Summary: Phosphoribosyl synthetase-associated domain
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Ribose-phosphate diphosphokinase Edit Wikipedia article
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
|phosphoribosyl pyrophosphate synthetase 1|
|Locus||Chr. X q21-q27|
|phosphoribosyl pyrophosphate synthetase 2|
|Locus||Chr. X pter-q21|
Ribose-phosphate diphosphokinase (or phosphoribosyl pyrophosphate synthetase or ribose-phosphate pyrophosphokinase) is an enzyme that converts ribose 5-phosphate into phosphoribosyl pyrophosphate (PRPP). It is classified under EC 188.8.131.52.
The enzyme is involved in the synthesis of nucleotides (purines and pyrimidines), cofactors NAD and NADP, and amino acids histidine and tryptophan, linking these biosynthetic processes to the pentose phosphate pathway, from which the substrate ribose 5-phosphate is derived. Ribose 5-phosphate is produced by the HMP Shunt Pathway from Glucose-6-Phosphate. The product phosphoribosyl pyrophosphate acts as an essential component of the purine salvage pathway and the de novo synthesis of purines. Dysfunction of the enzyme would thereby undermine purine metabolism. Ribose-phosphate pyrophosphokinase exists in bacteria, plants, and animals, and there are three isoforms of human ribose-phosphate pyrophosphokinase. In humans, the genes encoding the enzyme are located on the X chromosome.
Ribose-phosphate diphosphokinase transfers the diphosphoryl group from Mg-ATP (Mg2+ coordinated to ATP) to ribose 5-phosphate. The enzymatic reaction begins with the binding of ribose 5-phosphate, followed by binding of Mg-ATP to the enzyme. In the transition state upon binding of both substrates, the diphosphate is transferred. The enzyme first releases AMP before releasing the product phosphoribosyl pyrophosphate. Experiments using oxygen 18 labelled water demonstrate that the reaction mechanism proceeds with the nucleophilic attack of the anomeric hydroxyl group of ribose 5-phosphate on the beta-phosphorus of ATP in an SN2 reaction.
Crystallization and X-ray diffraction studies elucidated the structure of the enzyme, which was isolated by cloning, protein expression, and purification techniques. One subunit of ribose-phosphate diphosphokinase consists of 318 amino acids; the active enzyme complex consists of three homodimers (or six subunits, a hexamer). The structure of one subunit is a five-stranded parallel beta sheet (the central core) surrounded by four alpha helices at the N-terminal domain and five alpha helices at the C-terminal domain, with two short anti-parallel beta-sheets extending from the core. The catalytic site of the enzyme binds ATP and ribose 5-phosphate. The flexible loop (Phe92–Ser108), pyrophosphate binding loop (Asp171–Gly174), and flag region (Val30–Ile44 from an adjacent subunit) comprise the ATP binding site, located at the interface between two domains of one subunit. The flexible loop is so named because of the its large variability in conformation. The ribose 5-phosphate binding site consists of residues Asp220–Thr228, located in the C-terminal domain of one subunit. The allosteric site, which binds ADP, consists of amino acid residues from three subunits.
The product of this reaction, phosphoribosyl pyrophosphate (PRPP), is used in numerous biosynthesis (de novo and salvage) pathways. PRPP provides the ribose sugar in de novo synthesis of purines and pyrimidines, used in the nucleotide bases that form RNA and DNA. PRPP reacts with orotate to form orotidylate, which can be converted to uridylate (UMP). UMP can then be converted to the nucleotide cytidine triphosphate (CTP). The reaction of PRPP, glutamine, and ammonia forms 5-Phosphoribosyl-1-amine, a precursor to inosinate (IMP), which can ultimately be converted to adenosine triphosphate (ATP) or guanosine triphosphate (GTP). PRPP plays a role in purine salvage pathways by reacting with free purine bases to form adenylate, guanylate, and inosinate. PRPP is also used in the synthesis of NAD: the reaction of PRPP with nicotinic acid yields the intermediate nicotinic acid mononucleotide.
Ribose-phosphate diphosphokinase requires Mg2+ for activity; the enzyme acts only on ATP coordinated with Mg2+. Ribose-phosphate diphosphokinase is regulated by phosphorylation and allostery. It is activated by phosphate and inhibited by ADP; it is suggested that phosphate and ADP compete for the same regulatory site. At normal concentrations, phosphate activates the enzyme by binding to its allosteric regulatory site. However, at high concentrations, phosphate is shown to have an inhibitory effect by competing with the substrate ribose 5-phosphate for binding at the active site. ADP is the key allosteric inhibitor of ribose-phosphate diphosphokinase. It has been shown that at lower concentrations of the substrate ribose 5-phosphate, ADP may inhibit the enzyme competitively. Ribose-phosphate pyrophosphokinase is also inhibited by some of its downstream biosynthetic products.
Role in disease
Because its product is a key compound in many biosynthetic pathways, ribose-phosphate diphosphokinase is involved in some rare disorders and X-linked recessive diseases. Mutations that lead to super-activity (increased enzyme activity or de-regulation of the enzyme) result in purine and uric acid overproduction. Super-activity symptoms include gout, sensorineural hearing loss, weak muscle tone (hypotonia), impaired muscle coordination (ataxia), hereditary peripheral neuropathy, and neurodevelopmental disorder. Mutations that lead to loss-of-function in ribose-phosphate diphosphokinase result in Charcot-Marie-Tooth disease and ARTS syndrome.
- Visentin LP, Hasnain S, Gallin W (July 1977). "Ribosomal protein S1/S1A in bacteria". FEBS Lett. 79 (2): 258–63. doi:10.1016/0014-5793(77)80799-0. PMID 330231.
- Li S, Lu Y, Peng B, Ding J (January 2007). "Crystal structure of human phosphoribosylpyrophosphate synthetase 1 reveals a novel allosteric site". Biochem. J. 401 (1): 39–47. doi:10.1042/BJ20061066. PMC 1698673. PMID 16939420.
- Tang W, Li X, Zhu Z, Tong S, Li X, Zhang X, Teng M, Niu L (May 2006). "Expression, purification, crystallization and preliminary X-ray diffraction analysis of human phosphoribosyl pyrophosphate synthetase 1 (PRS1)". Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 62 (Pt 5): 432–4. doi:10.1107/S1744309106009067. PMC 2219982. PMID 16682768.
- Fox IH, Kelley WN (April 1972). "Human phosphoribosylpyrophosphate synthetase. Kinetic mechanism and end product inhibition". J. Biol. Chem. 247 (7): 2126–31. PMID 4335863.
- Miller GA, Rosenzweig S, Switzer RL (December 1975). "Oxygen-18 studies of the mechanism of pyrophosphoryl group transfer catalyzed by phosphoribosylpyrophosphate synthetase". Arch. Biochem. Biophys. 171 (2): 732–6. doi:10.1016/0003-9861(75)90086-7. PMID 173242.
- Eriksen TA, Kadziola A, Bentsen AK, Harlow KW, Larsen S (April 2000). "Structural basis for the function of Bacillus subtilis phosphoribosyl-pyrophosphate synthetase". Nat. Struct. Biol. 7 (4): 303–8. doi:10.1038/74069. PMID 10742175.
- Fox IH, Kelley WN (March 1971). "Phosphoribosylpyrophosphate in man: biochemical and clinical significance". Ann. Intern. Med. 74 (3): 424–33. doi:10.7326/0003-4819-74-3-424. PMID 4324023.
- Jr, Jeremy M. Berg, John L. Tymoczko, Lubert Stryer ; with Gregory J. Gatto, (2012). Biochemistry (7th ed. ed.). New York: W.H. Freeman. ISBN 1429229365.
- Rongvaux A, Andris F, Van Gool F, Leo O (July 2003). "Reconstructing eukaryotic NAD metabolism". BioEssays 25 (7): 683–90. doi:10.1002/bies.10297. PMID 12815723.
- Liu X, Han D, Li J, Han B, Ouyang X, Cheng J, Li X, Jin Z, Wang Y, Bitner-Glindzicz M, Kong X, Xu H, Kantardzhieva A, Eavey RD, Seidman CE, Seidman JG, Du LL, Chen ZY, Dai P, Teng M, Yan D, Yuan H (January 2010). "Loss-of-function mutations in the PRPS1 gene cause a type of nonsyndromic X-linked sensorineural deafness, DFN2". Am. J. Hum. Genet. 86 (1): 65–71. doi:10.1016/j.ajhg.2009.11.015. PMC 2801751. PMID 20021999.
- Kim HJ, Sohn KM, Shy ME, Krajewski KM, Hwang M, Park JH, Jang SY, Won HH, Choi BO, Hong SH, Kim BJ, Suh YL, Ki CS, Lee SY, Kim SH, Kim JW (September 2007). "Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5)". Am. J. Hum. Genet. 81 (3): 552–8. doi:10.1086/519529. PMC 1950833. PMID 17701900.
- Becker MA, Smith PR, Taylor W, Mustafi R, Switzer RL (November 1995). "The genetic and functional basis of purine nucleotide feedback-resistant phosphoribosylpyrophosphate synthetase superactivity". J. Clin. Invest. 96 (5): 2133–41. doi:10.1172/JCI118267. PMC 185862. PMID 7593598.
- Zoref E, De Vries A, Sperling O (November 1975). "Mutant feedback-resistant phosphoribosylpyrophosphate synthetase associated with purine overproduction and gout. Phosphoribosylpyrophosphate and purine metabolism in cultured fibroblasts". J. Clin. Invest. 56 (5): 1093–9. doi:10.1172/JCI108183. PMC 301970. PMID 171280.
- "Phosphoribosylpyrophosphate synthetase superactivity". Lister Hill National Center for Biomedical Communications. Retrieved 25 February 2014.
- Synofzik M, Müller Vom Hagen J, Haack TB, Wilhelm C, Lindig T, Beck-Wödl S, Nabuurs SB, van Kuilenburg AB, de Brouwer AP, Schöls L (2014). "X-linked Charcot-Marie-Tooth disease, Arts syndrome, and prelingual non-syndromic deafness form a disease continuum: evidence from a family with a novel PRPS1 mutation". Orphanet J Rare Dis 9 (1): 24. doi:10.1186/1750-1172-9-24. PMC 3931488. PMID 24528855.
- GeneReviews/NIH/NCBI/UW entry on Charcot-Marie-Tooth Neuropathy X Type 5
- OMIM entries on on Charcot-Marie-Tooth Neuropathy X Type 5
- GeneReviews/NCBI/NIH/UW entry on Arts Syndrome
- GeneReviews/NIH/NCBI/UW entry on Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity
- GeneReviews/NCBI/NIH/UW entry on DFNX1 Nonsyndromic Hearing Loss and Deafness
- Phosphoribosyl Pyrophosphate Synthetase at the US National Library of Medicine Medical Subject Headings (MeSH)
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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.
Phosphoribosyl synthetase-associated domain Provide feedback
This family includes several examples of enzymes from class EC:184.108.40.206, phosphoribosyl-pyrophosphate transferase.
Katashima R, Iwahana H, Fujimura M, Yamaoka T, Ishizuka T, Tatibana M, Itakura M;, Biochim Biophys Acta. 1998;1396:245-250.: Molecular cloning of a human cDNA for the 41-kDa phosphoribosylpyrophosphate synthetase-associated protein. PUBMED:9545573 EPMC:9545573
Internal database links
|Similarity to PfamA using HHSearch:||Pribosyltran|
External database links
This tab holds annotation information from the InterPro database.
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Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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This superfamily of phosphoribosyl-transferases (PRTases) and phosphoribosyl-pyrophosphate synthetase-like protein families is characterised by a core fold of three layers, a/b/a with a mixed beta-sheet of six strands. In one of the families consists of two domains of this fold.
The clan contains the following 6 members:Pribosyl_synth Pribosyltran PRTase_1 PRTase_2 PRTase_3 UPRTase
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 using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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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.
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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.
This family is new in this Pfam release.
|Seed source:||pdb_2c4k; Jackhmmer:Q14558|
|Number in seed:||11|
|Number in full:||6166|
|Average length of the domain:||127.90 aa|
|Average identity of full alignment:||40 %|
|Average coverage of the sequence by the domain:||39.16 %|
|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:||1|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
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.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
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.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
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.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
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.
You can use the tree controls to manipulate how the interactive tree is displayed:
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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 Pribosyl_synth domain has been found. There are 28 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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