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Protein

3-hydroxy-3-methylglutaryl-coenzyme A reductase

Gene

Hmgcr

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Transmembrane glycoprotein that is the rate-limiting enzyme in cholesterol biosynthesis as well as in the biosynthesis of nonsterol isoprenoids that are essential for normal cell function including ubiquinone and geranylgeranyl proteins.

Catalytic activityi

(R)-mevalonate + CoA + 2 NADP+ = (S)-3-hydroxy-3-methylglutaryl-CoA + 2 NADPH.PROSITE-ProRule annotation

Enzyme regulationi

Regulated by a negative feedback mechanism through sterols and non-sterol metabolites derived from mevalonate.

Pathwayi: (R)-mevalonate biosynthesis

This protein is involved in step 3 of the subpathway that synthesizes (R)-mevalonate from acetyl-CoA.
Proteins known to be involved in the 3 steps of the subpathway in this organism are:
  1. no protein annotated in this organism
  2. Hydroxymethylglutaryl-CoA synthase, mitochondrial (Hmgcs2), 3-hydroxy-3-methylglutaryl coenzyme A synthase (Hmgcs2), Hydroxymethylglutaryl-CoA synthase, cytoplasmic (Hmgcs1)
  3. 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr)
This subpathway is part of the pathway (R)-mevalonate biosynthesis, which is itself part of Metabolic intermediate biosynthesis.
View all proteins of this organism that are known to be involved in the subpathway that synthesizes (R)-mevalonate from acetyl-CoA, the pathway (R)-mevalonate biosynthesis and in Metabolic intermediate biosynthesis.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Active sitei558Charge relay systemBy similarity1
Active sitei690Charge relay systemBy similarity1
Active sitei766Charge relay systemBy similarity1
Active sitei865Proton donorPROSITE-ProRule annotation1

GO - Molecular functioni

  • hydroxymethylglutaryl-CoA reductase (NADPH) activity Source: GO_Central
  • hydroxymethylglutaryl-CoA reductase activity Source: RGD
  • NADPH binding Source: Ensembl
  • protein homodimerization activity Source: RGD
  • protein phosphatase 2A binding Source: RGD

GO - Biological processi

  • aging Source: RGD
  • cholesterol biosynthetic process Source: RGD
  • coenzyme A metabolic process Source: InterPro
  • farnesyl diphosphate biosynthetic process, mevalonate pathway Source: RGD
  • isoprenoid biosynthetic process Source: RGD
  • myoblast differentiation Source: RGD
  • negative regulation of apoptotic process Source: RGD
  • negative regulation of blood vessel diameter Source: RGD
  • negative regulation of insulin secretion involved in cellular response to glucose stimulus Source: RGD
  • negative regulation of MAP kinase activity Source: Ensembl
  • negative regulation of striated muscle cell apoptotic process Source: RGD
  • negative regulation of wound healing Source: RGD
  • positive regulation of cardiac muscle cell apoptotic process Source: RGD
  • positive regulation of cell proliferation Source: RGD
  • positive regulation of ERK1 and ERK2 cascade Source: RGD
  • positive regulation of skeletal muscle tissue development Source: RGD
  • positive regulation of smooth muscle cell proliferation Source: RGD
  • positive regulation of stress-activated MAPK cascade Source: RGD
  • protein tetramerization Source: Ensembl
  • response to ethanol Source: RGD
  • response to nutrient Source: RGD
  • ubiquinone metabolic process Source: RGD
  • visual learning Source: Ensembl

Keywordsi

Molecular functionOxidoreductase
Biological processCholesterol biosynthesis, Cholesterol metabolism, Lipid biosynthesis, Lipid metabolism, Steroid biosynthesis, Steroid metabolism, Sterol biosynthesis, Sterol metabolism
LigandNADP

Enzyme and pathway databases

BRENDAi1.1.1.34 5301
ReactomeiR-RNO-191273 Cholesterol biosynthesis
UniPathwayiUPA00058; UER00103

Names & Taxonomyi

Protein namesi
Recommended name:
3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC:1.1.1.34)
Short name:
HMG-CoA reductase
Gene namesi
Name:Hmgcr
OrganismiRattus norvegicus (Rat)
Taxonomic identifieri10116 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 2

Organism-specific databases

RGDi2803 Hmgcr

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Transmembranei10 – 39HelicalSequence analysisAdd BLAST30
Transmembranei57 – 78HelicalSequence analysisAdd BLAST22
Transmembranei90 – 114HelicalSequence analysisAdd BLAST25
Transmembranei124 – 149HelicalSequence analysisAdd BLAST26
Transmembranei160 – 187HelicalSequence analysisAdd BLAST28
Transmembranei192 – 220HelicalSequence analysisAdd BLAST29
Transmembranei315 – 339HelicalSequence analysisAdd BLAST25

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Chemistry databases

ChEMBLiCHEMBL3247
GuidetoPHARMACOLOGYi639

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00001144241 – 8873-hydroxy-3-methylglutaryl-coenzyme A reductaseAdd BLAST887

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki89Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki248Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Glycosylationi281N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi517N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi869N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei871Phosphoserine; by AMPK1 Publication1

Post-translational modificationi

Undergoes sterol-mediated ubiquitination and ER-associated degradation (ERAD). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1. This INSIG1 binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78 or RNF145, initiating ubiquitination of the reductase. 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. Lys-248 is the main site of ubiquitination. Ubiquitination is enhanced by the presence of a geranylgeranylated protein.By similarity
N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.By similarity

Keywords - PTMi

Glycoprotein, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP51639
PRIDEiP51639

PTM databases

iPTMnetiP51639
PhosphoSitePlusiP51639

Expressioni

Gene expression databases

BgeeiENSRNOG00000016122
GenevisibleiP51639 RN

Interactioni

Subunit structurei

Homodimer. Interacts with INSIG1 (via its SSD); the interaction, accelerated by sterols, leads to the recruitment of HMGCR to AMFR/gp78 for its ubiquitination by the sterol-mediated ERAD pathway. Interacts with UBIAD1 (By similarity).By similarity

GO - Molecular functioni

  • protein homodimerization activity Source: RGD
  • protein phosphatase 2A binding Source: RGD

Protein-protein interaction databases

BioGridi247704, 1 interactor
IntActiP51639, 1 interactor
MINTiP51639
STRINGi10116.ENSRNOP00000022055

Chemistry databases

BindingDBiP51639

Structurei

3D structure databases

ProteinModelPortaliP51639
SMRiP51639
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini61 – 218SSDPROSITE-ProRule annotationAdd BLAST158

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni340 – 449LinkerAdd BLAST110
Regioni450 – 887CatalyticAdd BLAST438

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi75 – 78INSIG-binding motifBy similarity4

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi243 – 246Poly-Glu4

Sequence similaritiesi

Belongs to the HMG-CoA reductase family.Curated

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2480 Eukaryota
COG1257 LUCA
GeneTreeiENSGT00910000144151
HOGENOMiHOG000183489
HOVERGENiHBG000453
InParanoidiP51639
KOiK00021
OMAiVVIHFLD
OrthoDBiEOG091G0I1B
PhylomeDBiP51639
TreeFamiTF105362

Family and domain databases

CDDicd00643 HMG-CoA_reductase_classI, 1 hit
Gene3Di1.10.3270.10, 1 hit
3.30.70.420, 1 hit
3.90.770.10, 2 hits
InterProiView protein in InterPro
IPR002202 HMG_CoA_Rdtase
IPR023074 HMG_CoA_Rdtase_cat_sf
IPR023076 HMG_CoA_Rdtase_CS
IPR004554 HMG_CoA_Rdtase_eu_arc
IPR004816 HMG_CoA_Rdtase_metazoan
IPR023282 HMG_CoA_Rdtase_N
IPR009023 HMG_CoA_Rdtase_NAD(P)-bd_sf
IPR009029 HMG_CoA_Rdtase_sub-bd_dom_sf
IPR000731 SSD
PANTHERiPTHR10572 PTHR10572, 1 hit
PfamiView protein in Pfam
PF00368 HMG-CoA_red, 1 hit
PF12349 Sterol-sensing, 1 hit
PRINTSiPR00071 HMGCOARDTASE
SUPFAMiSSF55035 SSF55035, 1 hit
SSF56542 SSF56542, 2 hits
TIGRFAMsiTIGR00920 2A060605, 1 hit
TIGR00533 HMG_CoA_R_NADP, 1 hit
PROSITEiView protein in PROSITE
PS00066 HMG_COA_REDUCTASE_1, 1 hit
PS00318 HMG_COA_REDUCTASE_2, 1 hit
PS01192 HMG_COA_REDUCTASE_3, 1 hit
PS50065 HMG_COA_REDUCTASE_4, 1 hit
PS50156 SSD, 1 hit

Sequencei

Sequence statusi: Complete.

P51639-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC
60 70 80 90 100
PKFEEDVLSS DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI
110 120 130 140 150
FSSFVFSTVV IHFLDKELTG LNEALPFFLL LIDLSRASAL AKFALSSNSQ
160 170 180 190 200
DEVRENIARG MAILGPTFTL DALVECLVIG VGTMSGVRQL EIMCCFGCMS
210 220 230 240 250
VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR VLEEEENKPN
260 270 280 290 300
PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTAEQSKVS LGLAEDVSKR
310 320 330 340 350
IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QAETESTLSL
360 370 380 390 400
KNPITSPVVT PKKAQDNCCR REPLLVRRNQ KLSSVEEDPG VNQDRKVEVI
410 420 430 440 450
KPLVAEAETS GRATFVLGAS AASPPLALGA QEPGIELPSE PRPNEECLQI
460 470 480 490 500
LESAEKGAKF LSDAEIIQLV NAKHIPAYKL ETLMETHERG VSIRRQLLSA
510 520 530 540 550
KLAEPSSLQY LPYRDYNYSL VMGACCENVI GYMPIPVGVA GPLCLDGKEY
560 570 580 590 600
QVPMATTEGC LVASTNRGCR AISLGGGASS RVLADGMSRG PVVRLPRACD
610 620 630 640 650
SAEVKSWLET PEGFAVVKEA FDSTSRFARL QKLHVTLAGR NLYIRLQSKT
660 670 680 690 700
GDAMGMNMIS KGTEKALLKL QEFFPELQIL AVSGNYCTDK KPAAINWIEG
710 720 730 740 750
RGKTVVCEAV IPAKVVREVL KTTTEAMVDV NINKNLVGSA MAGSIGGYNA
760 770 780 790 800
HAANIVTAIY IACGQDAAQN VGSSNCITLM EASGPTNEDL YISCTMPSIE
810 820 830 840 850
IGTVGGGTNL LPQQACLQML GVQGACKDNP GENARQLARI VCGTVMAGEL
860 870 880
SLMAALAAGH LVRSHMVHNR SKINLQDLQG TCTKKAA
Length:887
Mass (Da):96,688
Last modified:October 31, 2006 - v2
Checksum:i856D99A9D5FA965C
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti423S → T AA sequence (PubMed:2369897).Curated1
Sequence conflicti428L → V AA sequence (PubMed:2369897).Curated1
Sequence conflicti443P → N AA sequence (PubMed:2369897).Curated1
Sequence conflicti644 – 653IRLQSKTGDA → PIRSPKRGTS in CAA39001 (Ref. 3) Curated10
Sequence conflicti673 – 674FF → GV in AAA40608 (Ref. 1) Curated2
Sequence conflicti722T → S in CAA39001 (Ref. 3) Curated1
Sequence conflicti750A → L in AAA40608 (Ref. 1) Curated1
Sequence conflicti764G → A in CAA39001 (Ref. 3) Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M29249 Genomic DNA Translation: AAA40608.1
BC064654 mRNA Translation: AAH64654.1
X55286 mRNA Translation: CAA39001.1
PIRiS33175
RefSeqiNP_037266.2, NM_013134.2
UniGeneiRn.9437

Genome annotation databases

EnsembliENSRNOT00000022055; ENSRNOP00000022055; ENSRNOG00000016122
GeneIDi25675
KEGGirno:25675

Similar proteinsi

Entry informationi

Entry nameiHMDH_RAT
AccessioniPrimary (citable) accession number: P51639
Secondary accession number(s): Q64601, Q6P2A6
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 31, 2006
Last modified: July 18, 2018
This is version 164 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  2. SIMILARITY comments
    Index of protein domains and families

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