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Protein

3-hydroxy-3-methylglutaryl-coenzyme A reductase

Gene

Hmgcr

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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), 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)LengthDescriptionGraphical viewFeature identifierActions
Active sitei558 – 5581Charge relay systemBy similarity
Active sitei690 – 6901Charge relay systemBy similarity
Active sitei766 – 7661Charge relay systemBy similarity
Active sitei865 – 8651Proton donorPROSITE-ProRule annotation

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 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 vasodilation 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
Complete GO annotation...

Keywords - Molecular functioni

Oxidoreductase

Keywords - Biological processi

Cholesterol biosynthesis, Cholesterol metabolism, Lipid biosynthesis, Lipid metabolism, Steroid biosynthesis, Steroid metabolism, Sterol biosynthesis, Sterol metabolism

Keywords - Ligandi

NADP

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
Proteomesi
  • UP000002494 Componenti: Chromosome 2

Organism-specific databases

RGDi2803. Hmgcr.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei10 – 3930HelicalSequence analysisAdd
BLAST
Transmembranei57 – 7822HelicalSequence analysisAdd
BLAST
Transmembranei90 – 11425HelicalSequence analysisAdd
BLAST
Transmembranei124 – 14926HelicalSequence analysisAdd
BLAST
Transmembranei160 – 18728HelicalSequence analysisAdd
BLAST
Transmembranei192 – 22029HelicalSequence analysisAdd
BLAST
Transmembranei315 – 33925HelicalSequence analysisAdd
BLAST

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Chemistry

ChEMBLiCHEMBL3247.
GuidetoPHARMACOLOGYi639.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 8878873-hydroxy-3-methylglutaryl-coenzyme A reductasePRO_0000114424Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Cross-linki89 – 89Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki248 – 248Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Glycosylationi281 – 2811N-linked (GlcNAc...)Sequence analysis
Glycosylationi517 – 5171N-linked (GlcNAc...)Sequence analysis
Glycosylationi869 – 8691N-linked (GlcNAc...)Sequence analysis
Modified residuei871 – 8711Phosphoserine; by AMPK1 Publication

Post-translational modificationi

N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.By similarity
Undergoes sterol-mediated ubiquitination and ER-association degradation (ERAD). Accumulation of sterols in the endoplasmic reticulum (ER) membrane, triggers binding of the reductase to the ER membrane protein INSIG1. This INSIG binding leads to the recruitment of the ubiquitin ligase, AMFR/gp78, 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).By similarity

Keywords - PTMi

Glycoprotein, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP51639.
PRIDEiP51639.

PTM databases

iPTMnetiP51639.
PhosphoSiteiP51639.

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 interaction.
MINTiMINT-1347783.
STRINGi10116.ENSRNOP00000022055.

Chemistry

BindingDBiP51639.

Structurei

3D structure databases

ProteinModelPortaliP51639.
SMRiP51639. Positions 440-864.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini61 – 218158SSDPROSITE-ProRule annotationAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni340 – 449110LinkerAdd
BLAST
Regioni450 – 887438CatalyticAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi75 – 784INSIG-binding motifBy similarity

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi243 – 2464Poly-Glu

Sequence similaritiesi

Belongs to the HMG-CoA reductase family.Curated
Contains 1 SSD (sterol-sensing) domain.PROSITE-ProRule annotation

Keywords - Domaini

Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG2480. Eukaryota.
COG1257. LUCA.
GeneTreeiENSGT00840000129910.
HOGENOMiHOG000183489.
HOVERGENiHBG000453.
InParanoidiP51639.
KOiK00021.
OMAiPNEECLQ.
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.
InterProiIPR002202. HMG_CoA_Rdtase.
IPR023074. HMG_CoA_Rdtase_cat.
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_dom.
IPR009029. HMG_CoA_Rdtase_sub-bd_dom.
IPR000731. SSD.
[Graphical view]
PANTHERiPTHR10572. PTHR10572. 1 hit.
PfamiPF00368. HMG-CoA_red. 1 hit.
PF12349. Sterol-sensing. 1 hit.
[Graphical view]
PRINTSiPR00071. HMGCOARDTASE.
SUPFAMiSSF55035. SSF55035. 1 hit.
SSF56542. SSF56542. 2 hits.
TIGRFAMsiTIGR00920. 2A060605. 1 hit.
TIGR00533. HMG_CoA_R_NADP. 1 hit.
PROSITEiPS00066. 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.
[Graphical view]

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)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti423 – 4231S → T AA sequence (PubMed:2369897).Curated
Sequence conflicti428 – 4281L → V AA sequence (PubMed:2369897).Curated
Sequence conflicti443 – 4431P → N AA sequence (PubMed:2369897).Curated
Sequence conflicti644 – 65310IRLQSKTGDA → PIRSPKRGTS in CAA39001 (Ref. 3) Curated
Sequence conflicti673 – 6742FF → GV in AAA40608 (Ref. 1) Curated
Sequence conflicti722 – 7221T → S in CAA39001 (Ref. 3) Curated
Sequence conflicti750 – 7501A → L in AAA40608 (Ref. 1) Curated
Sequence conflicti764 – 7641G → A in CAA39001 (Ref. 3) Curated

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.

Cross-referencesi

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.

3D structure databases

ProteinModelPortaliP51639.
SMRiP51639. Positions 440-864.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi247704. 1 interaction.
MINTiMINT-1347783.
STRINGi10116.ENSRNOP00000022055.

Chemistry

BindingDBiP51639.
ChEMBLiCHEMBL3247.
GuidetoPHARMACOLOGYi639.

PTM databases

iPTMnetiP51639.
PhosphoSiteiP51639.

Proteomic databases

PaxDbiP51639.
PRIDEiP51639.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSRNOT00000022055; ENSRNOP00000022055; ENSRNOG00000016122.
GeneIDi25675.
KEGGirno:25675.

Organism-specific databases

CTDi3156.
RGDi2803. Hmgcr.

Phylogenomic databases

eggNOGiKOG2480. Eukaryota.
COG1257. LUCA.
GeneTreeiENSGT00840000129910.
HOGENOMiHOG000183489.
HOVERGENiHBG000453.
InParanoidiP51639.
KOiK00021.
OMAiPNEECLQ.
OrthoDBiEOG091G0I1B.
PhylomeDBiP51639.
TreeFamiTF105362.

Enzyme and pathway databases

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

Miscellaneous databases

PROiP51639.

Gene expression databases

BgeeiENSRNOG00000016122.
GenevisibleiP51639. RN.

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.
InterProiIPR002202. HMG_CoA_Rdtase.
IPR023074. HMG_CoA_Rdtase_cat.
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_dom.
IPR009029. HMG_CoA_Rdtase_sub-bd_dom.
IPR000731. SSD.
[Graphical view]
PANTHERiPTHR10572. PTHR10572. 1 hit.
PfamiPF00368. HMG-CoA_red. 1 hit.
PF12349. Sterol-sensing. 1 hit.
[Graphical view]
PRINTSiPR00071. HMGCOARDTASE.
SUPFAMiSSF55035. SSF55035. 1 hit.
SSF56542. SSF56542. 2 hits.
TIGRFAMsiTIGR00920. 2A060605. 1 hit.
TIGR00533. HMG_CoA_R_NADP. 1 hit.
PROSITEiPS00066. 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.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiHMDH_RAT
AccessioniPrimary (citable) accession number: P51639
Secondary accession number(s): Q64601, Q6P2A6
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 31, 2006
Last modified: September 7, 2016
This is version 148 of the entry and version 2 of the sequence. [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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.