Summary: Phosphoenolpyruvate phosphomutase

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Wikipedia: Phosphoenolpyruvate mutase
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Phosphoenolpyruvate mutase Edit Wikipedia article

phosphoenolpyruvate mutase

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In enzymology, a phosphoenolpyruvate mutase (EC 5.4.2.9) is an enzyme that catalyzes the chemical reaction

phosphoenolpyruvate $\rightleftharpoons$ 3-phosphonopyruvate

Hence, this enzyme has one substrate, phosphoenolpyruvate (PEP), and one product, 3-phosphonopyruvate (PPR), which are structural isomers.

This enzyme belongs to the family of isomerases, specifically the phosphotransferases (phosphomutases), which transfer phosphate groups within a molecule. The systematic name of this enzyme class is phosphoenolpyruvate 2,3-phosphonomutase. Other names in common use include phosphoenolpyruvate-phosphonopyruvate phosphomutase, PEP phosphomutase, phosphoenolpyruvate phosphomutase, PEPPM, and PEP phosphomutase. This enzyme participates in aminophosphonate metabolism.

Phosphoenolpyruvate mutase was discovered in 1988.^[1]^[2]

[edit] Structural studies

As of late 2007, 6 structures have been solved for this class of enzymes, all by the Herzberg group [1] at the University of Maryland using PEPPM from the blue mussel, Mytilus edulis. The first structure (PDB accession code 1PYM) was solved in 1999 and featured a magnesium oxalate inhibitor.^[3] This structure identified the enzyme as consisting of identical beta barrel subunits (exhibiting the TIM barrel fold, which consists of eight parallel beta strands). Dimerization was observed in which a helix from each subunit interacts with the other subunit's barrel; the authors called this feature "helix swapping." The dimers can dimerize as well to form a homotetrameric enzyme. A double phosphoryl transfer mechanism was proposed on the basis of this study: this would involve breakage of PEP's phosphorus-oxygen bond to form a phosphoenzyme intermediate, followed by transfer of the phosphoryl group from the enzyme to carbon-3, forming PPR.

However, more recently, a structure with a sulfopyruvate inhibitor, which is a closer substrate analogue, was solved (1M1B);^[4] this study supported instead a dissociative mechanism. A notable feature of these structures was the shielding of the active site from solvent; it was proposed that a significant conformational change takes place on binding to allow this, moving the protein from an "open" to a "closed" state, and this was supported by several crystal structures in the open state.^[5] Three of these were of the wild type: the apoenzyme in 1S2T, the enzyme plus its magnesium ion cofactor in 1S2V, and the enzyme at high ionic strength in 1S2W. A mutant (D58A, in one of the active-site loops) was crystallized as an apoenzyme also (1S2U). From these structures, an active-site "gating" loop (residues 115-133) that shields the substrate from solvent in the closed conformation was identified.

The two conformations, taken from the crystal structures 1M1B (closed) and 1S2T (open), are docked into each other in the images below; they differ negligibly except in the gating loop, which is colored purple for the closed conformation and blue for the open conformation. In the active-site closeup (left), several sidechains (cyan) that have been identified as important in catalysis are included as well; the overview (right) illustrates the distinctive helix-swapping fold. The images are still shots from ribbon kinemages. Both of these structures were crystallized as dimers. In chain A (used for the active-site closeup), helices are red while loops (other than the gating loop) are white and beta strands are green; in chain B, helices are yellow, beta strands are olive, and loops are gray; these colors are the same for the closed and open structures. Magnesium ions are gray and the sulfopyruvate ligands are pink; both are from the closed structure (though the enzyme has also been crystallized with only magnesium bound, and it adopted an open conformation).

The structure of PEPPM is very similar to that of methylisocitrate lyase, an enzyme involved in propanoate metabolism whose substrate is also a low-molecular weight carboxylic acidthe beta-barrel structure as well as the active site layout and multimerization geometry are the same. Isocitrate lyase is also quite similar, though each subunit has a second, smaller beta domain in addition to the main beta barrel.

[edit] Mechanism

Phosphoenolpyruvate mutase is thought to exhibit a dissociative mechanism.^[4] A magnesium ion is involved as a cofactor. The phosphoryl/phosphate group also appears to interact ionically with Arg159 and His190, stabilizing the reactive intermediate. A phosphoenzyme intermediate is unlikely because the most feasible residues for the covalent adduct can be mutated with only partial loss of function. The reaction involves dissociation of phosphorus from oxygen 2 and then a nucleophilic attack by carbon 3 on phosphorus. Notably, the configuration is retained at phosphorus, i.e. carbon 3 of PPR adds to the same face of phosphorus from which oxygen 2 of PEP was removed; this would be unlikely for a non-enzyme-catalyzed dissociative mechanism, but since the reactive intermediate interacts strongly with the amino acids and magnesium ions of the active site, it is to be expected in the presence of enzyme catalysis.

Residues in the active-site gating loop, particularly Lys120, Asn122, and Leu124, also appear to interact with the substrate and reactive intermediate; these interactions explain why the loop moves into the closed conformation on substrate binding.

[edit] Biological function

Because phosphoenolpyruvate mutase has the unusual ability to form a new carbon-phosphorus bond, it is essential to the synthesis of phosphonates, such as phosphonolipids and the antibiotics fosfomycin and bialaphos. The formation of this bond is quite thermodynamically unfavorable; even though PEP is a very high-energy phosphate compound, the equilibrium in PEP-PPR interconversion still favors PEP.^[1] The enzyme phosphonopyruvate decarboxylase presents a solution to this problem: it catalyzes the very thermodynamically favorable decarboxylation of PPR, and the resulting 2-phosphonoacetaldehyde is then converted into biologically useful phosphonates. This allows phosphoneolpyruvate's reaction to proceed in the forward direction, due to Le Chatelier's principle. The decarboxylation removes product quickly, and thus the reaction moves forward even though there would be much more reactant than product if the system were allowed to reach equilibrium by itself.

The enzyme carboxyphosphoenolpyruvate phosphonomutase performs a similar reaction, converting P-carboxyphosphoenolpyruvate to phosphinopyruvate and carbon dioxide. [2] ^[6]

[edit] References

^ ^a ^b Bowman E, McQueney M, Barry RJ and Dunaway-Mariano D (1988). "Catalysis and thermodynamics of the phosphoenolpyruvate phosphonopyruvate rearrangement - entry into the phosphonate class of naturally-occurring organo-phosphorus compounds". J. Am. Chem. Soc. 110 (16): 55755576. doi:10.1021/ja00224a054.
^ Seidel HM, Freeman S, Seto H, Knowles JR (1988). "Phosphonate biosynthesis: isolation of the enzyme responsible for the formation of a carbon-phosphorus bond". Nature. 335 (6189): 457458. doi:10.1038/335457a0. PMID 3138545.
^ Huang K, Li Z, Jia Y, Dunaway-Mariano D, Herzberg O (1999). "Helix swapping between two alpha/beta barrels: crystal structure of phosphoenolpyruvate mutase with bound Mg(2+)-oxalate". Structure Fold. Des. 7 (5): 53948. doi:10.1016/S0969-2126(99)80070-7. PMID 10378273.
^ ^a ^b Liu S, Lu Z, Jia Y, Dunaway-Mariano D, Herzberg O (2002). "Dissociative phosphoryl transfer in PEP mutase catalysis: structure of the enzyme/sulfopyruvate complex and kinetic properties of mutants". Biochemistry 41 (32): 1027010276. doi:10.1021/bi026024v. PMID 12162742.
^ Liu S, Lu Z, Han Y, Jia Y, Howard A, Dunaway-Mariano D, Herzberg O (2004). "Conformational flexibility of PEP mutase". Biochemistry 43 (15): 44474453. doi:10.1021/bi036255h. PMID 15078090.
^ Hidaka T, Imai S, Hara O, Anzai H, Murakami T, Nagaoka K, Seto H (1990). "Carboxyphosphonoenolpyruvate phosphonomutase, a novel enzyme catalyzing C-P bond formation". J. Bacteriol. 172 (6): 306672. PMC 209109. PMID 2160937. //www.ncbi.nlm.nih.gov/pmc/articles/PMC209109/.

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Phosphoenolpyruvate phosphomutase Provide feedback

This domain includes the enzyme Phosphoenolpyruvate phosphomutase ( EC:5.4.2.9). This protein O86937 has been characterised as catalysing the formation of a carbon-phosphorus bond by converting phosphoenolpyruvate (PEP) to phosphonopyruvate (P-Pyr) [1]. This enzyme has a TIM barrel fold.

Literature references

Schwartz D, Recktenwald J, Pelzer S, Wohlleben W;, FEMS Microbiol Lett. 1998;163:149-157.: Isolation and characterization of the PEP-phosphomutase and the phosphonopyruvate decarboxylase genes from the phosphinothricin tripeptide producer Streptomyces viridochromogenes Tu494. PUBMED:9673017 EPMC:9673017

External database links

PANDIT:	PF13714
Pseudofam:	PF13714
SYSTERS:	PEP_mutase

This tab holds annotation information from the InterPro database.

No InterPro data for this Pfam family.

Domain organisation

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

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Pfam Clan

This family is a member of clan PK_TIM (CL0151), which contains the following 10 members:

C-C_Bond_Lyase HpcH_HpaI ICL Malate_synthase Pantoate_transf PEP-utilizers_C PEP_mutase PEPcase PEPcase_2 PK

Alignments

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RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
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	Seed (124)	Full (2953)	Representative proteomes				NCBI (4275)	Meta (3390)
	Seed (124)	Full (2953)	RP15 (228)	RP35 (531)	RP55 (766)	RP75 (941)	NCBI (4275)	Meta (3390)
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¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (124)	Full (2953)	Representative proteomes				NCBI (4275)	Meta (3390)
	Seed (124)	Full (2953)	RP15 (228)	RP35 (531)	RP55 (766)	RP75 (941)	NCBI (4275)	Meta (3390)
Alignment:
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Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
Gaps:
Download/view:	Download View

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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 (124)	Full (2953)	Representative proteomes				NCBI (4275)	Meta (3390)
	Seed (124)	Full (2953)	RP15 (228)	RP35 (531)	RP55 (766)	RP75 (941)	NCBI (4275)	Meta (3390)
Raw Stockholm	Download	Download	Download	Download	Download	Download	Download	Download
Gzipped	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.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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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.

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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

Seed source:

Jackhmmer:A1B6C5

Previous IDs:

none

Type:

Domain

Author:

Bateman A

Number in seed:

124

Number in full:

2953

Average length of the domain:

240.70 aa

Average identity of full alignment:

35 %

Average coverage of the sequence by the domain:

79.80 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	30.0	30.0
Trusted cut-off	30.0	30.0
Noise cut-off	29.9	29.9

Model length:

238

Family (HMM) version:

1

Download:

download the raw HMM for this family

Species distribution

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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.

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Sub-species

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.

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Species trees

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Interactive tree

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.

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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.

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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 PEP_mutase domain has been found. There are 94 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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Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: PEP_mutase (PF13714)

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