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P04035

- HMDH_HUMAN

UniProt

P04035 - HMDH_HUMAN

Protein

3-hydroxy-3-methylglutaryl-coenzyme A reductase

Gene

HMGCR

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 176 (01 Oct 2014)
      Sequence version 1 (01 Nov 1986)
      Previous versions | rss
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    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. 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. 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. The first results can be seen after one week of statin use and the effect is maximal after four to six weeks.1 Publication

    Pathwayi

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Active sitei559 – 5591Charge relay system
    Active sitei691 – 6911Charge relay system
    Active sitei767 – 7671Charge relay system
    Active sitei866 – 8661Proton donor

    GO - Molecular functioni

    1. coenzyme binding Source: UniProtKB
    2. hydroxymethylglutaryl-CoA reductase (NADPH) activity Source: UniProtKB-EC
    3. hydroxymethylglutaryl-CoA reductase activity Source: UniProtKB
    4. NADPH binding Source: UniProtKB
    5. protein binding Source: IntAct

    GO - Biological processi

    1. aging Source: Ensembl
    2. cellular lipid metabolic process Source: Reactome
    3. cholesterol biosynthetic process Source: Reactome
    4. coenzyme A metabolic process Source: InterPro
    5. embryo development Source: Ensembl
    6. isoprenoid biosynthetic process Source: Ensembl
    7. myoblast differentiation Source: Ensembl
    8. negative regulation of insulin secretion involved in cellular response to glucose stimulus Source: Ensembl
    9. negative regulation of MAP kinase activity Source: Ensembl
    10. negative regulation of striated muscle cell apoptotic process Source: Ensembl
    11. negative regulation of vasodilation Source: Ensembl
    12. negative regulation of wound healing Source: Ensembl
    13. positive regulation of cardiac muscle cell apoptotic process Source: Ensembl
    14. positive regulation of ERK1 and ERK2 cascade Source: Ensembl
    15. positive regulation of skeletal muscle tissue development Source: Ensembl
    16. positive regulation of smooth muscle cell proliferation Source: Ensembl
    17. positive regulation of stress-activated MAPK cascade Source: Ensembl
    18. protein tetramerization Source: UniProtKB
    19. response to ethanol Source: Ensembl
    20. response to nutrient Source: Ensembl
    21. small molecule metabolic process Source: Reactome
    22. ubiquinone metabolic process Source: Ensembl
    23. visual learning Source: Ensembl

    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

    BioCyciMetaCyc:HS03652-MONOMER.
    ReactomeiREACT_116145. PPARA activates gene expression.
    REACT_147904. Activation of gene expression by SREBF (SREBP).
    REACT_9405. Cholesterol biosynthesis.
    SABIO-RKP04035.
    UniPathwayiUPA00058; UER00103.

    Protein family/group databases

    TCDBi2.A.6.6.5. the resistance-nodulation-cell division (rnd) superfamily.

    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
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 5

    Organism-specific databases

    HGNCiHGNC:5006. HMGCR.

    Subcellular locationi

    GO - Cellular componenti

    1. endoplasmic reticulum Source: UniProtKB
    2. endoplasmic reticulum membrane Source: UniProtKB
    3. integral component of membrane Source: UniProtKB-KW
    4. peroxisomal membrane Source: UniProtKB

    Keywords - Cellular componenti

    Endoplasmic reticulum, Membrane

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi75 – 773YIY → AIA: Reduced sterol-mediated release from the ER. Not deglycosylated in response to sterols.
    Mutagenesisi89 – 891K → R: Abolishes sterol-mediated ubiquitination and degradation; when associated with R-248. 1 Publication
    Mutagenesisi248 – 2481K → R: Abolishes sterol-mediated ubiquitination and degradation; when associated with R-89. 1 Publication

    Organism-specific databases

    MIMi142910. gene+phenotype.
    PharmGKBiPA189.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 8888883-hydroxy-3-methylglutaryl-coenzyme A reductasePRO_0000114419Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Cross-linki89 – 89Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Cross-linki248 – 248Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
    Glycosylationi281 – 2811N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi296 – 2961N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi419 – 4191N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi518 – 5181N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi870 – 8701N-linked (GlcNAc...)Sequence Analysis
    Modified residuei872 – 8721Phosphoserine; by AMPKBy similarity

    Post-translational modificationi

    N-glycosylated. Deglycosylated by NGLY1 on release from the endoplasmic reticulum (ER) in a sterol-mediated manner.1 Publication
    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 INSIG1 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.3 Publications

    Keywords - PTMi

    Glycoprotein, Isopeptide bond, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiP04035.
    PaxDbiP04035.
    PRIDEiP04035.

    PTM databases

    PhosphoSiteiP04035.

    Expressioni

    Gene expression databases

    ArrayExpressiP04035.
    BgeeiP04035.
    CleanExiHS_HMGCR.
    GenevestigatoriP04035.

    Organism-specific databases

    HPAiCAB016797.
    HPA008338.

    Interactioni

    Subunit structurei

    Homodimer. 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. Interacts with UBIAD1.5 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    UBIAD1Q9Y5Z93EBI-465513,EBI-2819725
    UBIAD1Q9Y5Z9-15EBI-465513,EBI-6621921

    Protein-protein interaction databases

    BioGridi109399. 10 interactions.
    IntActiP04035. 3 interactions.
    STRINGi9606.ENSP00000287936.

    Structurei

    Secondary structure

    1
    888
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi445 – 4539
    Turni455 – 4573
    Helixi458 – 4603
    Helixi464 – 4729
    Beta strandi474 – 4763
    Helixi478 – 4803
    Helixi481 – 4844
    Beta strandi485 – 4873
    Helixi488 – 50215
    Beta strandi503 – 5053
    Helixi508 – 5114
    Beta strandi515 – 5173
    Helixi519 – 5213
    Turni522 – 5254
    Beta strandi528 – 54619
    Beta strandi549 – 5568
    Helixi562 – 57514
    Beta strandi579 – 59012
    Beta strandi593 – 5953
    Helixi599 – 61012
    Helixi612 – 62312
    Beta strandi635 – 6395
    Beta strandi642 – 6509
    Helixi657 – 67418
    Beta strandi679 – 6835
    Beta strandi686 – 6883
    Helixi695 – 7006
    Beta strandi703 – 71210
    Helixi714 – 7196
    Beta strandi721 – 7233
    Helixi725 – 73612
    Helixi738 – 7425
    Beta strandi746 – 7527
    Helixi753 – 76311
    Helixi768 – 7703
    Helixi771 – 7744
    Beta strandi777 – 7859
    Beta strandi790 – 80011
    Beta strandi804 – 8063
    Helixi807 – 8104
    Helixi812 – 8209
    Beta strandi828 – 8303
    Helixi833 – 85927
    Helixi862 – 8698

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1DQ8X-ray2.10A/B/C/D426-888[»]
    1DQ9X-ray2.80A/B/C/D426-888[»]
    1DQAX-ray2.00A/B/C/D426-888[»]
    1HW8X-ray2.10A/B/C/D426-888[»]
    1HW9X-ray2.33A/B/C/D426-888[»]
    1HWIX-ray2.30A/B/C/D426-888[»]
    1HWJX-ray2.26A/B/C/D426-888[»]
    1HWKX-ray2.22A/B/C/D426-888[»]
    1HWLX-ray2.10A/B/C/D426-888[»]
    2Q1LX-ray2.05A/B/C/D441-875[»]
    2Q6BX-ray2.00A/B/C/D441-875[»]
    2Q6CX-ray2.00A/B/C/D441-875[»]
    2R4FX-ray1.70A/B/C/D441-875[»]
    3BGLX-ray2.23A/B/C/D441-875[»]
    3CCTX-ray2.12A/B/C/D441-875[»]
    3CCWX-ray2.10A/B/C/D441-875[»]
    3CCZX-ray1.70A/B/C/D441-875[»]
    3CD0X-ray2.40A/B/C/D441-875[»]
    3CD5X-ray2.39A/B/C/D441-875[»]
    3CD7X-ray2.05A/B/C/D441-875[»]
    3CDAX-ray2.07A/B/C/D441-875[»]
    3CDBX-ray2.30A/B/C/D441-875[»]
    ProteinModelPortaliP04035.
    SMRiP04035. Positions 441-864.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP04035.

    Transmembrane

    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

    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 – 888439CatalyticAdd
    BLAST

    Motif

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

    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

    eggNOGiCOG1257.
    HOGENOMiHOG000183489.
    HOVERGENiHBG000453.
    InParanoidiP04035.
    KOiK00021.
    OMAiPNEECLQ.
    OrthoDBiEOG7GXP9T.
    PhylomeDBiP04035.
    TreeFamiTF105362.

    Family and domain databases

    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.
    [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]

    Sequences (3)i

    Sequence statusi: Complete.

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Isoform 1 (identifier: P04035-1) [UniParc]FASTAAdd to Basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide

    MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC    50
    PKFEEDVLSS DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI 100
    FSSFVFSTVV IHFLDKELTG LNEALPFFLL LIDLSRASTL AKFALSSNSQ 150
    DEVRENIARG MAILGPTFTL DALVECLVIG VGTMSGVRQL EIMCCFGCMS 200
    VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR VLEEEENKPN 250
    PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTADTSKVS LGLDENVSKR 300
    IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QTETESTLSL 350
    KNPITSPVVT QKKVPDNCCR REPMLVRNNQ KCDSVEEETG INRERKVEVI 400
    KPLVAETDTP NRATFVVGNS SLLDTSSVLV TQEPEIELPR EPRPNEECLQ 450
    ILGNAEKGAK FLSDAEIIQL VNAKHIPAYK LETLMETHER GVSIRRQLLS 500
    KKLSEPSSLQ YLPYRDYNYS LVMGACCENV IGYMPIPVGV AGPLCLDEKE 550
    FQVPMATTEG CLVASTNRGC RAIGLGGGAS SRVLADGMTR GPVVRLPRAC 600
    DSAEVKAWLE TSEGFAVIKE AFDSTSRFAR LQKLHTSIAG RNLYIRFQSR 650
    SGDAMGMNMI SKGTEKALSK LHEYFPEMQI LAVSGNYCTD KKPAAINWIE 700
    GRGKSVVCEA VIPAKVVREV LKTTTEAMIE VNINKNLVGS AMAGSIGGYN 750
    AHAANIVTAI YIACGQDAAQ NVGSSNCITL MEASGPTNED LYISCTMPSI 800
    EIGTVGGGTN LLPQQACLQM LGVQGACKDN PGENARQLAR IVCGTVMAGE 850
    LSLMAALAAG HLVKSHMIHN RSKINLQDLQ GACTKKTA 888
    Length:888
    Mass (Da):97,476
    Last modified:November 1, 1986 - v1
    Checksum:i49B610DCCCFA26B6
    GO
    Isoform 2 (identifier: P04035-2) [UniParc]FASTAAdd to Basket

    The sequence of this isoform differs from the canonical sequence as follows:
         522-574: Missing.

    Note: No experimental confirmation available.

    Show »
    Length:835
    Mass (Da):92,021
    Checksum:i20BBFC6C1FB46ADA
    GO
    Isoform 3 (identifier: P04035-3) [UniParc]FASTAAdd to Basket

    Also known as: HMGCR-1b

    The sequence of this isoform differs from the canonical sequence as follows:
         1-1: M → MQWMSHTRERDAGSKDSVATM

    Note: Most highly expressed transcript in skin, esophagus, and uterine cervix.

    Show »
    Length:908
    Mass (Da):99,752
    Checksum:iA5CAD1217E9C40B9
    GO

    Sequence cautioni

    The sequence BAH12375.1 differs from that shown. Reason: Frameshift at position 122.

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti638 – 6381I → V.1 Publication
    Corresponds to variant rs5908 [ dbSNP | Ensembl ].
    VAR_011954

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei1 – 11M → MQWMSHTRERDAGSKDSVAT M in isoform 3. 1 PublicationVSP_046492
    Alternative sequencei522 – 57453Missing in isoform 2. 1 PublicationVSP_002207Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M11058 mRNA. Translation: AAA52679.1.
    AF273765
    , AF273754, AF273755, AF273756, AF273757, AF273758, AF273759, AF273760, AF273761, AF273762, AF273763, AF273764 Genomic DNA. Translation: AAG21343.1.
    AY321356 Genomic DNA. Translation: AAP72015.1.
    AK296499 mRNA. Translation: BAH12375.1. Frameshift.
    AC008897 Genomic DNA. No translation available.
    BC033692 mRNA. Translation: AAH33692.1.
    CCDSiCCDS4027.1. [P04035-1]
    CCDS47234.1. [P04035-2]
    PIRiA00356. RDHUE.
    RefSeqiNP_000850.1. NM_000859.2. [P04035-1]
    NP_001124468.1. NM_001130996.1. [P04035-2]
    UniGeneiHs.628096.
    Hs.643495.

    Genome annotation databases

    EnsembliENST00000287936; ENSP00000287936; ENSG00000113161. [P04035-1]
    ENST00000343975; ENSP00000340816; ENSG00000113161. [P04035-2]
    ENST00000511206; ENSP00000426745; ENSG00000113161. [P04035-1]
    GeneIDi3156.
    KEGGihsa:3156.
    UCSCiuc003kdp.3. human. [P04035-1]
    uc003kdq.3. human. [P04035-2]

    Polymorphism databases

    DMDMi123343.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M11058 mRNA. Translation: AAA52679.1 .
    AF273765
    , AF273754 , AF273755 , AF273756 , AF273757 , AF273758 , AF273759 , AF273760 , AF273761 , AF273762 , AF273763 , AF273764 Genomic DNA. Translation: AAG21343.1 .
    AY321356 Genomic DNA. Translation: AAP72015.1 .
    AK296499 mRNA. Translation: BAH12375.1 . Frameshift.
    AC008897 Genomic DNA. No translation available.
    BC033692 mRNA. Translation: AAH33692.1 .
    CCDSi CCDS4027.1. [P04035-1 ]
    CCDS47234.1. [P04035-2 ]
    PIRi A00356. RDHUE.
    RefSeqi NP_000850.1. NM_000859.2. [P04035-1 ]
    NP_001124468.1. NM_001130996.1. [P04035-2 ]
    UniGenei Hs.628096.
    Hs.643495.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1DQ8 X-ray 2.10 A/B/C/D 426-888 [» ]
    1DQ9 X-ray 2.80 A/B/C/D 426-888 [» ]
    1DQA X-ray 2.00 A/B/C/D 426-888 [» ]
    1HW8 X-ray 2.10 A/B/C/D 426-888 [» ]
    1HW9 X-ray 2.33 A/B/C/D 426-888 [» ]
    1HWI X-ray 2.30 A/B/C/D 426-888 [» ]
    1HWJ X-ray 2.26 A/B/C/D 426-888 [» ]
    1HWK X-ray 2.22 A/B/C/D 426-888 [» ]
    1HWL X-ray 2.10 A/B/C/D 426-888 [» ]
    2Q1L X-ray 2.05 A/B/C/D 441-875 [» ]
    2Q6B X-ray 2.00 A/B/C/D 441-875 [» ]
    2Q6C X-ray 2.00 A/B/C/D 441-875 [» ]
    2R4F X-ray 1.70 A/B/C/D 441-875 [» ]
    3BGL X-ray 2.23 A/B/C/D 441-875 [» ]
    3CCT X-ray 2.12 A/B/C/D 441-875 [» ]
    3CCW X-ray 2.10 A/B/C/D 441-875 [» ]
    3CCZ X-ray 1.70 A/B/C/D 441-875 [» ]
    3CD0 X-ray 2.40 A/B/C/D 441-875 [» ]
    3CD5 X-ray 2.39 A/B/C/D 441-875 [» ]
    3CD7 X-ray 2.05 A/B/C/D 441-875 [» ]
    3CDA X-ray 2.07 A/B/C/D 441-875 [» ]
    3CDB X-ray 2.30 A/B/C/D 441-875 [» ]
    ProteinModelPortali P04035.
    SMRi P04035. Positions 441-864.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 109399. 10 interactions.
    IntActi P04035. 3 interactions.
    STRINGi 9606.ENSP00000287936.

    Chemistry

    BindingDBi P04035.
    ChEMBLi CHEMBL402.
    DrugBanki DB01076. Atorvastatin.
    DB01393. Bezafibrate.
    DB00439. Cerivastatin.
    DB01095. Fluvastatin.
    DB00227. Lovastatin.
    DB00157. NADH.
    DB00175. Pravastatin.
    DB01098. Rosuvastatin.
    DB00641. Simvastatin.
    GuidetoPHARMACOLOGYi 639.

    Protein family/group databases

    TCDBi 2.A.6.6.5. the resistance-nodulation-cell division (rnd) superfamily.

    PTM databases

    PhosphoSitei P04035.

    Polymorphism databases

    DMDMi 123343.

    Proteomic databases

    MaxQBi P04035.
    PaxDbi P04035.
    PRIDEi P04035.

    Protocols and materials databases

    DNASUi 3156.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000287936 ; ENSP00000287936 ; ENSG00000113161 . [P04035-1 ]
    ENST00000343975 ; ENSP00000340816 ; ENSG00000113161 . [P04035-2 ]
    ENST00000511206 ; ENSP00000426745 ; ENSG00000113161 . [P04035-1 ]
    GeneIDi 3156.
    KEGGi hsa:3156.
    UCSCi uc003kdp.3. human. [P04035-1 ]
    uc003kdq.3. human. [P04035-2 ]

    Organism-specific databases

    CTDi 3156.
    GeneCardsi GC05P074635.
    HGNCi HGNC:5006. HMGCR.
    HPAi CAB016797.
    HPA008338.
    MIMi 142910. gene+phenotype.
    neXtProti NX_P04035.
    PharmGKBi PA189.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi COG1257.
    HOGENOMi HOG000183489.
    HOVERGENi HBG000453.
    InParanoidi P04035.
    KOi K00021.
    OMAi PNEECLQ.
    OrthoDBi EOG7GXP9T.
    PhylomeDBi P04035.
    TreeFami TF105362.

    Enzyme and pathway databases

    UniPathwayi UPA00058 ; UER00103 .
    BioCyci MetaCyc:HS03652-MONOMER.
    Reactomei REACT_116145. PPARA activates gene expression.
    REACT_147904. Activation of gene expression by SREBF (SREBP).
    REACT_9405. Cholesterol biosynthesis.
    SABIO-RK P04035.

    Miscellaneous databases

    ChiTaRSi Hmgcr. human.
    EvolutionaryTracei P04035.
    GeneWikii HMG-CoA_reductase.
    GenomeRNAii 3156.
    NextBioi 12500.
    PROi P04035.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P04035.
    Bgeei P04035.
    CleanExi HS_HMGCR.
    Genevestigatori P04035.

    Family and domain databases

    Gene3Di 1.10.3270.10. 1 hit.
    3.30.70.420. 1 hit.
    3.90.770.10. 2 hits.
    InterProi IPR002202. 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 ]
    PANTHERi PTHR10572. PTHR10572. 1 hit.
    Pfami PF00368. HMG-CoA_red. 1 hit.
    [Graphical view ]
    PRINTSi PR00071. HMGCOARDTASE.
    SUPFAMi SSF55035. SSF55035. 1 hit.
    SSF56542. SSF56542. 2 hits.
    TIGRFAMsi TIGR00920. 2A060605. 1 hit.
    TIGR00533. HMG_CoA_R_NADP. 1 hit.
    PROSITEi 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.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Human 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation."
      Luskey K.L., Stevens B.
      J. Biol. Chem. 260:10271-10277(1985) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
    2. "Human HMG-CoA reductase gene."
      Nakajima T., Iwaki K., Hamakubo T., Kodama T., Emi M.
      Submitted (JUN-2000) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    3. Rieder M.J., da Ponte S.H., Kuldanek S.A., Rajkumar N., Smith J.D., Toth E.J., Nickerson D.A.
      Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    4. "Complete sequencing and characterization of 21,243 full-length human cDNAs."
      Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.
      , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
      Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
      Tissue: Thalamus.
    5. "The DNA sequence and comparative analysis of human chromosome 5."
      Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S., Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M., She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.
      , Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M., Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K., Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C., Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M., Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A., Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M., Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M., Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S., Richardson P., Lucas S.M., Myers R.M., Rubin E.M.
      Nature 431:268-274(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    6. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
      Tissue: Blood.
    7. "Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth."
      Brown M.S., Goldstein J.L.
      J. Lipid Res. 21:505-517(1980) [PubMed] [Europe PMC] [Abstract]
      Cited for: ENZYME REGULATION.
    8. "Accelerated degradation of HMG CoA reductase mediated by binding of insig-1 to its sterol-sensing domain."
      Sever N., Yang T., Brown M.S., Goldstein J.L., DeBose-Boyd R.A.
      Mol. Cell 11:25-33(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH INSIG1, UBIQUITINATION.
    9. "Dislocation of HMG-CoA reductase and Insig-1, two polytopic endoplasmic reticulum proteins, en route to proteasomal degradation."
      Leichner G.S., Avner R., Harats D., Roitelman J.
      Mol. Biol. Cell 20:3330-3341(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH INSIG1, UBIQUITINATION AT LYS-89 AND LYS-248, GLYCOSYLATION, MUTAGENESIS OF 75-TYR--TYR-77; LYS-89 AND LYS-248.
    10. "Metabolically regulated endoplasmic reticulum-associated degradation of 3-hydroxy-3-methylglutaryl-CoA reductase: evidence for requirement of a geranylgeranylated protein."
      Leichner G.S., Avner R., Harats D., Roitelman J.
      J. Biol. Chem. 286:32150-32161(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: UBIQUITINATION.
    11. "A novel 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) splice variant with an alternative exon 1 potentially encoding an extended N-terminus."
      Stormo C., Kringen M.K., Grimholt R.M., Berg J.P., Piehler A.P.
      BMC Mol. Biol. 13:29-29(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: TISSUE SPECIFICITY (ISOFORM 3), ALTERNATIVE SPLICING.
    12. Cited for: INTERACTION WITH UBIAD1.
    13. "Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis."
      Istvan E.S., Palnitkar M., Buchanan S.K., Deisenhofer J.
      EMBO J. 19:819-830(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 422-888, SUBUNIT.
    14. "Structural mechanism for statin inhibition of HMG-CoA reductase."
      Istvan E.S., Deisenhofer J.
      Science 292:1160-1164(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 426-888.
    15. "Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase."
      Sarver R.W., Bills E., Bolton G., Bratton L.D., Caspers N.L., Dunbar J.B., Harris M.S., Hutchings R.H., Kennedy R.M., Larsen S.D., Pavlovsky A., Pfefferkorn J.A., Bainbridge G.
      J. Med. Chem. 51:3804-3813(2008) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.39 ANGSTROMS) OF 441-875 IN COMPLEX WITH STATIN-BASED INHIBITORS.
    16. Cited for: VARIANT VAL-638.

    Entry informationi

    Entry nameiHMDH_HUMAN
    AccessioniPrimary (citable) accession number: P04035
    Secondary accession number(s): B7Z3Y9, Q8N190
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: November 1, 1986
    Last sequence update: November 1, 1986
    Last modified: October 1, 2014
    This is version 176 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 5
      Human chromosome 5: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PATHWAY comments
      Index of metabolic and biosynthesis pathways
    6. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    7. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3