Summary: Diaminopimelate epimerase
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Diaminopimelate epimerase Edit Wikipedia article
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
- LL-2,6-diaminoheptanedioate meso-diaminoheptanedioate
This enzyme belongs to the family of isomerases, specifically those racemases and epimerases acting on amino acids and derivatives. The systematic name of this enzyme class is LL-2,6-diaminoheptanedioate 2-epimerase. This enzyme participates in lysine biosynthesis.
Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids - lysine, threonine, methionine and isoleucine - in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not possess this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see.
The lysine/diaminopimelic acid branch of the aspartate pathway produces the essential amino acid lysine via the intermediate meso-diaminopimelic acid (meso-DAP), which is also a vital cell wall component in Gram-negative bacteria. The production of dihydropicolinate from aspartate-semialdehyde controls flux into the lysine/diaminopimelic acid pathway. Three variants of this pathway exist, differing in how tetrahydropicolinate (formed by reduction of dihydropicolinate) is metabolised to meso-DAP. One variant, the most commonly found one in archaea and bacteria, uses primarily succinyl intermediates, while a second variant, found only in Bacillus, utilises primarily acetyl intermediates. In the third variant, found in some Gram-positive bacteria, a dehydrogenase converts tetrahydropicolinate directly to meso-DAP. In all variants meso-DAP is subsequently converted to lysine by a decarboxylase, or, in Gram-negative bacteria, assimilated into the cell wall. Evidence exists that a fourth, currently unknown, variant of this pathway may function in plants.
Diaminopimelate epimerase (EC 220.127.116.11), which catalyses the isomerisation of L,L-dimaminopimelate to meso-DAP in the biosynthetic pathway leading from aspartate to lysine. It is a member of the broader family of PLP-independent amino acid racemases. This enzyme is a monomeric protein of about 30 kDa consisting of two domains which are homologus in structure though they share little sequence similarity. Each domain consists of mixed beta-sheets which fold into a barrel around the central helix. The active site cleft is formed from both domains and contains two conserved cysteines thought to function as the acid and base in the catalytic reaction. Other PLP-independent racemases such as glutamate racemase have been shown to share a similar structure and mechanism of catalysis.
 Structural studies
- Viola RE (2001). "The central enzymes of the aspartate family of amino acid biosynthesis". Acc. Chem. Res. 34 (5): 339–49. doi:10.1021/ar000057q. PMID 11352712.
- Blanchard JS, Born TL (1999). "Structure/function studies on enzymes in the diaminopimelate pathway of bacterial cell wall biosynthesis". Curr Opin Chem Biol 3 (5): 607–13. PMID 10508663.
- Leustek T, Hudson AO, Bless C, Macedo P, Chatterjee SP, Singh BK, Gilvarg C (2005). "Biosynthesis of lysine in plants: evidence for a variant of the known bacterial pathways". Biochim. Biophys. Acta 1721 (1): 27–36. doi:10.1016/j.bbagen.2004.09.008. PMID 15652176.
- Scapin G, Blanchard JS, Cirilli M, Zheng R (1998). "Structural symmetry: the three-dimensional structure of Haemophilus influenzae diaminopimelate epimerase". Biochemistry 37 (47): 16452–16458. doi:10.1021/bi982138o. PMID 9843410.
- Roper DI, Huyton T, Lloyd AJ, Turkenburg J (2004). "Refinement of Haemophilus influenzae diaminopimelic acid epimerase (DapF) at 1.75 A resolution suggests a mechanism for stereocontrol during catalysis". Acta Crystallogr. D 60 (Pt 2): 397–400. doi:10.1107/S0907444903027999. PMID 14747737.
 Further reading
- ANTIA M, HOARE DS, WORK E (1957). "The stereoisomers of α∈-diaminopimelic acid. 3. Properties and distribution of diaminopimelic acid racemase, an enzyme causing interconversion of the ll and meso isomers". Biochem. J. 65 (3): 448–59. PMC 1199896. PMID 13412646. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1199896/.
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Diaminopimelate epimerase contains two domains of the same alpha/beta fold, both contained in this family.
Cirilli M, Zheng R, Scapin G, Blanchard JS; , Biochemistry 1998;37:16452-16458.: Structural symmetry: the three-dimensional structure of Haemophilus influenzae diaminopimelate epimerase. PUBMED:9843410 EPMC:9843410
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR001653
Bacteria, plants and fungi metabolise aspartic acid to produce four amino acids - lysine, threonine, methionine and isoleucine - in a series of reactions known as the aspartate pathway. Additionally, several important metabolic intermediates are produced by these reactions, such as diaminopimelic acid, an essential component of bacterial cell wall biosynthesis, and dipicolinic acid, which is involved in sporulation in Gram-positive bacteria. Members of the animal kingdom do not posses this pathway and must therefore acquire these essential amino acids through their diet. Research into improving the metabolic flux through this pathway has the potential to increase the yield of the essential amino acids in important crops, thus improving their nutritional value. Additionally, since the enzymes are not present in animals, inhibitors of them are promising targets for the development of novel antibiotics and herbicides. For more information see [PUBMED:11352712].Two lysine biosynthesis pathways evolved separately in organisms, the diaminopimelic acid (DAP) and aminoadipic acid (AAA) pathways. The DAP pathway synthesizes L-lysine from aspartate and pyruvate, and diaminopimelic acid is an intermediate. This pathway is utilised by most bacteria, some archaea, some fungi, some algae, and plants. The AAA pathway synthesizes L-lysine from alpha-ketoglutarate and acetyl coenzyme A (acetyl-CoA), and alpha-aminoadipic acid is an intermediate. This pathway is utilised by most fungi, some algae, the bacterium Thermus thermophilus, and probably some archaea, such as Sulfolobus, Thermoproteus, and Pyrococcus. No organism is known to possess both pathways [PUBMED:20418392].
There four known variations of the DAP pathway in bacteria: the succinylase, acetylase, aminotransferase, and dehydrogenase pathways. These pathways share the steps converting L-aspartate to L-2,3,4,5- tetrahydrodipicolinate (THDPA), but the subsequent steps leading to the production of meso-diaminopimelate, the immediate precursor of L-lysine, are different [PUBMED:20418392].
- The succinylase pathway acylates THDPA with succinyl-CoA to generate N-succinyl-LL-2-amino-6-ketopimelate and forms meso-DAP by subsequent transamination, desuccinylation, and epimerization. This pathway is utilised by proteobacteria and many firmicutes and actinobacteria.
- The acetylase pathway is analogous to the succinylase pathway but uses N-acetyl intermediates. This pathway is limited to certain Bacillus species, in which the corresponding genes have not been identified.
- The aminotransferase pathway converts THDPA directly to LL-DAP by diaminopimelate aminotransferase (DapL) without acylation. This pathway is shared by cyanobacteria, Chlamydia, the archaeon Methanothermobacter thermautotrophicus, and the plant Arabidopsis thaliana.
- The dehydrogenase pathway forms meso-DAP directly from THDPA, NADPH, and NH4 _ by using diaminopimelate dehydrogenase (Ddh). This pathway is utilised by some Bacillus and Brevibacterium species and Corynebacterium glutamicum.
Most bacteria use only one of the four variants, although certain bacteria, such as C. glutamicum and Bacillus macerans, possess both the succinylase and dehydrogenase pathways.
This entry represents diaminopimelate epimerase (EC), which catalyses the isomerisation of L,L-dimaminopimelate to meso-DAP in the biosynthetic pathway leading from aspartate to lysine. It is a member of the broader family of PLP-independent amino acid racemases. This enzyme is a monomeric protein of about 30 kDa consisting of two domains which are homologus in structure though they share little sequence similarity [PUBMED:9843410]. Each domain consists of mixed beta-sheets which fold into a barrel around the central helix. The active site cleft is formed from both domains and contains two conserved cysteines thought to function as the acid and base in the catalytic reaction [PUBMED:14747737]. Other PLP-independent racemases such as glutamate racemase have been shown to share a similar structure and mechanism of catalysis.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Molecular function||diaminopimelate epimerase activity (GO:0008837)|
|Biological process||lysine biosynthetic process via diaminopimelate (GO:0009089)|
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|Seed source:||Pfam-B_2089 (release 4.1)|
|Author:||Bateman A, Griffiths-Jones SR|
|Number in seed:||28|
|Number in full:||7321|
|Average length of the domain:||119.90 aa|
|Average identity of full alignment:||25 %|
|Average coverage of the sequence by the domain:||83.62 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||14|
|Download:||download the raw HMM for this family|
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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 DAP_epimerase domain has been found. There are 42 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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