| 3-oxoacyl-ACP synthase, mitochondrial | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | OXSM | ||||||
| NCBI gene | 54995 | ||||||
| HGNC | 26063 | ||||||
| OMIM | 610324 | ||||||
| RefSeq | NM_017897 | ||||||
| UniProt | Q9NWU1 | ||||||
| Other data | |||||||
| EC number | 2.3.1.41 | ||||||
| Locus | Chr. 3p24.2 | ||||||
| |||||||
| Beta-ketoacyl synthase, N-terminal domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 the crystal structure of beta-ketoacyl-[acyl carrier protein] synthase ii from streptococcus pneumoniae, triclinic form | |||||||||
| Identifiers | |||||||||
| Symbol | ketoacyl-synt | ||||||||
| Pfam | PF00109 | ||||||||
| Pfam clan | CL0046 | ||||||||
| InterPro | IPR014030 | ||||||||
| PROSITE | PDOC00529 | ||||||||
| SCOP2 | 1kas /SCOPe /SUPFAM | ||||||||
| |||||||||
| Beta-ketoacyl synthase, C-terminal domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 arabidopsis thaliana mitochondrial beta-ketoacyl acp synthase hexanoic acid complex | |||||||||
| Identifiers | |||||||||
| Symbol | Ketoacyl-synt_C | ||||||||
| Pfam | PF02801 | ||||||||
| Pfam clan | CL0046 | ||||||||
| InterPro | IPR014031 | ||||||||
| PROSITE | PDOC00529 | ||||||||
| SCOP2 | 1kas /SCOPe /SUPFAM | ||||||||
| |||||||||
In molecular biology,Beta-ketoacyl-ACP synthaseEC2.3.1.41, is anenzyme involved infatty acid synthesis. It typically usesmalonyl-CoA as a carbon source to elongate ACP-boundacyl species, resulting in the formation of ACP-bound β-ketoacyl species such asacetoacetyl-ACP.[1]
Beta-ketoacyl-ACPsynthase is a highlyconserved enzyme that is found in almost all life onearth as adomain infatty acid synthase (FAS). FAS exists in two types, aptly named type I and II. Inanimals,fungi, and lowereukaryotes, Beta-ketoacyl-ACP synthases make up one of the catalytic domains of larger multifunctional proteins (Type I), whereas in mostprokaryotes as well as inplastids andmitochondria, Beta-ketoacyl-ACP synthases are separate protein chains that usually form dimers (Type II).[1][2]Beta-ketoacyl-ACP synthase III, perhaps the most well known of this family of enzymes,catalyzes aClaisen condensation betweenacetyl CoA andmalonyl 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 14carbon chain, at which point synthase II is the more efficient choice for further carbon additions. Type I FAS catalyzes all the reactions necessary to createpalmitic acid, which is a necessary function in animals formetabolic processes, one of which includes the formation ofsphingosines.[1]
Beta-ketoacyl-ACP synthase is found as a component of a number of enzymatic systems, includingfatty acid synthetase (FAS); the multi-functional 6-methysalicylic acid synthase (MSAS) fromPenicillium patulum,[3] which is involved in thebiosynthesis of apolyketideantibiotic; polyketide antibiotic synthase enzyme systems;Emericella nidulans multifunctionalprotein Wa, which is involved in the biosynthesis ofconidial greenpigment;Rhizobium nodulation protein nodE, which probably acts as a beta-ketoacyl synthase in the synthesis of the nodulationNod factor fatty acyl chain; andyeast mitochondrial protein CEM1.
Beta-ketoacyl synthase contains twoprotein domains. Theactive site is located between theN- andC-terminal domains. The N-terminal domain contains most of the structures involved indimer formation and also theactive sitecysteine. Residues from both domains contribute tosubstratebinding and catalysis[4]
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 inplants have been documented to have a range ofsubstrate specificities.[1] The presence of similar ketoacyl synthases present in all livingorganisms point to acommon ancestor.[5] Further examination of beta-ketoacyl-ACP synthases I and II ofE. coli revealed that both arehomodimeric, but synthase II is slightly larger. However, even though they are both involved infatty acid metabolism, they also have highly divergentprimary structure.[6] In synthase II, each subunit consists of a five-strandedbeta pleated sheet surrounded by multiplealpha helices, shown in the image on the left. The active sites are relatively close, only about 25angstroms apart, and consist of a mostlyhydrophobic pocket.[4] Certainexperiments have also suggested the presence of "fatty acid transport tunnels" within the beta-ketoacyl-ACP synthase domain that lead to one of many "fatty acid cavities", which essentially acts as the active site.[7]
Beta-ketoacyl-synthase’smechanism is a topic of debate among chemists. Many agree thatCys171 of the active site attacks acetyl ACP'scarbonyl, and, like most enzymes, stabilizes theintermediate with otherresidues in the active site.ACP is subsequently eliminated, and it deprotonatesHis311 in the process. Athioester is then regenerated with the cysteine in the active site.Decarboxylation of a malonyl CoA that is also in the active site initially creates anenolate, which is stabilized by His311 and His345. The enolatetautomerizes to acarbanion that attacks the thioester of the acetyl-enzyme complex.[8] Some sources speculate that an activatedwater molecule also resides in the active site as a means of hydrating the releasedCO2 or of attacking C3 of malonyl CoA. Another proposed mechanism considers the creation of atetrahedraltransition state.[1] The driving force of the reaction comes from the decarboxylation of malonyl ACP; theenergy captured in that bond technically comes fromATP, which is what is initially used tocarboxylate acetyl CoA to malonyl CoA.[9]
The main function of beta-ketoacyl-ACP synthase is to producefatty acids of various lengths for use by the organism. These uses includeenergy storage and creation ofcell membranes. Fatty acids can also be used tosynthesizeprostaglandins,phospholipids, andvitamins, 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 aprecursor of bothstearic andpalmitoleic acids. Palmitoleic can subsequently be used to create a number of other fatty acids.[10] Palmitic acid is also used to synthesizesphingosines, which play a role in cell membranes.[1]
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 surroundinglipoprotein,phospholipid, andlipopolysaccharide synthesis, they have become a target inantibacterial drug development. In order to adapt to theirenvironment,bacteria alter the phospholipid composition of their membranes.Inhibiting thispathway may thus be a leverage point in disruptingbacterial proliferation.[11] By studyingYersinia pestis, which causesbubonic,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 theirbinding sites. However, such a drug has not yet been developed.[12]Cerulenin, a molecule that appears to inhibit by mimicking the "condensation transition state" can only inhibit B or F, but not H. Another molecule, thiolactomycin, which mimics malonyl ACP in the active site, can only inhibit FabB.[13] Lastly,platensimycin also has possible antibiotic use due to its inhibition of FabF.[14]
These types of drugs are highly relevant. For example,Y. pestis was the main agent in theJustinian Plague,Black Death, and the modern plague. Even within the last five years,China,Peru, andMadagascar all experienced anoutbreak of infection byY. 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 possiblebiological warfareweapon.[12]
Unfortunately, many drugs that target prokaryotic beta-ketoacyl-synthases carry manyside 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 manybiological consequences for humans.[2]
Recent efforts inbioengineering include engineering of FAS proteins, which includes beta-ketoacyl-ACP synthase domains, in order to favor the synthesis ofbranched carbon chains as arenewable energy source. Branched carbon chains contain more energy and can be used incolder temperatures because of their lowerfreezing point. Using E. coli as the organism of choice, engineers have replaced the endogenous FabH domain on FAS, which favorsunbranched chains, with FabH versions that favor branching due to their high substrate specificity for branched acyl-ACPs.[15]