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Reviewed, UniProtKB/Swiss-Prot P04035 (HMDH_HUMAN)

Last modified November 25, 2008. Version 110. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    3-hydroxy-3-methylglutaryl-coenzyme A reductase
      Short name=HMG-CoA reductase
    EC=1.1.1.34
Gene names
Name: HMGCR
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length888 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

This transmembrane glycoprotein is involved in the control of cholesterol biosynthesis. It is the rate-limiting enzyme of sterol biosynthesis.

Catalytic activity

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

Enzyme regulation

Inhibited by statins, a class of hypolipidemic agents used as pharmaceuticals to lower cholesterol levels in people at risk for cardiovascular disease because of 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 use and the effect is maximal after four to six weeks.

Pathway

Metabolic intermediate biosynthesis; mevalonic acid biosynthesis; (R)-mevalonic acid from acetyl-CoA: step 3/3.

Subunit structure

Homodimer.

Subcellular location

Endoplasmic reticulum membrane; Multi-pass membrane protein. Peroxisome membrane; Multi-pass membrane protein.

Sequence similarities

Belongs to the HMG-CoA reductase family.

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P04035-1)

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.
Isoform 2 (identifier: P04035-2)

The sequence of this isoform differs from the canonical sequence as follows:
     522-574: Missing.
Notes: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 8888883-hydroxy-3-methylglutaryl-coenzyme A reductase
PRO_0000114419

Regions

Transmembrane10 – 3930 Potential
Transmembrane57 – 7822 Potential
Transmembrane90 – 11425 Potential
Transmembrane124 – 14926 Potential
Transmembrane160 – 18728 Potential
Transmembrane192 – 22029 Potential
Transmembrane315 – 33925 Potential
Region340 – 449110Linker
Region450 – 888439Catalytic

Sites

Active site5591Charge relay system
Active site6911Charge relay system
Active site7671Charge relay system
Active site8661Proton donor

Amino acid modifications

Glycosylation2811N-linked (GlcNAc...) Potential
Glycosylation2961N-linked (GlcNAc...) Potential
Glycosylation4191N-linked (GlcNAc...) Potential
Glycosylation5181N-linked (GlcNAc...) Potential
Glycosylation8701N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence522 – 57453Missing in isoform 2.
VSP_002207
Natural variant6381I → V: dbSNP rs5908.
VAR_011954

Secondary structure

................................................................... 888
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified November 1, 1986. Version 1.
Checksum: 49B610DCCCFA26B6

FASTA88897,476
        10         20         30         40         50         60 
MLSRLFRMHG LFVASHPWEV IVGTVTLTIC MMSMNMFTGN NKICGWNYEC PKFEEDVLSS 

        70         80         90        100        110        120 
DIIILTITRC IAILYIYFQF QNLRQLGSKY ILGIAGLFTI FSSFVFSTVV IHFLDKELTG 

       130        140        150        160        170        180 
LNEALPFFLL LIDLSRASTL AKFALSSNSQ DEVRENIARG MAILGPTFTL DALVECLVIG 

       190        200        210        220        230        240 
VGTMSGVRQL EIMCCFGCMS VLANYFVFMT FFPACVSLVL ELSRESREGR PIWQLSHFAR 

       250        260        270        280        290        300 
VLEEEENKPN PVTQRVKMIM SLGLVLVHAH SRWIADPSPQ NSTADTSKVS LGLDENVSKR 

       310        320        330        340        350        360 
IEPSVSLWQF YLSKMISMDI EQVITLSLAL LLAVKYIFFE QTETESTLSL KNPITSPVVT 

       370        380        390        400        410        420 
QKKVPDNCCR REPMLVRNNQ KCDSVEEETG INRERKVEVI KPLVAETDTP NRATFVVGNS 

       430        440        450        460        470        480 
SLLDTSSVLV TQEPEIELPR EPRPNEECLQ ILGNAEKGAK FLSDAEIIQL VNAKHIPAYK 

       490        500        510        520        530        540 
LETLMETHER GVSIRRQLLS KKLSEPSSLQ YLPYRDYNYS LVMGACCENV IGYMPIPVGV 

       550        560        570        580        590        600 
AGPLCLDEKE FQVPMATTEG CLVASTNRGC RAIGLGGGAS SRVLADGMTR GPVVRLPRAC 

       610        620        630        640        650        660 
DSAEVKAWLE TSEGFAVIKE AFDSTSRFAR LQKLHTSIAG RNLYIRFQSR SGDAMGMNMI 

       670        680        690        700        710        720 
SKGTEKALSK LHEYFPEMQI LAVSGNYCTD KKPAAINWIE GRGKSVVCEA VIPAKVVREV 

       730        740        750        760        770        780 
LKTTTEAMIE VNINKNLVGS AMAGSIGGYN AHAANIVTAI YIACGQDAAQ NVGSSNCITL 

       790        800        810        820        830        840 
MEASGPTNED LYISCTMPSI EIGTVGGGTN LLPQQACLQM LGVQGACKDN PGENARQLAR 

       850        860        870        880 
IVCGTVMAGE LSLMAALAAG HLVKSHMIHN RSKINLQDLQ GACTKKTA 

« Hide

Isoform 2 [UniParc].

Checksum: 20BBFC6C1FB46ADA
Show »

83592,021

References

« Hide 'large scale' references
[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: 2991281] [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]"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: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
Tissue: Blood.
[5]"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: 10698924] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 422-888, SUBUNIT.
[6]"Structural mechanism for statin inhibition of HMG-CoA reductase."
Istvan E.S., Deisenhofer J.
Science 292:1160-1164(2001) [PubMed: 11349148] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 426-888.
[7]"Characterization of single-nucleotide polymorphisms in coding regions of human genes."
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S.
Nat. Genet. 22:231-238(1999) [PubMed: 10391209] [Abstract]
Cited for: VARIANT VAL-638.
[8]Erratum
Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., Lander E.S.
Nat. Genet. 23:373-373(1999)
+Additional computationally mapped references.

Cross-references

Sequence databases

M11058 mRNA. Translation: AAA52679.1.
AF273765 expand/collapse EMBL AC list , AF273754, AF273755, AF273756, AF273757, AF273758, AF273759, AF273760, AF273761, AF273762, AF273763, AF273764 Genomic DNA. Translation: AAG21343.1.
AY321356 Genomic DNA. Translation: AAP72015.1.
BC033692 mRNA. Translation: AAH33692.1.
PIRRDHUE. A00356.
RefSeqNP_000850.1.
NP_001124468.1.
UniGeneHs.699171

3D structure databases

EntryMethodResolution (