EzCatDB: D00607
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DB codeD00607
RLCP classification9.5010.584100.113 : Hydride transfer
5.501.400060.67 : Elimination
9.5010.536000.113 : Hydride transfer
CATH domainDomain 13.30.70.420 : Alpha-Beta Plaits
Domain 23.90.770.10 : 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2Catalytic domain
E.C.1.1.1.88

CATH domainRelated DB codes (homologues)
3.30.70.420 : Alpha-Beta PlaitsM00180
3.90.770.10 : 3-hydroxy-3-methylglutaryl-coenzyme A Reductase; Chain A, domain 2M00180

Enzyme Name
UniProtKBKEGG

P13702Q8DNS5
Protein name3-hydroxy-3-methylglutaryl-coenzyme A reductase
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
SynonymsHMG-CoA reductase
EC 1.1.1.88
3-hydroxy-3-methylglutaryl-coenzyme a reductase
EC 1.1.1.88
RefSeq
NP_359162.1 (Protein)
NC_003098.1 (DNA/RNA sequence)
PfamPF00368 (HMG-CoA_red)
[Graphical view]
PF00368 (HMG-CoA_red)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00900Terpenoid backbone biosynthesis

UniProtKB:Accession NumberP13702Q8DNS5
Entry nameMVAA_PSEMVQ8DNS5_STRR6
Activity(R)-mevalonate + CoA + 2 NAD(+) = 3-hydroxy-3-methylglutaryl-CoA + 2 NADH.
SubunitHomotetramer.
Subcellular location

Cofactor


Compound table: links to PDB-related databases & PoSSuM

SubstratesProductsintermediates
KEGG-idC00356C00004C00080C00418C00010C00003I00101I00102
Compound3-hydroxy-3-methylglutaryl-CoANADHH+(R)-mevalonateCoANAD+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
16908
15378
17710
15346
15846


PubChem445127
439218
439153
1038
439230
87642
6816
5893


                
1qaxA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1qaxB01UnboundUnbound UnboundUnboundBound:NADUnboundUnbound
1qayA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1qayB01UnboundUnbound UnboundUnboundBound:NADUnboundUnbound
1r31A01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1r31B01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1r7iA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1r7iB01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1t02A01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1t02B01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
3qaeA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
3qauA01UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1qaxA02Bound:HMGUnbound UnboundUnboundUnboundUnboundUnbound
1qaxB02UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1qayA02UnboundUnbound Bound:MEVUnboundUnboundUnboundUnbound
1qayB02UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1r31A02UnboundUnbound UnboundBound:COAUnboundUnboundBound:MEV
1r31B02UnboundUnbound UnboundUnboundUnboundUnboundBound:MEV
1r7iA02UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1r7iB02UnboundUnbound UnboundUnboundUnboundUnboundUnbound
1t02A02UnboundUnbound UnboundUnboundUnboundAnalogue:LVAUnbound
1t02B02UnboundUnbound UnboundUnboundUnboundUnboundUnbound
3qaeA02UnboundUnbound UnboundUnboundUnboundUnboundAnalogue:CIT
3qauA02UnboundUnbound UnboundUnboundUnboundUnboundUnbound

Active-site residues
resource
literature [1], [3], [7], [9], [10] & Swiss-prot;P13702
pdbCatalytic residuescomment
          
1qaxA01 
 
1qaxB01 
 
1qayA01 
 
1qayB01 
 
1r31A01 
 
1r31B01 
 
1r7iA01 
 
1r7iB01 
 
1t02A01 
 
1t02B01 
 
3qaeA01 
 
3qauA01 
 
1qaxA02GLU  83;LYS 267;ASP 283;HIS 381
 
1qaxB02GLU 583;LYS 767;ASP 783;       
invisible 876-928
1qayA02GLU  83;LYS 267;ASP 283;HIS 381
 
1qayB02GLU 583;LYS 767;ASP 783;       
invisible 878-928
1r31A02GLU  83;LYS 267;ASP 283;       
invisible 379-428
1r31B02GLU 583;LYS 767;ASP 783;       
invisible 878-928
1r7iA02GLU  83;LYS 267;ASP 283;       
invisible 375-428
1r7iB02GLU 583;LYS 767;ASP 783;       
invisible 878-928
1t02A02GLU  83;LYS 267;ASP 283;       
invisible 375-428
1t02B02GLU  83;LYS 267;ASP 283;       
invisible 378-428
3qaeA02GLU  81;LYS 263;ASP 279;       
invisible 373-424
3qauA02GLU  81;LYS 263;ASP 279;HIS 379
 

References for Catalytic Mechanism
ReferencesSectionsNo. 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]
PubMed ID1634543
JournalJ Biol Chem
Year1992
Volume267
Pages15064-70
AuthorsDarnay BG, Wang Y, Rodwell VW
TitleIdentification of the catalytically important histidine of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.
[2]
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.
[3]
PubMed ID7792601
JournalScience
Year1995
Volume268
Pages1758-62
AuthorsLawrence CM, Rodwell VW, Stauffacher CV
TitleCrystal structure of Pseudomonas mevalonii HMG-CoA reductase at 3.0 angstrom resolution.
[4]
CommentsX-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
PubMed ID10377386
JournalProc Natl Acad Sci U S A
Year1999
Volume96
Pages7167-71
AuthorsTabernero L, Bochar DA, Rodwell VW, Stauffacher CV
TitleSubstrate-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 PDB1qax,1qay
Related UniProtKBP13702
[5]
PubMed ID11111074
JournalBiochim Biophys Acta
Year2000
Volume1529
Pages9-18
AuthorsIstvan ES, Deisenhofer J
TitleThe structure of the catalytic portion of human HMG-CoA reductase.
[6]
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
[7]
PubMed ID11751057
JournalCurr Opin Struct Biol
Year2001
Volume11
Pages746-51
AuthorsIstvan ES
TitleBacterial and mammalian HMG-CoA reductases: related enzymes with distinct architectures.
[8]
PubMed ID12621048
JournalJ Biol Chem
Year2003
Volume278
Pages19933-8
AuthorsTabernero L, Rodwell VW, Stauffacher CV
TitleCrystal structure of a statin bound to a class II hydroxymethylglutaryl-CoA reductase.
Related PDB1t02
[9]
PubMed ID15535874
JournalGenome Biol
Year2004
Volume5
Pages248
AuthorsFriesen JA, Rodwell VW
TitleThe 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases.
[10]
PubMed ID15028676
JournalJ Bacteriol
Year2004
Volume186
Pages1927-32
AuthorsHedl M, Tabernero L, Stauffacher CV, Rodwell VW
TitleClass II 3-hydroxy-3-methylglutaryl coenzyme A reductases.

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.

createdupdated
2010-04-282011-08-26


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