DB code: D00607

RLCP classification 9.5010.584100.113 : Hydride transfer
5.501.400060.67 : Elimination
9.5010.536000.113 : Hydride transfer
CATH domain 3.30.70.420 : Alpha-Beta Plaits
3.90.770.10 : 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 Catalytic domain
E.C. 1.1.1.88
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
3.30.70.420 : Alpha-Beta Plaits M00180
3.90.770.10 : 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2 M00180

Uniprot Enzyme Name
UniprotKB Protein name Synonyms Pfam RefSeq
P13702 3-hydroxy-3-methylglutaryl-coenzyme A reductase
HMG-CoA reductase
EC 1.1.1.88
PF00368 (HMG-CoA_red)
[Graphical View]
Q8DNS5
3-hydroxy-3-methylglutaryl-coenzyme a reductase
EC 1.1.1.88
PF00368 (HMG-CoA_red)
[Graphical View] 		NP_359162.1 (Protein)
NC_003098.1 (DNA/RNA sequence)

KEGG enzyme name
Hydroxymethylglutaryl-CoA reductase
Beta-hydroxy-beta-methylglutaryl coenzyme A reductase
Beta-hydroxy-beta-methylglutaryl CoA-reductase
3-Hydroxy-3-methylglutaryl coenzyme A reductase
Hydroxymethylglutaryl coenzyme A reductase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P13702 MVAA_PSEMV (R)-mevalonate + CoA + 2 NAD(+) = 3-hydroxy-3-methylglutaryl-CoA + 2 NADH. Homotetramer.
Q8DNS5 Q8DNS5_STRR6

KEGG Pathways
Map code Pathways E.C.
MAP00900 Terpenoid backbone biosynthesis

Compound table
Substrates Products Intermediates
KEGG-id C00356 C00004 C00080 C00418 C00010 C00003 I00101 I00102
E.C.
Compound 3-hydroxy-3-methylglutaryl-CoA NADH H+ (R)-mevalonate CoA NAD+ Mevaldyl-CoA Mevaldehyde
Type amine group,carbohydrate,carboxyl group,nucleotide ,peptide/protein,sulfide group amide group,amine group,nucleotide others carbohydrate,carboxyl group amine group,carbohydrate,nucleotide ,peptide/protein,sulfhydryl group amide group,amine group,nucleotide
ChEBI 15467
 15467
 		16908
 16908
 		15378
 15378
 		17710
 17710
 		15346
 15346
 		15846
 15846
PubChem 439218
 445127
 439218
 445127
 		439153
 439153
 		1038
 1038
 		439230
 439230
 		6816
 87642
 6816
 87642
 		5893
 5893
1qaxA01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1qaxB01 Unbound Unbound Unbound Unbound Bound:NAD Unbound Unbound
1qayA01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1qayB01 Unbound Unbound Unbound Unbound Bound:NAD Unbound Unbound
1r31A01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1r31B01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1r7iA01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1r7iB01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1t02A01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1t02B01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3qaeA01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3qauA01 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1qaxA02 Bound:HMG Unbound Unbound Unbound Unbound Unbound Unbound
1qaxB02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1qayA02 Unbound Unbound Bound:MEV Unbound Unbound Unbound Unbound
1qayB02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1r31A02 Unbound Unbound Unbound Bound:COA Unbound Unbound Bound:MEV
1r31B02 Unbound Unbound Unbound Unbound Unbound Unbound Bound:MEV
1r7iA02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1r7iB02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
1t02A02 Unbound Unbound Unbound Unbound Unbound Analogue:LVA Unbound
1t02B02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound
3qaeA02 Unbound Unbound Unbound Unbound Unbound Unbound Analogue:CIT
3qauA02 Unbound Unbound Unbound Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
literature [1], [3], [7], [9], [10] & Swiss-prot;P13702

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1qaxA01
1qaxB01
1qayA01
1qayB01
1r31A01
1r31B01
1r7iA01
1r7iB01
1t02A01
1t02B01
3qaeA01
3qauA01
1qaxA02 GLU 83;LYS 267;ASP 283;HIS 381
1qaxB02 GLU 583;LYS 767;ASP 783; invisible 876-928
1qayA02 GLU 83;LYS 267;ASP 283;HIS 381
1qayB02 GLU 583;LYS 767;ASP 783; invisible 878-928
1r31A02 GLU 83;LYS 267;ASP 283; invisible 379-428
1r31B02 GLU 583;LYS 767;ASP 783; invisible 878-928
1r7iA02 GLU 83;LYS 267;ASP 283; invisible 375-428
1r7iB02 GLU 583;LYS 767;ASP 783; invisible 878-928
1t02A02 GLU 83;LYS 267;ASP 283; invisible 375-428
1t02B02 GLU 83;LYS 267;ASP 283; invisible 378-428
3qaeA02 GLU 81;LYS 263;ASP 279; invisible 373-424
3qauA02 GLU 81;LYS 263;ASP 279;HIS 379

References for Catalytic Mechanism
References Sections No. of steps in catalysis
[1]
Fig.1, p.15064, p.15069-15070
[3]
Fig.3, p.7168-7171
[7]
p.748-749
[9]
Fig.4
[10]
Fig.2

References
[1]
Resource
Comments
Medline ID
PubMed ID 1634543
Journal J Biol Chem
Year 1992
Volume 267
Pages 15064-70
Authors Darnay BG, Wang Y, Rodwell VW
Title Identification of the catalytically important histidine of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
Related PDB
Related UniProtKB
[2]
Resource
Comments
Medline ID
PubMed ID 7908908
Journal J Biol Chem
Year 1994
Volume 269
Pages 11478-83
Authors Frimpong K, Rodwell VW
Title Catalysis by Syrian hamster 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Proposed roles of histidine 865, glutamate 558, and aspartate 766.
Related PDB
Related UniProtKB
[3]
Resource
Comments
Medline ID
PubMed ID 7792601
Journal Science
Year 1995
Volume 268
Pages 1758-62
Authors Lawrence CM, Rodwell VW, Stauffacher CV
Title Crystal structure of Pseudomonas mevalonii HMG-CoA reductase at 3.0 angstrom resolution.
Related PDB
Related UniProtKB
[4]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
Medline ID
PubMed ID 10377386
Journal Proc Natl Acad Sci U S A
Year 1999
Volume 96
Pages 7167-71
Authors Tabernero L, Bochar DA, Rodwell VW, Stauffacher CV
Title Substrate-induced closure of the flap domain in the ternary complex structures provides insights into the mechanism of catalysis by 3-hydroxy-3-methylglutaryl-CoA reductase.
Related PDB 1qax 1qay
Related UniProtKB P13702
[5]
Resource
Comments
Medline ID
PubMed ID 11111074
Journal Biochim Biophys Acta
Year 2000
Volume 1529
Pages 9-18
Authors Istvan ES, Deisenhofer J
Title The structure of the catalytic portion of human HMG-CoA reductase.
Related PDB
Related UniProtKB
[6]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 422-888, AND SUBUNIT.
Medline ID
PubMed ID 10698924
Journal EMBO J
Year 2000
Volume 19
Pages 819-30
Authors Istvan ES, Palnitkar M, Buchanan SK, Deisenhofer J
Title Crystal structure of the catalytic portion of human HMG-CoA reductase: insights into regulation of activity and catalysis.
Related PDB 1dq8 1dq9 1dqa 1dq8 1dq9
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 11751057
Journal Curr Opin Struct Biol
Year 2001
Volume 11
Pages 746-51
Authors Istvan ES
Title Bacterial and mammalian HMG-CoA reductases: related enzymes with distinct architectures.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 12621048
Journal J Biol Chem
Year 2003
Volume 278
Pages 19933-8
Authors Tabernero L, Rodwell VW, Stauffacher CV
Title Crystal structure of a statin bound to a class II hydroxymethylglutaryl-CoA reductase.
Related PDB 1t02
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 15535874
Journal Genome Biol
Year 2004
Volume 5
Pages 248
Authors Friesen JA, Rodwell VW
Title The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 15028676
Journal J Bacteriol
Year 2004
Volume 186
Pages 1927-32
Authors Hedl M, Tabernero L, Stauffacher CV, Rodwell VW
Title Class II 3-hydroxy-3-methylglutaryl coenzyme A reductases.
Related PDB
Related UniProtKB

Comments
This enzyme belongs to class II Hydroxymethylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.88) subfamily, which is homologous to class I HMG-Coa reductase (EC 1.1.1.34, M00180 in EzCatDB). According to the literature [7] and [10], class I HMG-Coa reductase includes the enzymes from eukaryotes and most archaea, whereas class II includes the enzymes of certain prokaryotes and archaea. An exception is the enzyme from Streptomyces, whose catalytic domain is closely related to class I enzymes (see [7]). These two classes of the enzymes share similar catalytic domain, although class I has an N-terminal membrane region. The catalytic sites from the two classes can be partially aligned, but a catalytic lysine residue is located differently. Thus, their catalytic mechanisms are slightly different from each other.
According to the literature [4], [9] and [10], this enzyme catalyzes the following reactions.
(A) Hydride transfer from NADH to HMG-CoA, forming the first intermediate, Mevaldyl-CoA (I00101):
(A0) Glu83 and Asp283 from the adjacent chain (Asp283') may modulate the charge/activity of Lys267.
(A1) Hydride transfer occurs from nicotinamide group of NADH to the carbonyl carbon of the substrate HMG-CoA. Simultaneously, Lys267 stabilizes the negative charge on the oxygen during the formation of Mevaldyl-CoA.
(B) Elimination of CoA from mevaldyl-CoA, forming the second intermediate, Mevaldehyde (I00102):
(B0) Glu83 and Asp283' may modulate the charge/activity of Lys267.
(B1) Lys267 stabilizes the negative charge on the oxygen atom of the intermediate.
(B2) His381 on the movable flap domain acts as general acid to protonate the sulfur atom of the eliminated group, CoA, to complete the reaction. This elimination reaction seems to be E1cB-like reaction.
(C) Hydride transfer from NADH to Mevaldehyde, forming the product, Mevalonate:
(C0) Glu83 and Asp283' may modulate the charge/activity of Lys267.
(C1) Lys267 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.

Created Updated
2010-04-28 2011-08-26