BioPAX pathway converted from "HMGCR dimer reduces bHMG-CoA to MVA" in the Reactome database.LEFT-TO-RIGHT1.1.1.34HMGCR dimer reduces bHMG-CoA to MVAReduction of HMG-CoA produces mevalonateDimeric 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR dimer) catalyzes the four-electron reduction of beta-hydroxy-beta-methylglutaryl-CoA (bHMG-CoA) to mevalonate (MVA). MVA concentrations in the cell are tightly controlled through the activity of HMGCR dimer, which is one of the most highly regulated enzymes in metabolism (Goldstein & Brown 1990).Authored: Jassal, B, 2007-01-24 15:15:12Reviewed: D'Eustachio, P, 2007-01-22 01:32:07TPNHNADPHReactome DB_ID: 29364cytosolGENE ONTOLOGYGO:0005829NADPH [ChEBI:16474]NADPHTPNHChEBICHEBI:16474Reactome Database ID Release 7529364Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29364ReactomeR-ALL-293642Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29364.2Reactomehttp://www.reactome.orgCOMPOUNDC00005additional informationMIMI:03612HMG-CoAbHMG-CoAbeta-hydroxy-beta-methylglutaryl-CoA(3S)-3-hydroxy-3-methylglutaryl-CoA3-hydroxy-3-methylglutaryl-CoAReactome DB_ID: 191374(3S)-3-hydroxy-3-methylglutaryl-CoA [ChEBI:15467](3S)-3-hydroxy-3-methylglutaryl-CoAChEBICHEBI:15467Reactome Database ID Release 75191374Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191374ReactomeR-ALL-1913743Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-191374.3COMPOUNDC00356H+protonhydronReactome DB_ID: 70106hydron [ChEBI:15378]hydronChEBICHEBI:15378Reactome Database ID Release 7570106Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70106ReactomeR-ALL-701064Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-70106.4COMPOUNDC000802TPNNADP+NADPNADP(+)Nicotinamide adenine dinucleotide phosphatebeta-Nicotinamide adenine dinucleotide phosphateTriphosphopyridine nucleotideReactome DB_ID: 29366NADP(+) [ChEBI:18009]NADP(+)ChEBICHEBI:18009Reactome Database ID Release 7529366Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29366ReactomeR-ALL-293663Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29366.3COMPOUNDC000062MVAMevalonate(R)-mevalonic acidReactome DB_ID: 191424(R)-mevalonic acid [ChEBI:17710](R)-mevalonic acidChEBICHEBI:17710Reactome Database ID Release 75191424Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191424ReactomeR-ALL-1914243Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-191424.3COMPOUNDC00418CoA-SHcoenzyme AReactome DB_ID: 76194coenzyme A [ChEBI:15346]coenzyme AChEBICHEBI:15346Reactome Database ID Release 7576194Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76194ReactomeR-ALL-761943Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76194.3COMPOUNDC00010ACTIVATIONHMGCR dimerHydroxymethyl glutaryl CoA reductase homodimerReactome DB_ID: 191277endoplasmic reticulum membraneGENE ONTOLOGYGO:0005789Converted from EntitySet in ReactomeHydroxymethyl glutaryl CoA reductaseReactome DB_ID: 191355HMGCR-13-hydroxy-3-methylglutaryl-coenzyme A reductase-1HMDH_HUMANHMGCR isoform 1Reactome DB_ID: 191308UniProt:P04035-1 HMGCRHMGCRFUNCTION Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis (PubMed:2991281, PubMed:21357570, PubMed:6995544). HMGCR is the main target of statins, a class of cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668).ACTIVITY REGULATION Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate (PubMed:6995544). Phosphorylation at Ser-872 down-regulates the catalytic activity (By similarity). Inhibited by statins, a class of hypolipidemic agents used as pharmaceuticals to lower cholesterol levels in individuals at risk from cardiovascular disease due to hypercholesterolemia (PubMed:11349148, PubMed:18540668). Inhibition of HMGCR in the liver stimulates the LDL-receptors, which results in an increased clearance of LDL from the bloodstream and a decrease in blood cholesterol levels (PubMed:11349148, PubMed:18540668). The first results can be seen after one week of statin use and the effect is maximal after four to six weeks (PubMed:11349148, PubMed:18540668).PATHWAY Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.SUBUNIT Homotetramer (PubMed:10698924). Homodimer (PubMed:10698924). Interacts (via its SSD) with INSIG1; the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway (PubMed:12535518, PubMed:19458199). Interacts with UBIAD1 (PubMed:23169578).PTM N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.PTM Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD) (PubMed:12535518, PubMed:19458199, PubMed:21778231). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2 (PubMed:12535518, PubMed:19458199, PubMed:21778231, PubMed:22143767). The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase (PubMed:12535518, PubMed:19458199, PubMed:21778231). The ubiquitinated reductase is then extracted from the ER membrane and delivered to cytosolic 26S proteosomes by a mechanism probably mediated by the ATPase Valosin-containing protein VCP/p97 (PubMed:12535518, PubMed:19458199, PubMed:21778231). The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase (PubMed:22143767). Lys-248 is the main site of ubiquitination (PubMed:19458199). Ubiquitination is enhanced by the presence of a geranylgeranylated protein (PubMed:21778231).PTM Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic activity.SIMILARITY Belongs to the HMG-CoA reductase family.Homo sapiensNCBI Taxonomy9606UniProt IsoformP04035-11EQUAL888EQUALReactome Database ID Release 75191308Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191308ReactomeR-HSA-1913081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-191308.1HMGCR-23-hydroxy-3-methylglutaryl-coenzyme A reductase-2HMDH_HUMANHMGCR isoform 2Reactome DB_ID: 191426UniProt:P04035-2 HMGCRHMGCRFUNCTION Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis (PubMed:2991281, PubMed:21357570, PubMed:6995544). HMGCR is the main target of statins, a class of cholesterol-lowering drugs (PubMed:11349148, PubMed:18540668).ACTIVITY REGULATION Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate (PubMed:6995544). Phosphorylation at Ser-872 down-regulates the catalytic activity (By similarity). Inhibited by statins, a class of hypolipidemic agents used as pharmaceuticals to lower cholesterol levels in individuals at risk from cardiovascular disease due to hypercholesterolemia (PubMed:11349148, PubMed:18540668). Inhibition of HMGCR in the liver stimulates the LDL-receptors, which results in an increased clearance of LDL from the bloodstream and a decrease in blood cholesterol levels (PubMed:11349148, PubMed:18540668). The first results can be seen after one week of statin use and the effect is maximal after four to six weeks (PubMed:11349148, PubMed:18540668).PATHWAY Metabolic intermediate biosynthesis; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.SUBUNIT Homotetramer (PubMed:10698924). Homodimer (PubMed:10698924). Interacts (via its SSD) with INSIG1; the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway (PubMed:12535518, PubMed:19458199). Interacts with UBIAD1 (PubMed:23169578).PTM N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.PTM Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD) (PubMed:12535518, PubMed:19458199, PubMed:21778231). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1 or INSIG2 (PubMed:12535518, PubMed:19458199, PubMed:21778231, PubMed:22143767). The INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, RNF139 or RNF145, initiating ubiquitination of the reductase (PubMed:12535518, PubMed:19458199, PubMed:21778231). The ubiquitinated reductase is then extracted from the ER membrane and delivered to cytosolic 26S proteosomes by a mechanism probably mediated by the ATPase Valosin-containing protein VCP/p97 (PubMed:12535518, PubMed:19458199, PubMed:21778231). The INSIG2-binding leads to the recruitment of the ubiquitin ligase RNF139, initiating ubiquitination of the reductase (PubMed:22143767). Lys-248 is the main site of ubiquitination (PubMed:19458199). Ubiquitination is enhanced by the presence of a geranylgeranylated protein (PubMed:21778231).PTM Phosphorylated. Phosphorylation at Ser-872 reduces the catalytic activity.SIMILARITY Belongs to the HMG-CoA reductase family.UniProt IsoformP04035-21EQUAL888EQUALReactome Database ID Release 75191426Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191426ReactomeR-HSA-1914261Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-191426.1Reactome Database ID Release 75191355Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191355ReactomeR-HSA-1913551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-191355.12Reactome Database ID Release 75191277Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191277ReactomeR-HSA-1912771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-191277.1GENE ONTOLOGYGO:0004420gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 75191301Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191301Reactome Database ID Release 75191352Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=191352ReactomeR-HSA-1913522Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-191352.21967820Pubmed1990Regulation of the mevalonate pathwayGoldstein, JLBrown, MSNature 343:425-3010698924Pubmed2000Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysisIstvan, ESPalnitkar, MBuchanan, SKDeisenhofer, JEMBO J 19:819-30