Fragile X syndrome (Homo sapiens)

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P9664354972653512215351203585328049672163772190456620229052, 6869216321635741, 56202190201956862741196687415254632144225669205222, 528720266627472776190898921, 507627238990NMDA ReceptorPoolOther targetsstalled polyribosomesFXS:loss of FMRPNMDARinternalizationNMDARsubunitsGABA A Receptor SubunitsAnterior cingulate cortexBasolateral AmygdalaDefective cAMP production8214RISC ComplexGABAergic synapse components19Dysregulated metabolic homeostasis48, 84TSC complex PKAeIF4F complexmGluR-LTD25Receptor subunitsHippocampus CA18AMPA ReceptorEnteric innervation of the ileum95upregulationTrkB ReceptorLTD proteins179ClathrinNMDA ReceptorAMPAR internalizationAMPA Receptor PoolDysregulation of GABAergic synaptic transmissiondeletionrelease of Ca2+Lipid and glucose metabolsim48AP-2Group I mGluR27mTORC16GDPGABRDGRM5FYNKCND2EEF1A1MMP9GRIN2AGRIN2ADUSP3BDNF-TrkB SignallingHOMER1HCN1glutamateKCNC1EPS8L1CNR1SRCCYFIP23611ABAT1PI3K-Akt-mTOR Pathway17CAMKIV-CREB PathwayglutamateBDNFAP2A1PLCB1GAD1cAMPCLTCL1PPP3CAGRIP2CREB1DLG4DLG44, 15SLC6A158PRKCAGAD173PRKACAMEK-ERK-Mnk1 Pathway17EIF4G1ALDH5A15γ-aminobutyric acid18SHC1GRIA1CLTCAP2B1CPT1APRKACAPIP2PTPN5GRB2CLTBGPHN46GRIP1DLG4GRIA2APPmiR-125bCAMK4CREB1PTPN11GRIA1AP2S1AGO2AKAP559GABRG2CAMK1ARHGAP3288GAB1GABRA1PTPN552, 92Dynamin-1DICER174AP2M1PICK1DAG1GRIN2B51, 63GABRB2endocannabinoidsNTRK2SLC16A1CLTAGRIA2SYNGAP1ITPR1PPP1CA40PLCG1CAMK2BSHANK1DLG4DLGAP3MAP2K2FMR152MAP1BARCMKNK1RPS6KB1MAP1B52MAPK1KRASCYFIP191AKT1S1ARC97MAP2K1CAMK2ASOS194PPP2R5BEIF4EBP2RAF1NF131EIF4ECAMK2A3, 24FMR1DEPTORTELO2RPTORMLST8MTORPIK3CBTTI1GRM5RHEBHOMER1GRM1PDK1AGAP2PIP2PTENTSC1AKT1PIP3TSC2TBC1D7RHEBGTPP at Ser500KRASGDPGTPPPPPPDLGAP334, 38SHANK181GRIN2BGRIN2B29GABRA1GABRB2GABRG2GPHNSLC6A1ABATALDH5A1ALDH3A2ABCD3TECRCPT1A37, 48SLC16A148ALDH3A216, 48ABCD393TECR60PPRKAR1APRKAR1APFMR1Influx Ca2+GRIA1GRIA2AMPA ReceptorPGRIA2GRIA159GRIA1GRIA2miR-132miR-196aSH3GL1DNM268279379PP at Thr308EIF4A1TARBP2EIF4EBP286MECP278EPHA483GRIN2ACDKN2AHOXB8MAP2K2MAP2K1MAPK1MKNK1BRAFARAFPSH3GL3mGluR-LTPAMPA ReceptorAMPAR exocytosis5970307275downregulation484848NMDARLTD2PKAPRKACAPRKACAPRKAR1APRKAR1AAPP13, 4353Cerebellar cortex71Amygdala20, 55, 95Corticostriatal synapse95Neocortical layer5 neurons95Audiogenic seizures95C-fiber innervation95Suprachiasmatic nucleus9594392GRIN2B63P at Y1472PAP-2AP2A1AP2B1AP2S1AP2M1ClathrinCLTCL1CLTC35CLTBCLTAGRIN2B63overactivationSomatosensoryCortexStriatumSubiculum Hippocampus CA1PTENPTEN2828GRIN1GRIN1DUSP31010NMDARLTPNMDARintsertionEEF1A1CYFIP2GABRD53GRM5HCN1KCNC1KCND2MMP9PRKCAPPRAP1GAP33, 39PEPS8L1P42SHANK181PTPN5MAP1B52, 9252PTPN5DUSP352, 9210hypofunction


Description

Fragile X syndrome (FXS) is a monogenetic disorder cause by a mutation in the FMR1 gene and the most common form of inherited intellectual disability and autism spectrum disorder (ASD). Patients with FXS show a range of typical physical features such as macro-orchidism in males, a long and narrow face, large and protruding ears and hyperextensible joints. Common comorbidities of FXS are neuropsychiatric disorders such as hyperactivity, depression and anxiety. The mutation of FMR1 in FXS disrupts production of the FMR1 gene product, the fragile mental retardation protein (FMRP). The main function of FMRP is to locally act as a translational repressor for target mRNAs and thereby regulate de novo protein synthesis and ultimately synaptic plasticity. FMRP, together with the mTOR pathway and the ERK pathway regulates expression of target mRNAsn mediated by stimulation of Group I metabotropic glutamate receptors (mGluR) and thereby regulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalisation and thus long term depression (LTD). LTD is a form of synaptic plasticity which is involved in learning and memory. Lack of FMRP leads to exaggerated mGluR dependant LTD, which accounts for most of FXS pathogenesis.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
134295view05:59, 20 July 2024EgonwRemoved a template comment
127643view19:49, 13 November 2023Khanspersremoved one final it ref for protein database
127642view19:44, 13 November 2023Khanspersremoved literature references to protein/gene databases
127609view14:38, 7 November 2023LarsgwRemove tab character from bp:DB
125304view17:46, 31 January 2023LarsgwFix PMID in reference
124287view13:32, 9 October 2022EgonwModern Uniprot data source
124286view10:37, 9 October 2022VanessaSousa
124285view10:34, 9 October 2022VanessaSousa
123421view06:15, 26 July 2022EgonwMade two pathways clickable
119333view08:04, 24 June 2021FinterlyFixed Biopax PublicationXrefs with missing ID, and removed duplicates
118442view14:46, 27 May 2021Mkutmonfix publication refs
117111view21:38, 17 May 2021EweitzModified title
108088view11:54, 28 November 2019FehrhartOntology Term : 'disease pathway' added !
104796view08:08, 18 June 2019FehrhartConnected unconnected lines
104314view12:15, 16 May 2019MkassChanged direction of arrows from Kras-GTP to Kras-GDP (they were pointed at the wrong direction)
104286view12:39, 15 May 2019FehrhartOntology Term : 'autism spectrum disorder' added !
104285view12:38, 15 May 2019FehrhartOntology Term : 'brain disease pathway' added !
104284view12:37, 15 May 2019FehrhartOntology Term : 'neuron' added !
104037view18:35, 25 April 2019MkassChanged mim conversion arrows from FMR1 to phosphorylated FMR1 because they pointed at the wrong direction
103984view12:12, 23 April 2019MkassChanged location of 'mGluR-LTP --> Amygdala'
103983view09:39, 23 April 2019MkassAddition of MIM inhibition from stalled polyribosomes to target mRNA
103982view09:15, 23 April 2019MkassAdded MIM stimulation (in blue) from FMR1 to GABA mRNAs
103972view12:21, 18 April 2019MkassAdded grey backgroud to AMPAR
103971view12:17, 18 April 2019MkassAdded some annotations on how NMDAR, TrkB and cAMP are affected in FXS
103970view11:16, 18 April 2019MkassRestructuring of the pathway to have a better overview
103892view12:48, 14 April 2019Mkass
103823view13:35, 9 April 2019Mkassupdated legend
103822view13:30, 9 April 2019Mkass
103817view09:57, 9 April 2019Mkass
103814view09:09, 9 April 2019MkassFixed unconnected interactions
103804view19:04, 8 April 2019MkassModified description
103803view18:36, 8 April 2019MkassModified description
103802view18:32, 8 April 2019Mkass
103780view18:11, 5 April 2019Mkass
103776view15:01, 5 April 2019Mkass
103775view10:52, 5 April 2019Mkass
103774view09:23, 5 April 2019Mkass
103773view08:17, 5 April 2019Mkass
103772view07:54, 5 April 2019EgonwFixed a Pubmed identifier.
103762view09:49, 4 April 2019Mkass
103735view13:38, 2 April 2019Mkass
103734view10:15, 1 April 2019Mkass
103733view10:04, 1 April 2019Mkass
103732view09:12, 1 April 2019Mkass
103731view21:11, 31 March 2019Mkass
103730view20:40, 31 March 2019AndraOntology Term : 'fragile X syndrome' added !
103726view10:56, 31 March 2019Mkass
103685view12:39, 28 March 2019Mkass
103684view12:27, 28 March 2019Mkass
103683view11:20, 28 March 2019Mkass

External references

DataNodes

View all...
NameTypeDatabase referenceComment
ABATRnaENSG00000183044 (Ensembl)
ABCD3GeneProductENSG00000117528 (Ensembl) ABCD3, a peroxisomal membrane protein, is involved in the transport of branched chain acyl-CoA into peroxisomes. ABCD3 is a fatty acid (FA) transporter protein.
AGAP2GeneProductENSG00000135439 (Ensembl)
AGO2GeneProductENSG00000123908 (Ensembl)
AKAP5GeneProductENSG00000179841 (Ensembl) A-kinase anchor protein 5 (AKAP5) anchors protein kinase A (PKA) at the PSD by directly interacting with PSD-95. This interaction is important for NMDAR-dependant AMPAR endocytosis and LTD.
AKT1GeneProductENSG00000142208 (Ensembl)
AKT1S1GeneProductENSG00000204673 (Ensembl)
ALDH3A2GeneProductENSG00000072210 (Ensembl) Fatty aldehyde dehydrogenase (ALDH3A2) catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acids. ALDH3A2 has shown to be essential for the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation.
ALDH5A1RnaENSG00000112294 (Ensembl)
AP2A1GeneProductENSG00000196961 (Ensembl)
AP2B1GeneProductENSG00000006125 (Ensembl)
AP2M1GeneProductENSG00000161203 (Ensembl)
AP2S1GeneProductENSG00000042753 (Ensembl)
APPGeneProductENSG00000142192 (Ensembl)
  • Amyloid-beta precursor protein (APP), large membrane-spanning glycoprotein, is implicated in neurogenesis and synapse formation. It is mainly expressed in synapses. APP is suspected to contribute to altered mGluR-LTD.
  • Type your comment here
ARAFGeneProductENSG00000078061 (Ensembl)
ARCGeneProductENSG00000198576 (Ensembl) Activity-regulated cytoskeleton-associated protein (ARC) is a key regulator of synaptic plasticity. It is required for protein synthesis-dependent LTP and LTD as well as for the formation of long-term memory. ARC regulates synaptic plasticity by promoting endocytosis of AMPA receptors AMPAR and thus, LTD.
ARHGAP32GeneProductENSG00000134909 (Ensembl) Rho GTPase activating protein 32 (ARHGAP32) is a neuron-associated GAP that may regulate dendritic spine morphology and strength through modulation of Rho GTPase activity.
BDNF-TrkB SignallingPathwayWP3676 (WikiPathways)
BDNFGeneProductENSG00000176697 (Ensembl)
BRAFGeneProductENSG00000157764 (Ensembl)
CAMK1GeneProductENSG00000134072 (Ensembl)
CAMK2AGeneProductENSG00000070808 (Ensembl) calcium/calmodulin dependent protein kinase II alpha (CAMKIIα) is expressed at synapses where its translation is negatively regulated by FMRP. CAMKIIα is a key determinant for AMPAR internalization and thus LTD. The protein kinase mediates AMPAR internalization through phosphorylation of AMPAR subunits. CAMKIIα is involved in synaptic plasticity, neurotransmitter release and LTP.
CAMK2BGeneProductENSG00000058404 (Ensembl) CAMKII catalyzes the phosphorylation of AMPAR an
CAMK4GeneProductENSG00000152495 (Ensembl) CAMK4 or CAMKIV
CAMKIV-CREB PathwayPathway
CDKN2AGeneProductENSG00000147889 (Ensembl) Cyclin-dependent kinase inhibitor 2A (CDKC2A)
CLTAGeneProductENSG00000122705 (Ensembl)
CLTBGeneProductENSG00000175416 (Ensembl)
CLTCGeneProductENSG00000141367 (Ensembl) Clathrin mediates the endocytosis of NMDAR by binding to AP-2
CLTCL1GeneProductENSG00000070371 (Ensembl)
CNR1GeneProductENSG00000118432 (Ensembl)
CPT1AGeneProductENSG00000110090 (Ensembl) CPT1A encodes the hepatic enzyme carnitine palmitoyltransferase 1A. The enzyme is responsible for fatty acid oxidation within the mitochondria, it connects carnitine to long-chain fatty acids thereby enabling the crossing of the fatty acid into the inner membrane of mitochondria. FMRP negatively regulates CPT1A and thus lipid metabolism.
CREB1GeneProductENSG00000118260 (Ensembl)
CYFIP1GeneProductENSG00000273749 (Ensembl) CYFIP1 interacts with FMRP and with translation initiation factor eIF4E
CYFIP2RnaENSG00000055163 (Ensembl)
DAG1GeneProductENSG00000173402 (Ensembl)
DEPTORGeneProductENSG00000155792 (Ensembl)
DICER1GeneProductENSG00000100697 (Ensembl) DICER, is an endonuclease, which cleaves double stranded RNA (dsRNA) into short single stranded RNA called miRNA and tehreby faciliates the activation of RISC
DLG4RnaENSG00000132535 (Ensembl)
DLGAP3GeneProductENSG00000116544 (Ensembl) SAP90/PSD-95-associated protein 3 (SAPAP3) plays a role in the organization of synapses and neuronal cell signaling and is negatively regulated by FMRP. SAPAP3 is a postsynaptic scaffolding protein which is associated with PSD-95 and localized in dendrites. SAPAP3 plays an improtant role in maturation of synapses
DNM2GeneProductENSG00000079805 (Ensembl) Dynamin is a large GTPase modulating release of endosomes from the membrane by pinching off and fissioning the membrane.
DUSP3GeneProductENSG00000108861 (Ensembl) Also referred to as VHR, a ERK specific phosphatase
Dynamin-1ProteinA0A0D9SFB1 (Uniprot-TrEMBL)
EEF1A1GeneProductENSG00000156508 (Ensembl) Eukarytic translation elongation factor (EF1α)
EIF4A1GeneProductENSG00000161960 (Ensembl)
EIF4EBP2GeneProductENSG00000148730 (Ensembl) Phosphorylated 4E-BP cannot bind to eIF4E anymore, this means that its inhibitory effect on translation is repressed
EIF4EGeneProductENSG00000151247 (Ensembl)
EIF4G1GeneProductENSG00000114867 (Ensembl)
EPHA4GeneProductENSG00000116106 (Ensembl) Ephrin type-A receptor 4 (EPHA4) is a receptor tyrosine kinase binding tp ephrin ligands. EPHA4 is has a function in the development of the nervous system.
EPS8L1GeneProductENSG00000131037 (Ensembl) Epidermal growth factor receptor pathway substrate 8-related protein 1 (EPS8L1) is an FMRP target and important for teh remodelling of actin in response to EGF stimulation. EPS8L1 gene product EPS8 is needed for normal spine morphology, synaptic plasticity, and memory formation. EPS8 has been shown to be downregulated in autism, since it's a binding partner of FMRP, it is likely that it is also downregulated in FXS.
FMR1GeneProductENSG00000102081 (Ensembl)
FYNGeneProductENSG00000010810 (Ensembl) Tyrosine-protein kinase Fyn (FYN) is a member of the Src family of tyrosine kinases which is involved in the regulation of brain function.
GAB1GeneProductENSG00000109458 (Ensembl)
GABRA1RnaENSG00000022355 (Ensembl)
GABRB2RnaENSG00000145864 (Ensembl)
GABRDProteinENSG00000187730 (Ensembl)
GABRG2RnaENSG00000113327 (Ensembl)
GAD1GeneProductENSG00000128683 (Ensembl) Glutamate decarboxylase 1 (GAD1) encoded an enzyme (glutamic acid decarboxylase) that has a role in γ-aminobutyric acid (GABA) synthesis. The enzyme catalyzes the production of GABA from L-glutamic acid.
GPHNRnaENSG00000171723 (Ensembl)
GRB2GeneProductENSG00000177885 (Ensembl)
GRIA1GeneProductENSG00000155511 (Ensembl) AMPAR subunit GuA1
GRIA2GeneProductENSG00000120251 (Ensembl) AMPAR subunit GluA2
GRIN1GeneProductENSG00000176884 (Ensembl)
GRIN2AGeneProductENSG00000183454 (Ensembl) NMDA receptor subunit 2 A
GRIN2BGeneProductENSG00000273079 (Ensembl) N-methyl-D-aspartate (NMDA)-type glutamate receptors (NMDAR) are ionotropic receptors activated by glutamate. NMDAR activation allows Ca2+ influx leading to NMDAR-dependant LTP and LTD
GRIP1GeneProductENSG00000155974 (Ensembl)
GRIP2GeneProductENSG00000144596 (Ensembl) Glutamate receptor-interacting protein 2 (GRIP2) also called AMPAR binding protein (ABP) interacts with GRIP1 to regulate AMPAR trafficking
GRM1GeneProductENSG00000152822 (Ensembl)
GRM5RnaENSG00000168959 (Ensembl)
HCN1GeneProductENSG00000164588 (Ensembl) Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1)
HOMER1GeneProductENSG00000152413 (Ensembl) Long homer variant
HOXB8GeneProductENSG00000120068 (Ensembl)
ITPR1GeneProductENSG00000150995 (Ensembl)
KCNC1GeneProductENSG00000129159 (Ensembl)
KCND2GeneProductENSG00000184408 (Ensembl)
KRASGeneProductENSG00000133703 (Ensembl)
MAP1BGeneProductENSG00000131711 (Ensembl) Microtubule-associated protein 1B (MAP1B) is involved in mcirotubule assembly and neurogenesis. MAP1b is involved in the regulation of the morphology of dendritic spines in glutamatergic synapses. Furthermore, MAP1b is a negative regulator of AMPAR surface expression thereby contributing to mGluR-LTD.
MAP2K1GeneProductENSG00000169032 (Ensembl)
MAP2K2GeneProductENSG00000126934 (Ensembl)
MAPK1GeneProductENSG00000100030 (Ensembl)
MECP2GeneProductENSG00000169057 (Ensembl) Methyl-CpG-binding protein 2 (MECP2) is a nuclear protein that is capable of binding to methylated DNA. It is essential for nerve cell functionality.
MEK-ERK-Mnk1 PathwayPathwaymap04010 (KEGG Pathway) Activation of ERK pathway is required for mGlur-LTD. ERK activation is thought to control the activation of specific mRNAs such as the LTD proteins.
MKNK1GeneProductENSG00000079277 (Ensembl)
MLST8GeneProductENSG00000167965 (Ensembl)
MMP9GeneProductENSG00000100985 (Ensembl)
MTORGeneProductENSG00000198793 (Ensembl)
NF1GeneProductENSG00000196712 (Ensembl) NF1 functions as a guanine exchange factors (GEF), stimulating the conversion of GTP-bound RAS into GDP-bound RAS and tehreby negatively regulating the MEK-ERK-Mnk1 pathway.
NTRK2GeneProductENSG00000148053 (Ensembl)
PDK1GeneProductENSG00000152256 (Ensembl)
PI3K-Akt-mTOR

Pathway

PathwayWP4172 (WikiPathways) Activation of mTOR pathway is required for mGlur-LTD. mTOR activation is believed to sustain the increase in overall rate of mRNA translation at the synapse.
PICK1GeneProductENSG00000100151 (Ensembl) Protein Interacting with Kinase C 1 (PICK1)
PIK3CBGeneProductENSG00000051382 (Ensembl)
PIP2MetaboliteCHEBI:18348 (ChEBI)
PIP3MetaboliteCHEBI:16618 (ChEBI)
PLCB1GeneProductENSG00000182621 (Ensembl)
PLCG1GeneProductENSG00000124181 (Ensembl)
PPP1CAGeneProductENSG00000172531 (Ensembl) PP1 had 4 isomforms, however, in this pathway, only one (gene PPP1CA) has been used since literature did not specify which isoform is involved in this specific case.
PPP2R5BGeneProductENSG00000068971 (Ensembl)
PPP3CAGeneProductENSG00000138814 (Ensembl) Calcineurin
PRKACAGeneProductENSG00000072062 (Ensembl)
PRKAR1AGeneProductENSG00000108946 (Ensembl)
PRKCAGeneProductENSG00000154229 (Ensembl)
  • Protein Kinase C
  • mGluR activation leads to activation of the PLC pathway which induces release of Ca2+ and PKC. PKC will phohsphorylate and activate RAF1 and tehereby activate RAF1 and thus the ERK pathway
PTENRnaENSG00000171862 (Ensembl) PTEN is enhanced by FMRP and negatively regulates GABA A receptor subunits, this way PTEN has a protective role in reducing GABA A deficiency-indiced incidence of seizures
PTPN11GeneProductENSG00000179295 (Ensembl)
PTPN5GeneProductENSG00000110786 (Ensembl) Tyrosine-protein phosphatase non-receptor type 5 (STEP) is involves to regulate AMPAR trafficking and negatively regulates AMPAR surface expression thereby contributing to mGluR-LTD. STEP promotes LTD by stimulating synaptic weakening by dephosphorylation of ERK1/2 and subunits of NDMA and AMPA receptors. STEP has been shown to promote NMDA internalization.
RAF1GeneProductENSG00000132155 (Ensembl)
RAP1GAPGeneProductENSG00000076864 (Ensembl) RAP1 is phsohprylated and activated by PKA and in turn stimulates the activation of B-Raf, thus leading to the activation of the ERK pathway
RHEBGeneProductENSG00000106615 (Ensembl)
RPS6KB1GeneProductENSG00000108443 (Ensembl)
RPTORGeneProductENSG00000141564 (Ensembl)
SH3GL1GeneProductENSG00000141985 (Ensembl) Endophoilin 2
SH3GL3GeneProductENSG00000140600 (Ensembl) Endopilin 3
SHANK1GeneProductENSG00000161681 (Ensembl) Shank, an adapter protein in the PSD of excitatory synapses, is necessary for the structural and functional integrity of dendritic spines and synaptic junction.
SHC1GeneProductENSG00000160691 (Ensembl)
SLC16A1GeneProductENSG00000155380 (Ensembl) Monocarboxylate transporter 1 (MCT1) is a proton coupled monocarboxylate transporter which function is to catalyse the rapid transport of many monocarboxylates across the plasma membrane.
SLC6A1RnaENSG00000157103 (Ensembl)
SOS1GeneProductENSG00000115904 (Ensembl) SOS, a guanine-associated echange factor (GEF), activates Ras by inducing the exchange of GTDP by GTP. This positively regulates Ras signalling.
SRCGeneProductENSG00000197122 (Ensembl)
SYNGAP1GeneProductENSG00000197283 (Ensembl)
TARBP2GeneProductENSG00000139546 (Ensembl)
TBC1D7GeneProductENSG00000145979 (Ensembl)
TECRGeneProductENSG00000099797 (Ensembl) Very-long-chain enoyl-CoA reductase (TECR) is responsible to catalyze the last of the four reactions of the long-chain fatty acids elongation cycle.
TELO2GeneProductENSG00000100726 (Ensembl)
TSC1GeneProductENSG00000165699 (Ensembl)
TSC2GeneProductENSG00000103197 (Ensembl)
TTI1GeneProductENSG00000101407 (Ensembl)
cAMPMetaboliteCHEBI:17489 (ChEBI)
endocannabinoidsMetaboliteCHEBI:67197 (ChEBI)
glutamateMetaboliteCHEBI:14321 (ChEBI)
miR-125b RnaMIMAT0042091 (miRBase mature sequence)
miR-132 RnaMIMAT0004594 (miRBase mature sequence)
miR-196a RnaMIMAT0000226 (miRBase mature sequence)
γ-aminobutyric acidMetaboliteCHEBI:16865 (ChEBI) γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system.

Annotated Interactions

No annotated interactions

Retrieved from "https://classic.wikipathways.org/index.php/Pathway:WP4549"
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