EzCatDB: M00180
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DB codeM00180
RLCP classification9.5010.584100.976 : Hydride transfer
5.501.400060.67 : Elimination
9.5010.536000.976 : Hydride transfer
CATH domainDomain 1-.-.-.-
Domain 21.10.3270.10 : HMGR, N-terminal domain
Domain 33.90.770.10 : 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2Catalytic domain
Domain 43.30.70.420 : Alpha-Beta PlaitsCatalytic domain
E.C.1.1.1.34
CSA1dqa
MACiEM0093

CATH domainRelated DB codes (homologues)
3.30.70.420 : Alpha-Beta PlaitsD00607
3.90.770.10 : 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2D00607

Enzyme Name
UniProtKBKEGG

P04035
Protein name3-hydroxy-3-methylglutaryl-coenzyme A reductasehydroxymethylglutaryl-CoA reductase (NADPH)
hydroxymethylglutaryl coenzyme A reductase (reduced nicotinamideadenine dinucleotide phosphate)
3-hydroxy-3-methylglutaryl-CoA reductase
beta-hydroxy-beta-methylglutaryl coenzyme A reductase
hydroxymethylglutaryl CoA reductase (NADPH)
S-3-hydroxy-3-methylglutaryl-CoA reductase
NADPH-hydroxymethylglutaryl-CoA reductase
HMGCoA reductase-mevalonate:NADP-oxidoreductase (acetylating-CoA)
3-hydroxy-3-methylglutaryl CoA reductase (NADPH)
hydroxymethylglutaryl-CoA reductase (NADPH2)
SynonymsHMG-CoA reductase
EC 1.1.1.34
RefSeqNP_000850.1 (Protein)
NM_000859.2 (DNA/RNA sequence)
NP_001124468.1 (Protein)
NM_001130996.1 (DNA/RNA sequence)
PfamPF00368 (HMG-CoA_red)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00100Biosynthesis of steroids

UniProtKB:Accession NumberP04035
Entry nameHMDH_HUMAN
Activity(R)-mevalonate + CoA + 2 NADP(+) = (S)-3- hydroxy-3-methylglutaryl-CoA + 2 NADPH.
SubunitHomodimer.
Subcellular locationEndoplasmic reticulum membrane, Multi-pass membrane protein. Peroxisome membrane, Multi-pass membrane protein.
Cofactor

Compound table: links to PDB-related databases & PoSSuM

SubstratesProductsintermediates
KEGG-idC00356C00005C00080C00418C00010C00006I00101I00102
Compound(S)-3-Hydroxy-3-methylglutaryl-CoANADPHH+(R)-MevalonateCoANADP+Mevaldyl-CoAMevaldehyde
Typeamine group,carbohydrate,carboxyl group,nucleotide,peptide/protein,sulfide groupamide group,amine group,nucleotideotherscarbohydrate,carboxyl groupamine group,carbohydrate,nucleotide,peptide/protein,sulfhydryl groupamide group,amine group,nucleotide

ChEBI15467
16474
15378
17710
15346
18009


PubChem445127
439218
5884
1038
439230
87642
6816
5886


                
1dq8A01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq8B01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq8C01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq8D01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq9A01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq9B01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq9C01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq9D01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dqaA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dqaB01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dqaC01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dqaD01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw8A01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw8B01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw8C01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw8D01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw9A01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw9B01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw9C01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw9D01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwiA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwiB01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwiC01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwiD01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwjA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwjB01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwjC01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwjD01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwkA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwkB01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwkC01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwkD01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwlA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwlB01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwlC01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwlD01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq8A02UnboundUnbound  Bound:COAUnboundUnboundIntermediate-analogue:MAH
1dq8B02UnboundUnbound  Bound:COAUnboundUnboundIntermediate-analogue:MAH
1dq8C02UnboundUnbound  Bound:COAUnboundUnboundIntermediate-analogue:MAH
1dq8D02UnboundUnbound  Bound:COAUnboundUnboundIntermediate-analogue:MAH
1dq9A02Bound:HMGUnbound UnboundUnboundUnboundUnboundUnbound
1dq9B02Bound:HMGUnbound UnboundUnboundUnboundUnboundUnbound
1dq9C02Bound:HMGUnbound UnboundUnboundUnboundUnboundUnbound
1dq9D02Bound:HMGUnbound UnboundUnboundUnboundUnboundUnbound
1dqaA02UnboundUnbound  Bound:COAUnboundUnboundIntermediate-analogue:MAH
1dqaB02UnboundUnbound  Bound:COAUnboundUnboundIntermediate-analogue:MAH
1dqaC02UnboundUnbound  Bound:COAUnboundUnboundIntermediate-analogue:MAH
1dqaD02UnboundUnbound  Bound:COAUnboundUnboundIntermediate-analogue:MAH
1hw8A02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:114Unbound
1hw8B02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:114Unbound
1hw8C02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:114Unbound
1hw8D02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:114Unbound
1hw9A02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:SIMUnbound
1hw9B02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:SIMUnbound
1hw9C02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:SIMUnbound
1hw9D02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:SIMUnbound
1hwiA02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:115Unbound
1hwiB02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:115Unbound
1hwiC02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:115Unbound
1hwiD02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:115Unbound
1hwjA02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:116Unbound
1hwjB02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:116Unbound
1hwjC02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:116Unbound
1hwjD02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:116Unbound
1hwkA02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:117Unbound
1hwkB02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:117Unbound
1hwkC02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:117Unbound
1hwkD02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:117Unbound
1hwlA02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:FBIUnbound
1hwlB02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:FBIUnbound
1hwlC02UnboundUnbound UnboundUnboundUnboundIntermediate-analogue:FBIUnbound
1hwlD02UnboundUnbound UnboundAnalogue:ADPUnboundIntermediate-analogue:FBIUnbound
1dq8A03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq8B03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq8C03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq8D03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq9A03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq9B03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq9C03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dq9D03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1dqaA03UnboundUnbound UnboundUnboundBound:NAPUnboundUnbound
1dqaB03UnboundUnbound UnboundUnboundBound:NAPUnboundUnbound
1dqaC03UnboundUnbound UnboundUnboundBound:NAPUnboundUnbound
1dqaD03UnboundUnbound UnboundUnboundBound:NAPUnboundUnbound
1hw8A03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw8B03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw8C03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw8D03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hw9A03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw9B03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hw9C03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hw9D03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwiA03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwiB03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwiC03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwiD03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwjA03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwjB03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwjC03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwjD03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwkA03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwkB03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwkC03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwkD03UnboundUnbound UnboundUnboundAnalogue:ADPUnboundUnbound
1hwlA03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwlB03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwlC03UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1hwlD03UnboundUnbound UnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
Swiss-prot;P04035 & literature [19]
pdbCatalytic residuescomment
          
1dq8A01 
mutant M485I
1dq8B01 
mutant M485I
1dq8C01 
mutant M485I
1dq8D01 
mutant M485I
1dq9A01 
mutant M485I
1dq9B01 
mutant M485I
1dq9C01 
mutant M485I
1dq9D01 
mutant M485I
1dqaA01 
mutant M485I
1dqaB01 
mutant M485I
1dqaC01 
mutant M485I
1dqaD01 
mutant M485I
1hw8A01 
mutant M485I
1hw8B01 
mutant M485I
1hw8C01 
mutant M485I
1hw8D01 
mutant M485I
1hw9A01 
mutant M485I
1hw9B01 
mutant M485I
1hw9C01 
mutant M485I
1hw9D01 
mutant M485I
1hwiA01 
mutant M485I
1hwiB01 
mutant M485I
1hwiC01 
mutant M485I
1hwiD01 
mutant M485I
1hwjA01 
mutant M485I
1hwjB01 
mutant M485I
1hwjC01 
mutant M485I
1hwjD01 
mutant M485I
1hwkA01 
mutant M485I
1hwkB01 
mutant M485I
1hwkC01 
mutant M485I
1hwkD01 
mutant M485I
1hwlA01 
mutant M485I
1hwlB01 
mutant M485I
1hwlC01 
mutant M485I
1hwlD01 
mutant M485I
1dq8A02GLU 559;ASP 767;       
invisible H866
1dq8B02GLU 559;ASP 767;       
invisible H866
1dq8C02GLU 559;ASP 767;       
invisible H866
1dq8D02GLU 559;ASP 767;       
invisible H866
1dq9A02GLU 559;ASP 767;       
invisible H866
1dq9B02GLU 559;ASP 767;       
invisible H866
1dq9C02GLU 559;ASP 767;HIS 866
 
1dq9D02GLU 559;ASP 767;       
invisible H866
1dqaA02GLU 559;ASP 767;HIS 866
 
1dqaB02GLU 559;ASP 767;HIS 866
 
1dqaC02GLU 559;ASP 767;HIS 866
 
1dqaD02GLU 559;ASP 767;HIS 866
 
1hw8A02GLU 559;ASP 767;       
invisible H866
1hw8B02GLU 559;ASP 767;       
invisible H866
1hw8C02GLU 559;ASP 767;       
invisible H866
1hw8D02GLU 559;ASP 767;       
invisible H866
1hw9A02GLU 559;ASP 767;       
invisible H866
1hw9B02GLU 559;ASP 767;       
invisible H866
1hw9C02GLU 559;ASP 767;       
invisible H866
1hw9D02GLU 559;ASP 767;       
invisible H866
1hwiA02GLU 559;ASP 767;       
invisible H866
1hwiB02GLU 559;ASP 767;       
invisible H866
1hwiC02GLU 559;ASP 767;       
invisible H866
1hwiD02GLU 559;ASP 767;       
invisible H866
1hwjA02GLU 559;ASP 767;       
invisible H866
1hwjB02GLU 559;ASP 767;       
invisible H866
1hwjC02GLU 559;ASP 767;       
invisible H866
1hwjD02GLU 559;ASP 767;       
invisible H866
1hwkA02GLU 559;ASP 767;       
invisible H866
1hwkB02GLU 559;ASP 767;       
invisible H866
1hwkC02GLU 559;ASP 767;       
invisible H866
1hwkD02GLU 559;ASP 767;       
invisible H866
1hwlA02GLU 559;ASP 767;       
invisible H866
1hwlB02GLU 559;ASP 767;       
invisible H866
1hwlC02GLU 559;ASP 767;       
invisible H866
1hwlD02GLU 559;ASP 767;       
invisible H866
1dq8A03LYS 691
 
1dq8B03LYS 691
 
1dq8C03LYS 691
 
1dq8D03LYS 691
 
1dq9A03LYS 691
 
1dq9B03LYS 691
 
1dq9C03LYS 691
 
1dq9D03LYS 691
 
1dqaA03LYS 691
 
1dqaB03LYS 691
 
1dqaC03LYS 691
 
1dqaD03LYS 691
 
1hw8A03LYS 691
 
1hw8B03LYS 691
 
1hw8C03LYS 691
 
1hw8D03LYS 691
 
1hw9A03LYS 691
 
1hw9B03LYS 691
 
1hw9C03LYS 691
 
1hw9D03LYS 691
 
1hwiA03LYS 691
 
1hwiB03LYS 691
 
1hwiC03LYS 691
 
1hwiD03LYS 691
 
1hwjA03LYS 691
 
1hwjB03LYS 691
 
1hwjC03LYS 691
 
1hwjD03LYS 691
 
1hwkA03LYS 691
 
1hwkB03LYS 691
 
1hwkC03LYS 691
 
1hwkD03LYS 691
 
1hwlA03LYS 691
 
1hwlB03LYS 691
 
1hwlC03LYS 691
 
1hwlD03LYS 691
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[8]Fig.1
[13]Fig.7, p.11481-11482
[15]Fig.8, p.16865-16866
[17]Scheme 1, Scheme 2
[19]Fig. 1, Fig. 5, p.14-16
[20]p.826-827

references
[1]
PubMed ID6247408
JournalJ Lipid Res
Year1980
Volume21
Pages399-405
AuthorsHunter CF, Rodwell VW
TitleRegulation of vertebrate liver HMG-CoA reductase via reversible modulation of its catalytic activity.
[2]
PubMed ID2991281
JournalJ Biol Chem
Year1985
Volume260
Pages10271-7
AuthorsLuskey KL, Stevens B
TitleHuman 3-hydroxy-3-methylglutaryl coenzyme A reductase. Conserved domains responsible for catalytic activity and sterol-regulated degradation.
[3]
PubMed ID3058035
JournalArch Biochem Biophys
Year1988
Volume267
Pages110-8
AuthorsMayer RJ, Debouck C, Metcalf BW
TitlePurification and properties of the catalytic domain of human 3-hydroxy-3-methylglutaryl-CoA reductase expressed in Escherichia coli.
[4]
PubMed ID3065625
JournalMol Cell Biol
Year1988
Volume8
Pages3797-808
AuthorsBasson ME, Thorsness M, Finer-Moore J, Stroud RM, Rine J
TitleStructural and functional conservation between yeast and human 3-hydroxy-3-methylglutaryl coenzyme A reductases, the rate-limiting enzyme of sterol biosynthesis.
[5]
PubMed ID2491679
JournalPlant Mol Biol
Year1989
Volume13
Pages627-38
AuthorsCaelles C, Ferrer A, Balcells L, Hegardt FG, Boronat A
TitleIsolation and structural characterization of a cDNA encoding Arabidopsis thaliana 3-hydroxy-3-methylglutaryl coenzyme A reductase.
[6]
PubMed ID2813388
JournalProc Natl Acad Sci U S A
Year1989
Volume86
Pages8217-21
AuthorsRajkovic A, Simonsen JN, Davis RE, Rottman FM
TitleMolecular cloning and sequence analysis of 3-hydroxy-3-methylglutaryl-coenzyme A reductase from the human parasite Schistosoma mansoni.
[7]
PubMed ID2369897
JournalEMBO J
Year1990
Volume9
Pages2439-46
AuthorsClarke PR, Hardie DG
TitleRegulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver.
[8]
PubMed ID2123872
JournalJ Biol Chem
Year1990
Volume265
Pages21634-41
AuthorsWang Y, Darnay BG, Rodwell VW
TitleIdentification of the principal catalytically important acidic residue of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
[9]
PubMed ID1685759
JournalLipids
Year1991
Volume26
Pages637-48
AuthorsBach TJ, Boronat A, Caelles C, Ferrer A, Weber T, Wettstein A
TitleAspects related to mevalonate biosynthesis in plants.
[10]
PubMed ID8374303
JournalProtein Expr Purif
Year1993
Volume4
Pages337-44
AuthorsFrimpong K, Darnay BG, Rodwell VW
TitleSyrian hamster 3-hydroxy-3-methylglutaryl-coenzyme A reductase expressed in Escherichia coli: production of homogeneous protein.
[11]
PubMed ID8112324
JournalEur J Biochem
Year1994
Volume219
Pages743-50
AuthorsBall KL, Dale S, Weekes J, Hardie DG
TitleBiochemical characterization of two forms of 3-hydroxy-3-methylglutaryl-CoA reductase kinase from cauliflower (Brassica oleracia).
[12]
PubMed ID8288583
JournalJ Biol Chem
Year1994
Volume269
Pages1217-21
AuthorsFrimpong K, Rodwell VW
TitleThe active site of hamster 3-hydroxy-3-methylglutaryl-CoA reductase resides at the subunit interface and incorporates catalytically essential acidic residues from separate polypeptides.
[13]
PubMed ID7908908
JournalJ Biol Chem
Year1994
Volume269
Pages11478-83
AuthorsFrimpong K, Rodwell VW
TitleCatalysis by Syrian hamster 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proposed roles of histidine 865, glutamate 558, and aspartate 766.
[14]
PubMed ID8120043
JournalJ Biol Chem
Year1994
Volume269
Pages6810-4
AuthorsOmkumar RV, Darnay BG, Rodwell VW
TitleModulation of Syrian hamster 3-hydroxy-3-methylglutaryl-CoA reductase activity by phosphorylation. Role of serine 871.
[15]
PubMed ID8207009
JournalJ Biol Chem
Year1994
Volume269
Pages16862-6
AuthorsOmkumar RV, Rodwell VW
TitlePhosphorylation of Ser871 impairs the function of His865 of Syrian hamster 3-hydroxy-3-methylglutaryl-CoA reductase.
[16]
PubMed ID8302869
JournalProc Natl Acad Sci U S A
Year1994
Volume91
Pages927-31
AuthorsEnjuto M, Balcells L, Campos N, Caelles C, Arro M, Boronat A
TitleArabidopsis thaliana contains two differentially expressed 3-hydroxy-3-methylglutaryl-CoA reductase genes, which encode microsomal forms of the enzyme.
[17]
PubMed ID10413460
JournalBiochemistry
Year1999
Volume38
Pages8879-83
AuthorsBochar DA, Tabernero L, Stauffacher CV, Rodwell VW
TitleAminoethylcysteine can replace the function of the essential active site lysine of Pseudomonas mevalonii 3-hydroxy-3-methylglutaryl coenzyme A reductase.
[18]
PubMed ID9973353
JournalJ Bacteriol
Year1999
Volume181
Pages1256-63
AuthorsTakahashi S, Kuzuyama T, Seto H
TitlePurification, characterization, and cloning of a eubacterial 3-hydroxy-3-methylglutaryl coenzyme A reductase, a key enzyme involved in biosynthesis of terpenoids.
[19]
PubMed ID11111074
JournalBiochim Biophys Acta
Year2000
Volume1529
Pages9-18
AuthorsIstvan ES, Deisenhofer J
TitleThe structure of the catalytic portion of human HMG-CoA reductase.
[20]
CommentsX-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 422-888, AND SUBUNIT.
PubMed ID10698924
JournalEMBO J
Year2000
Volume19
Pages819-30
AuthorsIstvan ES, Palnitkar M, Buchanan SK, Deisenhofer J
TitleCrystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.
Related PDB1dq8,1dq9,1dqa,1dq8,1dq9
[21]
PubMed ID11370859
JournalMol Genet Genomics
Year2001
Volume265
Pages135-42
AuthorsKato-Emori S, Higashi K, Hosoya K, Kobayashi T, Ezura H
TitleCloning and characterization of the gene encoding 3-hydroxy-3-methylglutaryl coenzyme A reductase in melon (Cucumis melo L. reticulatus).
[22]
CommentsX-ray crystallography
PubMed ID11349148
JournalScience
Year2001
Volume292
Pages1160-4
AuthorsIstvan ES, Deisenhofer J
TitleStructural mechanism for statin inhibition of HMG-CoA reductase.
Related PDB1hw8,1hw9,1hwi,1hwj,1hwk,1hwl

comments
This enzyme is composed of the N-terminal transmembrane domain, linker region, and the C-terminal catalytic domains. Tertiary structures have been solved for the C-terminal catalytic domains (see [7]).
HMG-CoA reductase from Pseudomonas mevalonii, which does not have transmembrane domain, is homologous to this enzyme (EC 1.1.1.88; D00607 in EzCatDB). The active site of this enzyme is similar to that of the counterpart enzyme, but slightly different. Therefor the catalytic reaction is also similar but slightly different from that of the homologous enzyme.
According to the literature [13], [19] and [20], this enzyme catalyzes the following reactions:
(A) Hydride transfer from NADPH to HMG-CoA, forming the first intermediate, Mevaldyl-CoA (I00101):
(A0) Asp767 may modulate the charge/activity of Glu559 and Lys691. (Asp767 raise the pKa of Glu559 so that it could be protonated.)
(A1) Hydride transfer occurs from nicotinamide group of NADPH to the carbonyl carbon of the substrate HMG-CoA. Simultaneously, Lys691 and the protonated Glu559 stabilizes the negative charge on the oxygen during the formation of Mevaldyl-CoA.
(B) Eliminative double-bond formation; Elimination of CoASH from Mevaldyl-CoA, forming the second intermediate, Mevaldehyde (I00102):
(B0) Asp767 may modulate the charge/activity of Glu559 and Lys691.
(B1) Glu559 and Lys691 stabilizes the negative charge on the oxygen atom of the intermediate.
(B2) His866 on the C-terminal movable domain acts as general acid to protonate the sulfur atom (or thioanion) of the eliminated group, CoA, to complete the reaction. This elimination reaction seems to be E1cB-like reaction.
(C) Hydride transfer from NADPH to Mevaldehyde, forming product, Mevalonate:
(C0) Asp767 may modulate the charge/activity of Glu559 and Lys691.
(C1) Lys691 acts as a general acid to protonate the carbonyl oxygen of Mevaldehyde. At the same time, hydride transfer occurs from nicotinamide group of NADH to the carbonyl carbon of Mevaldehyde.

createdupdated
2004-03-242011-09-05


Copyright: Nozomi Nagano, JST & CBRC-AIST
Funded by PRESTO/Japan Science and Technology Corporation (JST) (December 2001 - November 2004)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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© Computational Biology Research Center, AIST, 2004-2016 All Rights Reserved.