Deadenylation-dependent mRNA decay (Homo sapiens)

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2, 3, 8, 9, 28...2, 3, 7-9, 17...2, 3, 8, 9, 28...1-3, 8, 9, 26...232-4, 8, 9, 13...392, 3, 5, 6, 8...2, 3, 8, 9, 16...2, 3, 8, 9, 13...2, 3, 8-10, 27...cytosolCNOT8 DCPSNT5C3BRQCD1 oligoribonucleotidewith a5'-diphosphateCNOT11 7-MeGDPEIF4E uridine5'-monophosphatemature mRNA (eukaryotic, capped and deadenylated) EXOSC6 PAIP1 DCP1-DCP2 DecappingComplexZCCHC6, ZCCHC11EXOSC3 H2OH2OLSM1 CNOT6 DCP1A EIF4A2 CNOT7 EXOSC4 PARN homodimermature mRNA(eukaryotic, cappedand deadenylated)EIF4A3 Decapped mRNA:LSM1-7ComplexPARN cappedoligoribonucleotideEXOSC7 EIF4E WDR61 CNOT6L PABPC1 PAIP1 uridine5'-monophosphateTTC37 LSM6 LSM1 HBS1L LSM7 AMPEIF4G1 H2OPATL1 H2ODIS3 H2OPAIP1 EIF4A3 EIF4A1 PABPC1 EIF4A2 uridine residue eIF4AEIF4A3 DDX6 XRN1LSM4 PATL1 mature mRNA (eukaryotic, capped and partially deadenylated) 7MGMPAMPLSM4 LSM7 uridine residueEIF4A2 EIF4B PABPC1 H2OH2OZCCHC6 LSM6 EXOSC5 EIF4A1 LSM3 EDC4 LSM1 PAN2 CCR4-NOT ComplexLSM5 EIF4ELSM3 cytidine5'-monophosphateUridylated partiallyDeadenylated mRNAComplexExosome:SKI complexTNKS1BP1 PATL1 LSM4 EIF4A1 DeadenylatedmRNA:Lsm1-7 ComplexTranslatable mRNAComplexguanosine5'-monophosphateEIF4A2 ZCCHC11 AMPLSM3 PAN2-PAN3 ComplexPABPC1EIF4B PAN3 cytidine5'-monophosphateEIF4G1 EXOSC8 CNOT1 guanosine5'-monophosphateLSM2 EIF4G1 AMPPiLSM7 EXOSC9 EIF4A3 LSM6 H2OSKIV2L EIF4B EDC3 CNOT3 DCP2 Lsm1-7 Complex7MGmature mRNA (eukaryotic, capped and partially deadenylated) CNOT10 CNOT2 LSM2 PartiallyDeadenylated mRNAComplexCNOT4 EIF4BEXOSC2 EXOSC1 EIF4G1EIF4E LSM5 LSM2 LSM5 EIF4A1 DCP1B decapped mRNA with 5' monophosphate mature mRNA (eukaryotic, capped and polyadenylated) PAIP110, 111, 19, 21, 4712, 3518, 42, 4538258


Description

After undergoing rounds of translation, mRNA is normally destroyed by the deadenylation-dependent pathway. Though the trigger is unclear, deadenylation likely proceeds in two steps: one catalyzed by the PAN2-PAN3 complex that shortens the poly(A) tail from about 200 adenosine residues to about 80 residues and one catalyzed by the CCR4-NOT complex or by the PARN enzyme that shortens the tail to about 10-15 residues.
After deadenylation the mRNA is then hydrolyzed by either the 5' to 3' pathway or the 3' to 5' pathway. It is unknown what determinants target a mRNA to one pathway or the other.
The 5' to 3' pathway is initiated by binding of the Lsm1-7 complex to the 3' oligoadenylate tail followed by decapping by the DCP1-DCP2 complex. The 5' to 3' exoribonuclease XRN1 then hydrolyzes the remaining RNA.
The 3' to 5' pathway is initiated by the exosome complex at the 3' end of the mRNA. The exosome processively hydrolyzes the mRNA from 3' to 5', leaving only a capped oligoribonucleotide. The cap is then removed by the scavenging decapping enzyme DCPS. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 429914
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

Quality Tags

Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
101587view11:45, 1 November 2018ReactomeTeamreactome version 66
101123view21:29, 31 October 2018ReactomeTeamreactome version 65
100651view20:03, 31 October 2018ReactomeTeamreactome version 64
100201view16:48, 31 October 2018ReactomeTeamreactome version 63
99752view15:14, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99316view12:46, 31 October 2018ReactomeTeamreactome version 62
93995view13:50, 16 August 2017ReactomeTeamreactome version 61
93604view11:28, 9 August 2017ReactomeTeamreactome version 61
87169view19:22, 18 July 2016MkutmonOntology Term : 'pathway pertinent to DNA replication and repair, cell cycle, maintenance of genomic integrity, RNA and protein biosynthesis' added !
86710view09:24, 11 July 2016ReactomeTeamreactome version 56
83258view10:34, 18 November 2015ReactomeTeamVersion54
81369view12:53, 21 August 2015ReactomeTeamVersion53
76837view08:06, 17 July 2014ReactomeTeamFixed remaining interactions
76541view11:52, 16 July 2014ReactomeTeamFixed remaining interactions
75874view09:52, 11 June 2014ReactomeTeamRe-fixing comment source
75574view10:39, 10 June 2014ReactomeTeamReactome 48 Update
74929view13:45, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74573view08:37, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
7-MeGDPMetaboliteCHEBI:20794 (ChEBI)
7MGMetaboliteCHEBI:20794 (ChEBI)
7MGMPMetaboliteCHEBI:17825 (ChEBI)
AMPMetaboliteCHEBI:16027 (ChEBI)
CCR4-NOT ComplexComplexR-HSA-429896 (Reactome) The human CCR4-NOT complex contains 7 core subunits: CNOT1, CNOT2, CNOT3, CNOT9/RCD1, CNOT10, TAB182, and C2ORF29. Complexes contain either CNOT7 or CNOT8 (with CNOT8-containing complexes apparently involved in nuclear RNA splicing and CNOT7-containing complexes involved in cytoplasmic mRNA decay) and CNOT6 or CNOT6L. CNOT6 and CNOT6L are catalytic exoribonucleases. CNOT7 and CNOT8 also have ribonuclease activity. CNOT1 is the largest subunit and, based on yeast two-hybrid assays, interacts with CNOT2, CNOT7, CNOT8, and CNOT9, thus acting as a scaffold.
CNOT1 ProteinA5YKK6 (Uniprot-TrEMBL)
CNOT10 ProteinQ9H9A5 (Uniprot-TrEMBL)
CNOT11 ProteinQ9UKZ1 (Uniprot-TrEMBL)
CNOT2 ProteinQ9NZN8 (Uniprot-TrEMBL)
CNOT3 ProteinO75175 (Uniprot-TrEMBL)
CNOT4 ProteinO95628 (Uniprot-TrEMBL)
CNOT6 ProteinQ9ULM6 (Uniprot-TrEMBL)
CNOT6L ProteinQ96LI5 (Uniprot-TrEMBL)
CNOT7 ProteinQ9UIV1 (Uniprot-TrEMBL)
CNOT8 ProteinQ9UFF9 (Uniprot-TrEMBL)
DCP1-DCP2 Decapping ComplexComplexR-HSA-429991 (Reactome)
DCP1A ProteinQ9NPI6 (Uniprot-TrEMBL)
DCP1B ProteinQ8IZD4 (Uniprot-TrEMBL)
DCP2 ProteinQ8IU60 (Uniprot-TrEMBL)
DCPSProteinQ96C86 (Uniprot-TrEMBL)
DDX6 ProteinP26196 (Uniprot-TrEMBL)
DIS3 ProteinQ9Y2L1 (Uniprot-TrEMBL)
Deadenylated mRNA:Lsm1-7 ComplexComplexR-HSA-429908 (Reactome)
Decapped mRNA:LSM1-7 ComplexComplexR-HSA-429996 (Reactome)
EDC3 ProteinQ96F86 (Uniprot-TrEMBL)
EDC4 ProteinQ6P2E9 (Uniprot-TrEMBL)
EIF4A1 ProteinP60842 (Uniprot-TrEMBL)
EIF4A2 ProteinQ14240 (Uniprot-TrEMBL)
EIF4A3 ProteinP38919 (Uniprot-TrEMBL)
EIF4B ProteinP23588 (Uniprot-TrEMBL)
EIF4BProteinP23588 (Uniprot-TrEMBL)
EIF4E ProteinP06730 (Uniprot-TrEMBL)
EIF4EProteinP06730 (Uniprot-TrEMBL)
EIF4G1 ProteinQ04637 (Uniprot-TrEMBL)
EIF4G1ProteinQ04637 (Uniprot-TrEMBL)
EXOSC1 ProteinQ9Y3B2 (Uniprot-TrEMBL)
EXOSC2 ProteinQ13868 (Uniprot-TrEMBL)
EXOSC3 ProteinQ9NQT5 (Uniprot-TrEMBL)
EXOSC4 ProteinQ9NPD3 (Uniprot-TrEMBL)
EXOSC5 ProteinQ9NQT4 (Uniprot-TrEMBL)
EXOSC6 ProteinQ5RKV6 (Uniprot-TrEMBL)
EXOSC7 ProteinQ15024 (Uniprot-TrEMBL)
EXOSC8 ProteinQ96B26 (Uniprot-TrEMBL)
EXOSC9 ProteinQ06265 (Uniprot-TrEMBL)
Exosome:SKI complexComplexR-HSA-8931494 (Reactome)
H2OMetaboliteCHEBI:15377 (ChEBI)
HBS1L ProteinQ9Y450 (Uniprot-TrEMBL)
LSM1 ProteinO15116 (Uniprot-TrEMBL)
LSM2 ProteinQ9Y333 (Uniprot-TrEMBL)
LSM3 ProteinP62310 (Uniprot-TrEMBL)
LSM4 ProteinQ9Y4Z0 (Uniprot-TrEMBL)
LSM5 ProteinQ9Y4Y9 (Uniprot-TrEMBL)
LSM6 ProteinP62312 (Uniprot-TrEMBL)
LSM7 ProteinQ9UK45 (Uniprot-TrEMBL)
Lsm1-7 ComplexComplexR-HSA-430001 (Reactome)
NT5C3BProteinQ969T7 (Uniprot-TrEMBL)
PABPC1 ProteinP11940 (Uniprot-TrEMBL)
PABPC1ProteinP11940 (Uniprot-TrEMBL)
PAIP1 ProteinQ9H074 (Uniprot-TrEMBL)
PAIP1ProteinQ9H074 (Uniprot-TrEMBL)
PAN2 ProteinQ504Q3 (Uniprot-TrEMBL)
PAN2-PAN3 ComplexComplexR-HSA-429882 (Reactome)
PAN3 ProteinQ58A45 (Uniprot-TrEMBL)
PARN ProteinO95453 (Uniprot-TrEMBL)
PARN homodimerComplexR-HSA-429886 (Reactome) Structural analysis has shown that PARN forms homodimers.
PATL1 ProteinQ86TB9 (Uniprot-TrEMBL)
Partially

Deadenylated mRNA

Complex
ComplexR-HSA-429989 (Reactome)
PiMetaboliteCHEBI:18367 (ChEBI)
RQCD1 ProteinQ92600 (Uniprot-TrEMBL)
SKIV2L ProteinQ15477 (Uniprot-TrEMBL)
TNKS1BP1 ProteinQ9C0C2 (Uniprot-TrEMBL)
TTC37 ProteinQ6PGP7 (Uniprot-TrEMBL)
Translatable mRNA ComplexComplexR-HSA-429977 (Reactome) mRNA's that are ready for translation have a circular structure caused by interaction between PABP bound to the 3' poly(A) tail and the eIF4E-eIF4G-PAIP complex bound to the 7-methylguanosine cap. The interaction between poly(A)-PABP and the eIF4G-eIF4E complex stimulates affinity of eIF4E for the cap and improves translation.
Uridylated partially

Deadenylated mRNA

Complex
ComplexR-HSA-8960059 (Reactome)
WDR61 ProteinQ9GZS3 (Uniprot-TrEMBL)
XRN1ProteinQ8IZH2 (Uniprot-TrEMBL)
ZCCHC11 ProteinQ5TAX3 (Uniprot-TrEMBL)
ZCCHC6 ProteinQ5VYS8 (Uniprot-TrEMBL)
ZCCHC6, ZCCHC11ComplexR-HSA-8941311 (Reactome)
capped oligoribonucleotideR-ALL-429926 (Reactome)
cytidine 5'-monophosphateMetaboliteCHEBI:17361 (ChEBI)
decapped mRNA with 5' monophosphate R-ALL-429875 (Reactome)
eIF4AComplexR-HSA-429842 (Reactome)
guanosine 5'-monophosphateMetaboliteCHEBI:17345 (ChEBI)
mature mRNA

(eukaryotic, capped

and deadenylated)
R-ALL-429974 (Reactome) After deadenylation, mRNAs have 10-15 3' adenosine residues remaining of about 200 initial adenosine residues.
mature mRNA (eukaryotic, capped and deadenylated) R-ALL-429974 (Reactome) After deadenylation, mRNAs have 10-15 3' adenosine residues remaining of about 200 initial adenosine residues.
mature mRNA (eukaryotic, capped and partially deadenylated) R-ALL-429909 (Reactome) A partially deadenylated mRNA has about 80 3' adenosine residues remaining of about 200 initial adenosine residues..
mature mRNA (eukaryotic, capped and polyadenylated) R-ALL-430014 (Reactome) A mature, translatable mRNA has a 5' cap structure and 3' polyadenylation. The cap comprises 7-methylguanosine triphosphate linked 5' to 5' to the first ribonucleotide residue of the mRNA. About 200 adenosine residues are polymerized at the 3' end.
oligoribonucleotide

with a

5'-diphosphate
R-ALL-429925 (Reactome)
uridine 5'-monophosphateMetaboliteCHEBI:16695 (ChEBI)
uridine residue MetaboliteCHEBI:73747 (ChEBI)
uridine residueMetaboliteCHEBI:73747 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
7-MeGDPArrowR-HSA-429860 (Reactome)
7MGArrowR-HSA-5694126 (Reactome)
7MGMPArrowR-HSA-429961 (Reactome)
7MGMPR-HSA-5694126 (Reactome)
AMPArrowR-HSA-429845 (Reactome)
AMPArrowR-HSA-429955 (Reactome)
AMPArrowR-HSA-429992 (Reactome)
AMPArrowR-HSA-430021 (Reactome)
AMPArrowR-HSA-430028 (Reactome)
CCR4-NOT Complexmim-catalysisR-HSA-429955 (Reactome)
DCP1-DCP2 Decapping Complexmim-catalysisR-HSA-429860 (Reactome)
DCPSmim-catalysisR-HSA-429961 (Reactome)
Deadenylated mRNA:Lsm1-7 ComplexArrowR-HSA-429978 (Reactome)
Deadenylated mRNA:Lsm1-7 ComplexR-HSA-429860 (Reactome)
Decapped mRNA:LSM1-7 ComplexArrowR-HSA-429860 (Reactome)
Decapped mRNA:LSM1-7 ComplexR-HSA-429845 (Reactome)
EIF4BArrowR-HSA-429955 (Reactome)
EIF4BArrowR-HSA-429992 (Reactome)
EIF4EArrowR-HSA-429955 (Reactome)
EIF4EArrowR-HSA-429992 (Reactome)
EIF4G1ArrowR-HSA-429955 (Reactome)
EIF4G1ArrowR-HSA-429992 (Reactome)
Exosome:SKI complexmim-catalysisR-HSA-430028 (Reactome)
H2OR-HSA-429845 (Reactome)
H2OR-HSA-429860 (Reactome)
H2OR-HSA-429955 (Reactome)
H2OR-HSA-429961 (Reactome)
H2OR-HSA-429992 (Reactome)
H2OR-HSA-430021 (Reactome)
H2OR-HSA-430028 (Reactome)
H2OR-HSA-5694126 (Reactome)
Lsm1-7 ComplexArrowR-HSA-429845 (Reactome)
Lsm1-7 ComplexR-HSA-429978 (Reactome)
NT5C3Bmim-catalysisR-HSA-5694126 (Reactome)
PABPC1ArrowR-HSA-429955 (Reactome)
PABPC1ArrowR-HSA-429992 (Reactome)
PAIP1ArrowR-HSA-429955 (Reactome)
PAIP1ArrowR-HSA-429992 (Reactome)
PAN2-PAN3 Complexmim-catalysisR-HSA-430021 (Reactome)
PARN homodimermim-catalysisR-HSA-429992 (Reactome)
Partially

Deadenylated mRNA

Complex
ArrowR-HSA-430021 (Reactome)
Partially

Deadenylated mRNA

Complex
R-HSA-429955 (Reactome)
Partially

Deadenylated mRNA

Complex
R-HSA-429992 (Reactome)
Partially

Deadenylated mRNA

Complex
R-HSA-8941312 (Reactome)
PiArrowR-HSA-5694126 (Reactome)
R-HSA-429845 (Reactome) The XRN1 exoribonuclease hydrolyzes decapped mRNA from 5' to 3' and yields ribonucleotides having 5'-monophosphates. In yeast Xrn1 associates with the Lsm1-7 complex.
R-HSA-429860 (Reactome) The DCP1-DCP2 decapping complex binds the 7-methylguanosine cap of mRNA and hydrolyzes the triphosphate bond to yield 7-methylguanosine 5'-diphosphate and RNA with 5'-monophosphate. The DCP2 subunit of the complex catalyzes the hydrolysis. DCP2 has higher affinity for some subsets of mRNA.
R-HSA-429955 (Reactome) The CCR4-NOT complex hydrolyzes adenosine residues at the 3' end of polyadenylated mRNA, shortening the number of adenosine residues to about 10-15 residues and yielding adenosine 5'-monophosphate. CNOT6 and CNOT6L are the exoribonucleases responsible for hydrolysis. Activity of the CCR4-NOT complex is inhibited by PABP bound to the poly(A) tail of the mRNA. The trigger for activation of deadenylation by the CCR4-NOT complex is unknown. Complexes containing CNOT7 rather than CNOT8 appear to be responsible for cytoplasmic mRNA decay.
R-HSA-429961 (Reactome) The scavenging nuclease DCPS hydrolyzes the triphosphate bond between the 7-methylguanosine cap and the remaining oligoribonucleotide body of the mRNA. The products are 7-methylguanosine 5'-monophosphate and an oligoribonucleotide with a 5'-diphosphate.
R-HSA-429978 (Reactome) The Lsm1-7 complex forms a heptameric ring that binds the 3' oligoadenylated ends of mRNAs that have been deadenylated. The bound Lsm1-7 may prevent access of the exosome (a 3' to 5' exonuclease) to the 3' end and thereby direct the mRNA to the 5' to 3' exonuclease pathway. The yeast Lsm1-7 complex has a preference for oligoadenylated RNA compared to polyadenylated RNA, however other determinants of binding by Lsm1-7 are unknown.
R-HSA-429992 (Reactome) The PARN exoribonuclease hydrolyzes adenosine residues at the 3' ends of polyadenylated mRNA, shortening the poly(A) tail from about 80 adenosine residues to about 10-15 residues and yielding adenosine 5'-monophosphate. PARN interacts simultaneously with the poly(A) tail and with the 7-methylguanosine cap of the mRNA, therefore it is believed that PARN displaces the eIF4F cap-binding complex. The trigger for deadenylation by PARN is unknown. PARN is also part of a complex that regulates poly(A) tail length and hence translation in developing oocytes.
R-HSA-430021 (Reactome) The PAN2-PAN3 exoribonuclease complex hydrolyzes the poly(A) tail of a mRNA, shortening the tail from about 200 adenosine residues to about 80 adenosine residues and yielding adenosine 5'-monophosphate. PAN2 is the exoribonuclease component of the complex; PAN3 is required for cellular localization. The poly(A)-binding protein (PABP) interacts with PAN3 and recruits the PAN2-PAN3 complex to mRNA.
R-HSA-430028 (Reactome) The exosome complex hydrolyzes capped, deadenylated mRNA from 3' to 5' and yields ribonucleotides having 5'-monophosphates. In yeast the Ski2-Ski3-Ski8 complex assists degradation by the exosome complex, however little is known about the function of the homologous Ski complex in mammals. Although many exosomal components contain exonuclease signatures, only two components have been shown to degrade RNA. Rrp6/PMSCL-100 has been shown to be involved in the 3’-5’ decay of nuclear mRNAs in yeast. Rrp6 may also function in the absence of the core exosomal components. The Rrp44/dDis3 component of the core exosome has been shown to possess both 3’-5’ exonuclease activity along with endonuclease activity via its PIN domain.
R-HSA-5694126 (Reactome) Cytosolic 7-methylguanosine phosphate-specific 5'-nucleotidase (NT5C3B) specifically hydrolyses N(7)-methylguanosine monophosphate (7MGMP) to 7-methylguanosine (7MG) and inorganic phosphate (Pi). 7MGP is a modified nucleotide byproduct of mRNA turnover and requires degradation as its incorporation into nucleic acids is undesirable (Buschmann et al. 2013).
R-HSA-8941312 (Reactome) Uridylyltransferases mediates the terminal uridylation of mRNAs, RISC-cleaved transcripts and of various non-coding RNAs including miRNAs and their precursors mRNAs (Scott and Norbury 2013, Lee et al. 2014, Munoz-Tello et al. 2015, Scheer et al. 2016). TUT4 and TUT7 (ZCCHC11, ZCCHC6) are mRNA uridylation enzymes that can act on the majority of mammalian mRNAs (Lim et al. 2014). More than 85% of mRNAs are uridylated at a frequency of higher than 1% in NIH 3T3 and HeLa cells (Chang et al. 2014). Uridylated tails were found mainly on mRNAs with polyA tails of less than 25 nucleotides, suggesting that uridylation may occur after deadenylation. There was a negative correlation between uridylation frequency and mRNA half‑life, suggesting a role of uridylation in general mRNA decay (Lim et al. 2014).. TUT4 and TUT7 (ZCCHC11, ZCCHC6) also uridylate replication-dependent histone mRNAs, which are not polyadenylated, to facilitate their degradation (Lackey et al 2016, Schmidt et al. 2011, Mullen & Marzluff 2008, Hoefig et al. 2013, Slevin et al. 2014). TUT4 and TUT7 also uridylate miRNAs and their precursors (Thornton et al. 2014, Lee et al. 2014, Ha & Kim 2014). Mono-uridylation of pre-miRNA facilitates miRNA processing, while polyuridylation of pre-miRNA triggers their degradation (Heo et al. 2012).
Translatable mRNA ComplexR-HSA-430021 (Reactome)
Uridylated partially

Deadenylated mRNA

Complex
ArrowR-HSA-8941312 (Reactome)
XRN1mim-catalysisR-HSA-429845 (Reactome)
ZCCHC6, ZCCHC11mim-catalysisR-HSA-8941312 (Reactome)
capped oligoribonucleotideArrowR-HSA-430028 (Reactome)
capped oligoribonucleotideR-HSA-429961 (Reactome)
cytidine 5'-monophosphateArrowR-HSA-429845 (Reactome)
cytidine 5'-monophosphateArrowR-HSA-430028 (Reactome)
eIF4AArrowR-HSA-429955 (Reactome)
eIF4AArrowR-HSA-429992 (Reactome)
guanosine 5'-monophosphateArrowR-HSA-429845 (Reactome)
guanosine 5'-monophosphateArrowR-HSA-430028 (Reactome)
mature mRNA

(eukaryotic, capped

and deadenylated)
ArrowR-HSA-429955 (Reactome)
mature mRNA

(eukaryotic, capped

and deadenylated)
ArrowR-HSA-429992 (Reactome)
mature mRNA

(eukaryotic, capped

and deadenylated)
R-HSA-429978 (Reactome)
mature mRNA

(eukaryotic, capped

and deadenylated)
R-HSA-430028 (Reactome)
oligoribonucleotide

with a

5'-diphosphate
ArrowR-HSA-429961 (Reactome)
uridine 5'-monophosphateArrowR-HSA-429845 (Reactome)
uridine 5'-monophosphateArrowR-HSA-430028 (Reactome)
uridine residueR-HSA-8941312 (Reactome)
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