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# The impact of SARS CoV-2 Nsp14 on metabolism
## Map description
The viral protein Nsp14 of the novel SARS-CoV-2 is known to interact with three human proteins: the ⍺-galactosidase A (GLA), sirtuin 5 (SIRT5), and the IMP dehydrogenase 2 (IMPDH2) [DOI 10.1038/s41586-020-2286-9]. GLA plays a central role in the galactose metabolism and catalyzes the hydrolysis of ⍺-D-galactopyranose residues [DOI 10.1016/j.jmb.2004.01.035]. SIRT5 is a NAD-dependent desuccinylase and demanlonylase [DOI 10.1126/science.1207861]. It is located in the mitochondria and plays a pivotal role in the oxidative metabolism and apoptosis initiation [DOI 10.1016/j.jmb.2008.07.048]. In liver cells, it controls the detoxification of ammonia [DOI 10.1080/15548627.2015.1009778]. It is furthermore associated with the human nicotinate and nicotinamide metabolism. The IMP dehydrogenase is the rate-limiting enzyme in the de novo synthesis of GTP [DOI 10.1186/s13008-018-0038-0]. This feature turns the IMPDH2 into an attractive target for the regulation of the purine metabolism. The purine metabolism contains potential antiviral-targets, including the IMPDH2, the guanylate kinase (GK1), and the adenylosuccinate lyase (ADSL) [DOI 10.5281/zenodo.3752641].
The map displays the three pathways (galactose metabolism, nicotinate and nicotinamide metabolism, and purine metabolism) that are affected by Nsp14. The modulating nature of Nsp14 on the three enzymes is currently not known.
## Cross-talk with other pathways
The galactose metabolism, harboring the GLA enzyme, is interconnected with the amino sugar and nucleotide sugar metabolism, as well as further sugar metabolisms, such as fructose or mannose. The enzyme SIRT5 can desuccinylate the serine hydroxymethyltransferase SHMT2, leading to increased serine catabolism [DOI 10.1158/0008-5472.CAN-17-1912]. The IMPDH plays a crucial role in the metabolism and proliferation of cells [DOI 10.1186/s13008-018-0038-0]. It is a central human metabolism, connected to a variety of other pathways, such as the riboflavin or histidine metabolism, or the pentose phosphate pathway. Downstream of the purine metabolism, the nucelobases guanine and adenine are synthesized.
## Creators
[Alina Renz](https://fairdomhub.org/people/1564)
[Andreas Draeger](https://fairdomhub.org/people/1569)
## Contributors and reviewers
[Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model at FairdomHub (https://fairdomhub.org/models/710)
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......@@ -8,7 +8,10 @@ The map describes the ubiquitin-activating enzymes (E1s), the ubiquitin-conjugat
The ubiquitin-proteasome system is a key regulator of protein degradation and influences the levels of various proteins within the cell. This results in the modulation of cellular processes, including cell cycle progression and apoptosis [DOI: 10.1128/JVI.00485-10]. Furthermore, it has been shown that the ubiquitin-proteasome system plays an important role during various stages of the infection cycle of coronaviruses [DOI: 10.1128/JVI.00485-10]. RNA synthesis is modulated [DOI: 10.1128/JVI.00485-10] and antigen presentation on MHC class I molecules depends on proteasomal function [DOI 10.1681/ASN.2006010083].
## Creators
Jan Hasenauer & Leonard Schmiester
[Jan Hasenauer](https://fairdomhub.org/people/842)
[Leonard Schmiester](https://fairdomhub.org/people/1799)
## Contributors and reviewers
Paul Stapor
**Paul Stapor**
## Model at FairdomHub (https://fairdomhub.org/models/702)
# SARS CoV-2 Virus replication cycle
## Map description
This map describes the SARS-CoV-2 replication cycle that is comprised of the following sequential events: virus attachment, entry, transcription, replication, assembly and release to extracellular space (ES). Only the virus attachment and entry processes shown in this map were from papers reporting findings directly related to SARS-CoV-2 [PMID 32142651, PMID 32094589, PMID 32047258, PMID 32362314]; the remaining processes were inferred based on papers reporting findings related to other coronaviruses [PMID 11907209, PMID 15564471, PMID 17316733. PMID 21203998, PMID 22438542, PMID 23035226, PMID 23943763, PMID 27712623, PMID 28484023, PMID 28720894, PMID 30632963, PMID 31226023, PMID 8830530, DOI 10.1101/2020.03.24.005298].
To attach to host cells, SARS-CoV-2 uses its envelope glycoprotein spike (S) that binds at least to one cellular membrane receptor, the angiotensin-converting enzyme 2 (ACE2) [PMID 32094589, PMID 32142651]. Once attached, SARS-CoV-2 can enter cells either by direct fusion of the virion and cell membranes in the presence of proteases transmembrane protease, serine 2 (TMPRSS2) and FURIN [PMID 32142651, PMID 32362314] or by endocytosis in the absence of these proteases [PMID 32142651]. Regardless of the entry mechanism, the S protein has to be activated to initiate the plasma or endosome membrane fusion process. While in the cell membrane S is activated by TMPRSS2 and FURIN [PMID 32142651, PMID 32362314], in the endosome S is activated by cathepsins B (CTSB) and L (CTSL) [PMID 32142651]. When activated, S promotes the cell or endosome membrane fusion [PMID 32047258] with the virion membrane and then the nucleocapsid is injected into the cytoplasm.
Within host cell, SARS-CoV-2 is expected to hijack the rough endoplasmic reticulum (RER)-linked host translational machinery that then synthesize the viral proteins replicase polyprotein 1a (pp1a) and replicase polyprotein 1ab (pp1ab) directly from the virus (+)genomic RNA (gRNA) [PMID 31226023, PMID 27712623]. Through a complex cascade of proteolytic cleavages, pp1a and pp1ab give raise to 16 non-structural proteins (Nsps) [PMID 11907209, PMID 15564471, PMID 21203998]. Most of these Nsps collectively form the replication transcription complex (RTC) that is anchored to the membrane of the double-membrane vesicle (DMV) [PMID 11907209, PMID 30632963], a coronavirus replication organelle induced by Nsps 3, 4 and 6 [PMID 23943763].
RTC is thought to play two main roles: (1) to trigger the synthesis of both (+)gRNA and (+)subgenomic messenger RNAs (sgmRNAs) via negative-stranded templates [PMID 8830530, PMID 22438542, DOI 10.1101/2020.03.24.005298] and (2) to protect intermediate double-stranded RNAs from the cell innate immunity sensors [PMID 17316733]. The (+)sgmRNAs are translated by the RER-attached translation machinery into structural (E, M, N and S) and accessory proteins (Orf3a, Orf6, Orf7a, Orf7b, Orf8, Orf9b, Orf10 and Orf14) [PMID 27712623, PMID 31226023]. The structural proteins and the newly generated (+)gRNAs are assembled into new virions in the endoplasmic reticulum-Golgi intermediate compartment and these virions are released to ES via smooth-walled vesicles [PMID 31226023].
## Cross-talk with other pathways (in the map, and in general)
To understand how COVID-19 develops, it is crucial to decipher the underlying molecular mechanisms of the SARS-CoV-2 replication cycle since all signalling cascades that culminate in the emergence of clinical symptoms derive essentially from the events encompassing the replication cycle. So, as expected, all other pathways described in this COVID-19 disease map are downstream to the replication cycle. It is worth noting, however, that two pathways, ER stress and linoleic acid metabolism, are apparently disconnected from the virus replication cycle.
## Creators
[Marcio Acencio](https://fairdomhub.org/people/1518)
[Alexander Mazein](https://fairdomhub.org/people/755)
## Contributors and reviewers
[Marek Ostaszewski](https://fairdomhub.org/people/665)
## Model at FairdomHub (https://fairdomhub.org/models/703)
Include,Resource,Type,Name
No,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4846.gpml,GPML,WP4846
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4853.gpml,GPML,Linoleic acid metabolism
No,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4860.gpml,GPML,WP4860
No,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4861.gpml,GPML,WP4861
No,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4862.gpml,GPML,WP4862
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4863.gpml,GPML,HCoVs autophagy (WP4863)
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4868.gpml,GPML,HCoVs Type I Ifn signaling (WP4868)
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4880.gpml,GPML,HCoVs Ifn induction (WP4880)
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4876.gpml,GPML,SARS-CoV-2 NLRP3 Inflammasome (WP4876)
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Apoptosis/Apoptosis_stable.xml,CellDesigner_SBML,Apoptosis
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Coagulation%20pathway/Coagulation-pathway_stable.xml,CellDesigner_SBML,Coagulation pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/ER%20Stress/ER_Stress_stable.xml,CellDesigner_SBML,ER stress
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/ETC/ETC_stable.xml,CellDesigner_SBML,ETC
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/HMOX1%20pathway/HMOX1_Pathway_stable.xml,CellDesigner_SBML,HMOX1 pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Interferon%20pathway/Interferon1_stable.xml,CellDesigner_SBML,Interferon 1 pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/JNK%20pathway/JNK_pathway_stable.xml,CellDesigner_SBML,JNK pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/PAMP%20signalling/PAMP_signaling_stable.xml,CellDesigner_SBML,PAMP signaling
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Pyrimidine%20deprivation/Pyrimidine_deprivation_stable.xml,CellDesigner_SBML,Pyrimidine deprivation
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Renin-angiotensin%20pathway/Renin_angiotensin_stable.xml,CellDesigner_SBML,Renin-angiotensin pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/RTC-and-transcription/RTC-and-transcription_stable.xml,CellDesigner_SBML,RTC and transcription
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/E/E_protein_stable.xml,CellDesigner_SBML,E protein interactions
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/Nsp4_Nsp6/Nsp4_Nsp6_proteins_stable.xml,CellDesigner_SBML,Nsp4 and Nsp6 interactions
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/Nsp9/Nsp9_protein_stable.xml,CellDesigner_SBML,Nsp9 interactions
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/Nsp14/Nsp14_stable.xml,CellDesigner_SBML,Nsp14 and metabolism
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/Orf3a/Orf3a_stable.xml,CellDesigner_SBML,Orf3a interactions
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Ubiquination%20and%20Protein%20Degradation/Orf10_Cul2_pathway_stable.xml,CellDesigner_SBML,Orf10 Cul2 pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Virus%20replication%20cycle/Virus_replication_cycle_stable.xml,CellDesigner_SBML,Virus replication cycle
Include,Resource,Type,Name
No,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4846.gpml,GPML,WP4846
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4853.gpml,GPML,Linoleic acid metabolism
No,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4860.gpml,GPML,WP4860
No,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4861.gpml,GPML,WP4861
No,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4862.gpml,GPML,WP4862
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4863.gpml,GPML,HCoVs autophagy (WP4863)
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4868.gpml,GPML,HCoVs Type I Ifn signaling (WP4868)
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4880.gpml,GPML,HCoVs Ifn induction (WP4880)
Yes,https://raw.githubusercontent.com/wikipathways/SARS-CoV-2-WikiPathways/master/gpml/WP4876.gpml,GPML,SARS-CoV-2 NLRP3 Inflammasome (WP4876)
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Apoptosis/Apoptosis_stable.xml,CellDesigner_SBML,Apoptosis
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Coagulation%20pathway/Coagulation-pathway_stable.xml,CellDesigner_SBML,Coagulation pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/ER%20Stress/ER_Stress_stable.xml,CellDesigner_SBML,ER stress
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/ETC/ETC_stable.xml,CellDesigner_SBML,ETC
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/HMOX1%20pathway/HMOX1_Pathway_stable.xml,CellDesigner_SBML,HMOX1 pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Interferon%20pathway/Interferon1_stable.xml,CellDesigner_SBML,Interferon 1 pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/JNK%20pathway/JNK_pathway_stable.xml,CellDesigner_SBML,JNK pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/PAMP%20signalling/PAMP_signaling_stable.xml,CellDesigner_SBML,PAMP signaling
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Pyrimidine%20deprivation/Pyrimidine_deprivation_stable.xml,CellDesigner_SBML,Pyrimidine deprivation
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Renin-angiotensin%20pathway/Renin_angiotensin_stable.xml,CellDesigner_SBML,Renin-angiotensin pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/RTC-and-transcription/RTC-and-transcription_stable.xml,CellDesigner_SBML,RTC and transcription
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/E/E_protein_stable.xml,CellDesigner_SBML,E protein interactions
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/Nsp4_Nsp6/Nsp4_Nsp6_proteins_stable.xml,CellDesigner_SBML,Nsp4 and Nsp6 interactions
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/Nsp9/Nsp9_protein_stable.xml,CellDesigner_SBML,Nsp9 interactions
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/Nsp14/Nsp14_stable.xml,CellDesigner_SBML,Nsp14 and metabolism
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/SARS-CoV-2%20proteins/Orf3a/Orf3a_stable.xml,CellDesigner_SBML,Orf3a interactions
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Ubiquination%20and%20Protein%20Degradation/Orf10_Cul2_pathway_stable.xml,CellDesigner_SBML,Orf10 Cul2 pathway
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Virus%20replication%20cycle/Virus_replication_cycle_stable.xml,CellDesigner_SBML,Virus replication cycle
Yes,https://git-r3lab.uni.lu/covid/models/-/raw/master/Curation/Interferon%20lambda%20pathway/IFN-lambda_stable.xml,CellDesigner_SBML,Interferon lambda pathway
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