidial green pigment; Rhizobium nodulation protein nodE, which probably acts as a beta-ketoacyl synthase in the synthesis of the nodulation Nod factor fatty acyl chain; and yeast mitochondrial protein CEM1.
Beta-ketoacyl synthase contains two protein domains. The active site is located between the N- and C-terminal domains. The N-terminal domain contains most of the structures involved in dimer formation and also the active site cysteine. Residues from both domains contribute to substrate binding and catalysis
In animals and in prokaryotes, beta-ketoacyl-ACP synthase is a domain on type I FAS, which is a large enzyme complex that has multiple domains to catalyze multiple different reactions. Analogously, beta-ketoacyl-ACP synthase in plants is found in type II FAS; note that synthases in plants have been documented to have a range of substrate specificities. The presence of similar ketoacyl synthases present in all living organisms point to a common ancestor. Further examination of beta-ketoacyl-ACP synthases I and II of E. coli revealed that both are homodimeric, but synthase II is slightly larger. However, even though they are both involved in fatty acid metabolism, they also have highly divergent primary structure. In synthase II, each subunit consists of a five-stranded beta pleated sheet surrounded by multiple alpha helices, shown in the image on the left. The active sites are relatively close, only about 25 angstroms apart, and consist of a mostly hydrophobic pocket. Certain experiments have also suggested the presence of â€œfatty acid transport tunnelsâ€ within the beta-ketoacyl-ACP synthase domain that lead to one of many â€œfatty acid cavitiesâ€, which essentially acts as the active site.
Beta-ketoacyl-synthaseâ€™s mechanism is a topic of debate among chemists. Many agree that Cys171 of the active site attacks acetyl ACP's carbonyl, and, like most enzymes, stabilizes the intermediate with other residues in the active site. ACP is subsequently eliminated, and it deprotonates His311 in the process. A thioester is then regenerated with the cysteine in the active site. Decarboxylation of a malonyl CoA that is also in the active site initially creates an enolate, which is stabilized by His311 and His345. The enolate tautomerizes to a carbanion that attacks the thioester of the acetyl-enzyme complex. Some sources speculate that an activated water molecule also resides in the active site as a means of hydrating the released CO2 or of attacking C3 of malonyl CoA. Another proposed mechanism considers the creation of a tetrahedral transition state. The driving force of the reaction comes from the decarboxylation of malonyl ACP; the energy captured in that bond technically comes from ATP, which is what is initially used to carboxylate acetyl CoA to malonyl CoA.
The main function of beta-ketoacyl-ACP synthase is to produce fatty acids of various lengths for use by the organism. These uses include energy storage and creation of cell membranes. Fatty acids can also be used to synthesize prostaglandins, phospholipids, and vitamins, among many other things. Further, palmitic acid, which is created by the beta-ketoacyl-synthases on type I FAS, is used in a number of biological capacities. It is a precursor of both stearic and palmitoleic acids. Palmitoleic can subsequently be used to create a number of other fatty acids. Palmitic acid is also used to synthesize sphingosines, which play a role in cell membranes.
The different types of beta-ketoacyl-ACP synthases in type II FAS are called FabB, FabF, and FabH synthases. FabH catalyzes the quintessential ketoacyl synthase reaction with malonyl ACP and acetyl CoA. FabB and FabF catalyze other related reactions. Given that their function is necessary for proper biological function surrounding lipoprotein, phospholipid, and lipopolysaccharide synthesis, they have become a target in antibacterial drug development. In order to adapt to their environment, bacteria alter the phospholipid composition of their membranes. Inhibiting this pathway may thus be a leverage point in disrupting bacterial proliferation. By studying Yersinia pestis, which causes bubonic, pneumonic, and septicaemic plagues, researchers have shown that FabB, FabF, and FabH can theoretically all be inhibited by the same drug due to similarities in their binding sites. However, such a drug has not yet been developed. Cerulenin, a molecule that appears to inhibit by mimicking the â€œcondensation transition stateâ€ can only inhibit B or F, but not H. Another molecule, thiolactomycin, which mimics malonyl ACP in the active site, can ony inhibit FabB. Lastly, platensimycin also has possible antibiotic use due to its inhibition of FabF.
These types of drugs are highly relevant. For example, Y. pestis was the main agent in the Justinian Plague, Black Death, and the modern plague. Even within the last five years, China, Peru, and Madagascar all experienced an outbreak of infection by Y. pestis. If it is not treated within 24 hours, it normally results in death. Furthermore, there is worry that it can now be used as a possible biological warfare weapon.
Unfortunately, many drugs that target prokaryotic beta-ketoacyl-synthases carry many side effects. Given the similarities between prokaryotic ketoacyl synthases and mitochondrial ones, these types of drugs tend to unintentionally also act upon mitochondrial synthases, leading to many biological consequences for humans.
Recent efforts in bioengineering include engineering of FAS proteins, which includes beta-ketoacyl-ACP synthase domains, in order to favor the synthesis of branched carbon chains as a renewable energy source. Branched carbon chains contain more energy and can be used in colder temperatures because of their lower freezing point. Using E. coli as the organism of choice, engineers have replaced the endogenous FabH domain on FAS, which favors unbranched chains, with FabH versions that favor branching due to their high substrate specificity for branched acyl-ACPs.
- Beta-ketoacyl-acyl-carrier-protein synthase I
- Beta-ketoacyl-acyl-carrier-protein synthase II
- 3-oxoacyl-(acyl-carrier-protein) reductase
- Witkowski, Andrzej; Joshi, Anil K.; Smith, Stuart (2002). "Mechanism of the Î²-Ketoacyl Synthase Reaction Catalyzed by the Animal Fatty Acid Synthase â€ ". Biochemistry. 41 (35): 10877â€“10887. doi:10.1021/bi0259047. PMID 12196027.
- Christensen, Caspar Elo; Kragelund, Birthe B.; von Wettstein-Knowles, Penny; Henriksen, Anette (2007-02-01). "Structure of the human Î²-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase". Protein Science. 16 (2): 261â€“272. doi:10.1110/ps.062473707. ISSN 0961-8368. PMC 2203288. PMID 17242430.
- Beck J, Ripka S, Siegner A, Schiltz E, Schweizer E (Sep 1990). "The multifunctional 6-methylsalicylic acid synthase gene of Penicillium patulum. Its gene structure relative to that of other polyketide synthases". European Journal of Biochemistry / FEBS. 192 (2): 487â€“98. doi:10.1111/j.1432-1033.1990.tb19252.x. PMID 2209605.
- Huang W, Jia J, Edwards P, Dehesh K, Schneider G, Lindqvist Y (Mar 1998). "Crystal structure of beta-ketoacyl-acyl carrier protein synthase II from E.coli reveals the molecular architecture of condensing enzymes". The EMBO Journal. 17 (5): 1183â€“91. doi:10.1093/emboj/17.5.1183. PMC 1170466. PMID 9482715.
- Beld, Joris; Blatti, Jillian L.; Behnke, Craig; Mendez, Michael; Burkart, Michael D. (2014-08-01). "Evolution of acyl-ACP-thioesterases and Î²-ketoacyl-ACP-synthases revealed by protein-protein interactions". Journal of Applied Phycology. 26 (4): 1619â€“1629. doi:10.1007/s10811-013-0203-4. ISSN 0921-8971. PMC 4125210. PMID 25110394.
- Garwin, J. L.; Klages, A. L.; Cronan, J. E. (1980-12-25). "Structural, enzymatic, and genetic studies of beta-ketoacyl-acyl carrier protein synthases I and II of Escherichia coli". Journal of Biological Chemistry. 255 (24): 11949â€“11956. ISSN 0021-9258. PMID 7002930.
- Cui, Wei; Liang, Yan; Tian, Weixi; Ji, Mingjuan; Ma, Xiaofeng (2016-03-01). "Regulating effect of Î²-ketoacyl synthase domain of fatty acid synthase on fatty acyl chain length in de novo fatty acid synthesis" (PDF). Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1861 (3): 149â€“155. doi:10.1016/j.bbalip.2015.12.002. PMID 26680361.
- Lee, Wook; Engels, Bernd (2014). "The Protonation State of Catalytic Residues in the Resting State of KasA Revisited: Detailed Mechanism for the Activation of KasA by Its Own Substrate". Biochemistry. 53 (5): 919â€“931. doi:10.1021/bi401308j. PMID 24479625.
- Tymoczko, John; Berg; Stryer (2013). Biochemistry A Short Course. United States of America: W.H. Freeman and Company. ISBN 978-1-4292-8360-1.
- "Palmitic acid, a saturated fatty acid, in Cell Culture". Sigma-Aldrich. Retrieved 2016-02-29.
- Zhang, Yong-Mei; Rock, Charles O. (2008-03-01). "Membrane lipid homeostasis in bacteria". Nature Reviews Microbiology. 6 (3): 222â€“233. doi:10.1038/nrmicro1839. ISSN 1740-1526. PMID 18264115.
- Nanson, Jeffrey D.; Himiari, Zainab; Swarbrick, Crystall M. D.; Forwood, Jade K. (2015-10-15). "Structural Characterisation of the Beta-Ketoacyl-Acyl Carrier Protein Synthases, FabF and FabH, of Yersinia pestis". Scientific Reports. 5: 14797. Bibcode:2015NatSR...514797N. doi:10.1038/srep14797. PMC 4606726. PMID 26469877.
- Price, Allen C.; Choi, Keum-Hwa; Heath, Richard J.; Li, Zhenmei; White, Stephen W.; Rock, Charles O. (2001-03-02). "Inhibition of Î²-Ketoacyl-Acyl Carrier Protein Synthases by Thiolactomycin and Cerulenin STRUCTURE AND MECHANISM". Journal of Biological Chemistry. 276 (9): 6551â€“6559. doi:10.1074/jbc.M007101200. ISSN 0021-9258. PMID 11050088.
- Wright, H Tonie; Reynolds, Kevin A (2007-10-01). "Antibacterial targets in fatty acid biosynthesis". Current Opinion in Microbiology. Antimicrobials/Genomics. 10 (5): 447â€“453. doi:10.1016/j.mib.2007.07.001. PMC 2271077. PMID 17707686.
- Jiang, Wen; Jiang, Yanfang; Bentley, Gayle J.; Liu, Di; Xiao, Yi; Zhang, Fuzhong (2015-08-01). "Enhanced production of branched-chain fatty acids by replacing Î²-ketoacyl-(acyl-carrier-protein) synthase III (FabH)". Biotechnology and Bioengineering. 112 (8): 1613â€“1622. doi:10.1002/bit.25583. ISSN 1097-0290. PMID 25788017.
- Jiang W, Jiang Y, Bentley GJ, Liu D, Xiao Y, Zhang F (Aug 2015). "Enhanced production of branched-chain fatty acids by replacing Î²-ketoacyl-(acyl-carrier-protein) synthase III (FabH)". Biotechnology and Bioengineering. 112 (8): 1613â€“22. doi:10.1002/bit.25583. PMID 25788017.
- Witkowski A, Joshi AK, Smith S (Sep 2002). "Mechanism of the beta-ketoacyl synthase reaction catalyzed by the animal fatty acid synthase". Biochemistry. 41 (35): 10877â€“87. doi:10.1021/bi0259047. PMID 12196027.
- Christensen CE, Kragelund BB, von Wettstein-Knowles P, Henriksen A (Feb 2007). "Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial type II fatty acid synthase". Protein Science. 16 (2): 261â€“72. doi:10.1110/ps.062473707. PMC 2203288. PMID 17242430.
- Lee W, Engels B (Feb 2014). "The protonation state of catalytic residues in the resting state of KasA revisited: detailed mechanism for the activation of KasA by its own substrate". Biochemistry. 53 (5): 919â€“31. doi:10.1021/bi401308j. PMID 24479625.
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Beta-ketoacyl synthase, C-terminal domain Provide feedback
The structure of beta-ketoacyl synthase is similar to that of the thiolase family (PF00108) and also chalcone synthase. The active site of beta-ketoacyl synthase is located between the N and C-terminal domains.
Huang W, Jia J, Edwards P, Dehesh K, Schneider G, Lindqvist Y; , EMBO J 1998;17:1183-1191.: Crystal structure of beta-ketoacyl-acyl carrier protein synthase II from E.coli reveals the molecular architecture of condensing enzymes. PUBMED:9482715 EPMC:9482715
Internal database links
|Similarity to PfamA using HHSearch:||Thiolase_C|
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR014031
Beta-ketoacyl-ACP synthase EC (KAS) [PUBMED:3076376] is the enzyme that catalyzes the condensation of malonyl-ACP with the growing fatty acid chain. It is found as a component of a number of enzymatic systems, including fatty acid synthetase (FAS), which catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH; the multi-functional 6-methysalicylic acid synthase (MSAS) from Penicillium patulum [PUBMED:2209605], which is involved in the biosynthesis of a polyketide antibiotic; polyketide antibiotic synthase enzyme systems; Emericella nidulans multifunctional protein Wa, which is involved in the biosynthesis of conidial green pigment; Rhizobium nodulation protein nodE, which probably acts as a beta-ketoacyl synthase in the synthesis of the nodulation Nod factor fatty acyl chain; and yeast mitochondrial protein CEM1. The condensation reaction is a two step process, first the acyl component of an activated acyl primer is transferred to a cysteine residue of the enzyme and is then condensed with an activated malonyl donor with the concomitant release of carbon dioxide.
This entry represents the C-terminal domain of beta-ketoacyl-ACP synthases. The active site is contained in a cleft betweeen N- and C-terminal domains, with residues from both domains contributing to substrate binding and catalysis [PUBMED:11152607].
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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 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
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|Author:||Sonnhammer ELL , Griffiths-Jones SR|
|Number in seed:||85|
|Number in full:||41902|
|Average length of the domain:||115.50 aa|
|Average identity of full alignment:||34 %|
|Average coverage of the sequence by the domain:||9.41 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||22|
|Download:||download the raw HMM for this family|
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There are 5 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 Ketoacyl-synt_C domain has been found. There are 315 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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