Phosphoribosyl pyrophosphate synthase 1, hexamer, Human
Identifiers
EC number
2.7.6.1
CAS number
9031-46-3
Databases
IntEnz
IntEnz view
BRENDA
BRENDA entry
ExPASy
NiceZyme view
KEGG
KEGG entry
MetaCyc
metabolic pathway
PRIAM
profile
PDB structures
RCSB PDB PDBe PDBsum
Gene Ontology
AmiGO / QuickGO
Search
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articles
PubMed
articles
NCBI
proteins
phosphoribosyl pyrophosphate synthetase 1
Identifiers
Symbol
PRPS1
Entrez
5631
HUGO
9462
OMIM
311850
RefSeq
NM_002764
UniProt
P60891
Other data
EC number
2.7.6.1
Locus
Chr. X q21-q27
phosphoribosyl pyrophosphate synthetase 2
Identifiers
Symbol
PRPS2
Entrez
5634
HUGO
9465
OMIM
311860
RefSeq
NM_002765
UniProt
P11908
Other data
EC number
2.7.6.1
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).[1][2] It is classified under EC 2.7.6.1.
The enzyme is involved in the synthesis of nucleotides (purines and pyrimidines), cofactors NAD and NADP, and amino acids histidine and tryptophan,[1][2][3] 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.[2] In humans, the genes encoding the enzyme are located on the X chromosome.[2]
Contents
1Reaction mechanism
2Structure
3Function
4Regulation
5Role in disease
6References
7External links
Reaction mechanism
Ribose-phosphate diphosphokinase transfers the diphosphoryl group from Mg-ATP (Mg2+ coordinated to ATP) to ribose 5-phosphate.[2] 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.[4]
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.[5]
Structure
PyMol rendering of one subunit of the enzyme phosphoribosyl pyrophosphate synthetase I (human). Flexible loop colored in green; ribose 5-phosphate binding region colored in blue.
PyMol rendering of phosphoribosyl pyrophosphate synthetase I (human) as a homodimer, formed by two subunits (red and blue). Three homodimers form the active enzyme complex.
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.[2]
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.[6] The ribose 5-phosphate binding site consists of residues Asp220–Thr228, located in the C-terminal domain of one subunit.[2][6]
The allosteric site, which binds ADP, consists of amino acid residues from three subunits.[2]
Function
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.[7][8] PRPP is also used in the synthesis of NAD: the reaction of PRPP with nicotinic acid yields the intermediate nicotinic acid mononucleotide.[9]
Regulation
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.[2][6]
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,[10] weak muscle tone (hypotonia), impaired muscle coordination (ataxia), hereditary peripheral neuropathy,[11] and neurodevelopmental disorder.[12][13][14]
Mutations that lead to loss-of-function in ribose-phosphate diphosphokinase result in Charcot-Marie-Tooth disease and ARTS syndrome.[15]
References
^ abVisentin 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.
^ abcdefghiLi 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 Crystallographica Section F. 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.
^ abcEriksen 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.
^Jeremy M. Berg; John L. Tymoczko; Lubert Stryer; Gregory J. Gatto Jr. (2012). Biochemistry (7th 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.
External links
Uniprot - Ribose-phosphate pyrophosphokinase 1
GeneReviews/NIH/NCBI/UW entry on Charcot-Marie-Tooth Neuropathy X Type 5
OMIM entries 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)
TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik.Theor Appl Genet.2014 Nov;127(11):2371-85. doi: 10.1007/s00122-014-2383-y. Epub 2014 Sep 4.
KEY MESSAGE: We have identified QTLs for stomatal characteristics on chromosome II of faba bean by applying SNPs derived from M. truncatula , and have identified candidate genes within these QTLs using synteny between the two species. Faba bean (Vicia faba L.) is a valuable food and feed crop worldw
The expanding spectrum of PRPS1-associated phenotypes: three novel mutations segregating with X-linked hearing loss and mild peripheral neuropathy.
Robusto M1, Fang M2, Asselta R1, Castorina P3, Previtali SC4, Caccia S1, Benzoni E5, De Cristofaro R6, Yu C2, Cesarani A3, Liu X2, Li W2, Primignani P5, Ambrosetti U3, Xu X2, Duga S1, Soldà G1.
European journal of human genetics : EJHG.Eur J Hum Genet.2014 Sep 3. doi: 10.1038/ejhg.2014.168. [Epub ahead of print]
Next-generation sequencing is currently the technology of choice for gene/mutation discovery in genetically-heterogeneous disorders, such as inherited sensorineural hearing loss (HL). Whole-exome sequencing of a single Italian proband affected by non-syndromic HL identified a novel missense variant
Inborn errors of purine metabolism: clinical update and therapies.
Balasubramaniam S1, Duley JA, Christodoulou J.
Journal of inherited metabolic disease.J Inherit Metab Dis.2014 Sep;37(5):669-86. doi: 10.1007/s10545-014-9731-6. Epub 2014 Jun 28.
Inborn errors of purine metabolism exhibit broad neurological, immunological, haematological and renal manifestations. Limited awareness of the phenotypic spectrum, the recent descriptions of newer disorders and considerable genetic heterogeneity, have contributed to long diagnostic odysseys for aff
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Complete nucleotide sequence of human phosphoribosylpyrophosphatesynthetase subunit I(PRS I) cDNA and a comparison with human and rat PRPS gene families.
Certain mutations in the PRPS1 gene cause PRS superactivity. The PRPS1 gene provides instructions for making an enzyme called phosphoribosyl pyrophosphate synthetase 1, or PRPP synthetase 1. This enzyme helps produce a ...
This gene encodes an enzyme that catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for purine metabolism and nucleotide biosynthesis. Defects in this gene are a ...