Reviewed, UniProtKB/Swiss-Prot P04035 (HMDH_HUMAN)

Names and origin

Protein names

Recommended name:
    3-hydroxy-3-methylglutaryl-coenzyme A reductase
      Short name=HMG-CoA reductase
    EC=1.1.1.34

Gene names

Name:

HMGCR

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	888 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence 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.

Ontologies

Keywords
Biological process	Cholesterol biosynthesis Lipid synthesis Steroid biosynthesis Sterol biosynthesis
Cellular component	Endoplasmic reticulum Membrane Peroxisome
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Transmembrane
Ligand	NADP
Molecular function	Oxidoreductase
PTM	Glycoprotein
Technical term	3D-structure
Gene Ontology (GO)
Biological process	cholesterol biosynthetic process Inferred from electronic annotation. Source: UniProtKB-KW coenzyme A metabolic process Inferred from electronic annotation. Source: InterPro germ cell migration Traceable author statement. Source: ProtInc gonad development Traceable author statement. Source: ProtInc isoprenoid biosynthetic process Inferred from electronic annotation. Source: InterPro oxidation reduction Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	endoplasmic reticulum membrane Ref.1 Ref.5 Traceable author statement. Source: ProtInc integral to membrane Inferred from electronic annotation. Source: InterPro peroxisomal membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	NADP binding Inferred from electronic annotation. Source: InterPro hydroxymethylglutaryl-CoA reductase (NADPH) activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 888

888

3-hydroxy-3-methylglutaryl-coenzyme A reductase

PRO_0000114419

Regions

Transmembrane

10 – 39

30

Potential

Transmembrane

57 – 78

22

Potential

Transmembrane

90 – 114

25

Potential

Transmembrane

124 – 149

26

Potential

Transmembrane

160 – 187

28

Potential

Transmembrane

192 – 220

29

Potential

Transmembrane

315 – 339

25

Potential

Region

340 – 449

110

Linker

Region

450 – 888

439

Catalytic

Sites

Active site

559

1

Charge relay system

Active site

691

1

Charge relay system

Active site

767

1

Charge relay system

Active site

866

1

Proton donor

Amino acid modifications

Glycosylation

281

1

N-linked (GlcNAc...) Potential

Glycosylation

296

1

N-linked (GlcNAc...) Potential

Glycosylation

419

1

N-linked (GlcNAc...) Potential

Glycosylation

518

1

N-linked (GlcNAc...) Potential

Glycosylation

870

1

N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence

522 – 574

53

Missing in isoform 2.

VSP_002207

Natural variant

638

1

I → V: dbSNP rs5908.

VAR_011954

Secondary structure

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888

Helix Strand Turn

Details...

Helix

445 – 448

4

Helix

464 – 473

10

Helix

478 – 480

3

Helix

481 – 484

4

Beta strand

485 – 487

3

Helix

488 – 500

13

Beta strand

503 – 505

3

Helix

506 – 511

6

Turn

520 – 525

6

Beta strand

528 – 546

19

Beta strand

549 – 556

8

Helix

562 – 574

13

Turn

575 – 577

3

Beta strand

579 – 590

12

Beta strand

593 – 595

3

Helix

599 – 609

11

Helix

612 – 623

12

Beta strand

630 – 639

10

Beta strand

642 – 650

9

Helix

657 – 674

18

Beta strand

679 – 683

5

Helix

695 – 700

6

Beta strand

703 – 712

10

Helix

714 – 719

6

Helix

725 – 736

12

Helix

738 – 742

5

Beta strand

746 – 752

7

Helix

753 – 763

11

Helix

768 – 770

3

Helix

771 – 774

4

Beta strand

777 – 788

12

Beta strand

790 – 800

11

Beta strand

804 – 806

3

Helix

807 – 810

4

Helix

812 – 820

9

Helix

833 – 859

27

Helix

866 – 869

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1986. Version 1. Checksum: 49B610DCCCFA26B6	FASTA	888	97,476
	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
	Isoform 2 [UniParc]. Checksum: 20BBFC6C1FB46ADA		835	92,021
	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 LLGGGASSRV LADGMTRGPV 550 560 570 580 590 600 VRLPRACDSA EVKAWLETSE GFAVIKEAFD STSRFARLQK LHTSIAGRNL YIRFQSRSGD 610 620 630 640 650 660 AMGMNMISKG TEKALSKLHE YFPEMQILAV SGNYCTDKKP AAINWIEGRG KSVVCEAVIP 670 680 690 700 710 720 AKVVREVLKT TTEAMIEVNI NKNLVGSAMA GSIGGYNAHA ANIVTAIYIA CGQDAAQNVG 730 740 750 760 770 780 SSNCITLMEA SGPTNEDLYI SCTMPSIEIG TVGGGTNLLP QQACLQMLGV QGACKDNPGE 790 800 810 820 830 NARQLARIVC GTVMAGELSL MAALAAGHLV KSHMIHNRSK INLQDLQGAC TKKTA

References

	« Hide 'large scale' referencesShow '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

EMBLGenBankDDBJ

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.
BC033692 mRNA. Translation: AAH33692.1.

PIR

RDHUE. A00356.

RefSeq

NP_000850.1.
NP_001124468.1.

UniGene

Hs.699171

3D structure databases

PDBMSD

Entry

Method

Resolution (