P04035 (HMDH_HUMAN) Reviewed, UniProtKB/Swiss-Prot

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.
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; (R)-mevalonate biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
Subunit structure	Homodimer. Ref.5
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 Transmembrane helix
Ligand	NADP
Molecular function	Oxidoreductase
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological process	cholesterol biosynthetic process Traceable author statement. Source: Reactome 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
Cellular component	endoplasmic reticulum membrane Traceable author statement. Source: Reactome integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW peroxisomal membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular function	NADP binding Inferred from electronic annotation. Source: InterPro hydroxymethylglutaryl-CoA reductase (NADPH) activity Traceable author statement. Source: Reactome
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.

Note: 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

Helical; Potential

Transmembrane

57 – 78

22

Helical; Potential

Transmembrane

90 – 114

25

Helical; Potential

Transmembrane

124 – 149

26

Helical; Potential

Transmembrane

160 – 187

28

Helical; Potential

Transmembrane

192 – 220

29

Helical; Potential

Transmembrane

315 – 339

25

Helical; 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

Modified residue

872

1

Phosphoserine; by AMPK By similarity

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. Ref.7
Corresponds to variant rs5908 [ dbSNP | Ensembl ].

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	FASTA	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

EMBL
GenBank
DDBJ

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.

IPI

IPI00021770.
IPI00221382.

PIR

RDHUE. A00356.

RefSeq

NP_000850.1. NM_000859.2.
NP_001124468.1. NM_001130996.1.

UniGene

Hs.628096.
Hs.643495.

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]

ProteinModelPortal

P04035.

SMR

P04035. Positions 441-864.

ModBase

Search...

Protein-protein interaction databases

IntAct

P04035. 1 interaction.

STRING

P04035.

Protein family/group databases

TCDB

2.A.6.6.5. resistance-nodulation-cell division (RND) superfamily.

PTM databases

PhosphoSite

P04035.

Polymorphism databases

DMDM

123343.

Proteomic databases

PRIDE

P04035.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000287936; ENSP00000287936; ENSG00000113161.

GeneID

3156.

KEGG

hsa:3156.

NMPDR

fig|9606.3.peg.25409.

UCSC

uc003kdp.1. human.
uc003kdq.1. human.

Organism-specific databases

CTD

3156.

GeneCards

GC05P074668.

H-InvDB

HIX0004954.

HGNC

HGNC:5006. HMGCR.

HPA

CAB016797.
HPA008338.

MIM

142910. gene+phenotype.

neXtProt

NX_P04035.

PharmGKB

PA189.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG10146.

GeneTree

ENSGT00390000006426.

HOGENOM

HBG355150.

HOVERGEN

HBG000453.

InParanoid

P04035.

OMA

SPVVTQK.

PhylomeDB

P04035.

Enzyme and pathway databases

BioCyc

MetaCyc:ENSG00000113161-MONOMER.

Reactome

REACT_22258. Metabolism of lipids and lipoproteins.

Gene expression databases

ArrayExpress

P04035.

Bgee

P04035.

CleanEx

HS_HMGCR.

Genevestigator

P04035.

GermOnline

ENSG00000113161. Homo sapiens.

Family and domain databases

InterPro

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.
IPR009029. HMG_CoA_Rdtase_sub-bd.
IPR000731. SSD.
[Graphical view]

Gene3D

G3DSA:3.30.70.420. G3DSA:3.30.70.420. 1 hit.
G3DSA:3.90.770.10. HMG-CoA_red. 2 hits.
G3DSA:1.10.3270.10. HMG_CoA_Rdtase_N. 1 hit.

KO

K00021.

PANTHER

PTHR10572. HMG-CoA_red. 1 hit.

Pfam

PF00368. HMG-CoA_red. 1 hit.
[Graphical view]

PRINTS

PR00071. HMGCOARDTASE.

SUPFAM

SSF55035. HMG_CoA_NAD_bind. 1 hit.
SSF56542. HMG_CoA_sub_bind. 1 hit.

TIGRFAMs

TIGR00920. 2A060605. 1 hit.
TIGR00533. HMG_CoA_R_NADP. 1 hit.

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.
[Graphical view]

ProtoNet

Search...

Other

DrugBank

DB01076. Atorvastatin.
DB01393. Bezafibrate.
DB00439. Cerivastatin.
DB01095. Fluvastatin.
DB00227. Lovastatin.
DB00157. NADH.
DB00175. Pravastatin.
DB01098. Rosuvastatin.
DB00641. Simvastatin.

NextBio

12500.

SOURCE

Search...

Entry information

Entry name

HMDH_HUMAN

Accession

Primary (citable) accession number: P04035
Secondary accession number(s): Q8N190

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1986
Last sequence update:	November 1, 1986
Last modified:	January 25, 2012
This is version 147 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.